WO2005065280A2 - Repair of spnal annular defects and annulo-nucleoplasty regeneration - Google Patents

Repair of spnal annular defects and annulo-nucleoplasty regeneration Download PDF

Info

Publication number
WO2005065280A2
WO2005065280A2 PCT/US2004/043455 US2004043455W WO2005065280A2 WO 2005065280 A2 WO2005065280 A2 WO 2005065280A2 US 2004043455 W US2004043455 W US 2004043455W WO 2005065280 A2 WO2005065280 A2 WO 2005065280A2
Authority
WO
WIPO (PCT)
Prior art keywords
reticulated
elastomeric
another embodiment
foam
elastomeric matrix
Prior art date
Application number
PCT/US2004/043455
Other languages
French (fr)
Other versions
WO2005065280A3 (en
Inventor
Craig D. Friedman
Arindam Datta
Original Assignee
Biomerix Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biomerix Corporation filed Critical Biomerix Corporation
Priority to AU2004311838A priority Critical patent/AU2004311838A1/en
Priority to CA002551133A priority patent/CA2551133A1/en
Priority to EP04815520A priority patent/EP1697082A2/en
Priority to JP2006547415A priority patent/JP2007531557A/en
Publication of WO2005065280A2 publication Critical patent/WO2005065280A2/en
Priority to US11/475,444 priority patent/US20070162131A1/en
Publication of WO2005065280A3 publication Critical patent/WO2005065280A3/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/44Joints for the spine, e.g. vertebrae, spinal discs
    • A61F2/442Intervertebral or spinal discs, e.g. resilient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/56Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor
    • A61B17/58Surgical instruments or methods for treatment of bones or joints; Devices specially adapted therefor for osteosynthesis, e.g. bone plates, screws, setting implements or the like
    • A61B17/68Internal fixation devices, including fasteners and spinal fixators, even if a part thereof projects from the skin
    • A61B17/70Spinal positioners or stabilisers ; Bone stabilisers comprising fluid filler in an implant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0095Packages or dispensers for prostheses or other implants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006Properties of materials and coating materials
    • A61F2002/30062(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006Properties of materials and coating materials
    • A61F2002/30062(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
    • A61F2002/30064Coating or prosthesis-covering structure made of biodegradable material
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006Properties of materials and coating materials
    • A61F2002/30072Coating made of plastically deformable or self-moulding material
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006Properties of materials and coating materials
    • A61F2002/3008Properties of materials and coating materials radio-opaque, e.g. radio-opaque markers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30316The prosthesis having different structural features at different locations within the same prosthesis; Connections between prosthetic parts; Special structural features of bone or joint prostheses not otherwise provided for
    • A61F2002/30535Special structural features of bone or joint prostheses not otherwise provided for
    • A61F2002/30579Special structural features of bone or joint prostheses not otherwise provided for with mechanically expandable devices, e.g. fixation devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30667Features concerning an interaction with the environment or a particular use of the prosthesis
    • A61F2002/30677Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/30767Special external or bone-contacting surface, e.g. coating for improving bone ingrowth
    • A61F2002/3092Special external or bone-contacting surface, e.g. coating for improving bone ingrowth having an open-celled or open-pored structure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/44Joints for the spine, e.g. vertebrae, spinal discs
    • A61F2/442Intervertebral or spinal discs, e.g. resilient
    • A61F2002/4435Support means or repair of the natural disc wall, i.e. annulus, e.g. using plates, membranes or meshes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/44Joints for the spine, e.g. vertebrae, spinal discs
    • A61F2/442Intervertebral or spinal discs, e.g. resilient
    • A61F2002/4445Means for culturing intervertebral disc tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/46Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor
    • A61F2002/4677Special tools or methods for implanting or extracting artificial joints, accessories, bone grafts or substitutes, or particular adaptations therefor using a guide wire
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0096Markers and sensors for detecting a position or changes of a position of an implant, e.g. RF sensors, ultrasound markers
    • A61F2250/0098Markers and sensors for detecting a position or changes of a position of an implant, e.g. RF sensors, ultrasound markers radio-opaque, e.g. radio-opaque markers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00365Proteins; Polypeptides; Degradation products thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389The prosthesis being coated or covered with a particular material
    • A61F2310/0097Coating or prosthesis-covering structure made of pharmaceutical products, e.g. antibiotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389The prosthesis being coated or covered with a particular material
    • A61F2310/00976Coating or prosthesis-covering structure made of proteins or of polypeptides, e.g. of bone morphogenic proteins BMP or of transforming growth factors TGF

Definitions

  • This invention relates to the repair of spinal annular defects. More particularly, this invention relates to a method and composition for the repair of spinal annular defects and annulo-nucleoplasty regeneration.
  • Back pain is one of the most common and often debilitating conditions affecting millions of people.
  • Some forms of back pain are muscular in nature and may be simply treated by rest, posture adjustments and painkillers.
  • LBP lower back pain
  • Unusual exertion such as heavy lifting or strenuous exercise may result in back pain due to a pulled muscle, a sprained muscle, a sprained ligament, a muscle spasm, or a combination thereof.
  • An injury caused by falling down or a blow to the back may cause bruising.
  • These forms of back pain are typically non-chronic and may be self-treated and cured in a few days or weeks.
  • Non-chronic back pain may be treated by improvements in physical condition, posture and/or work conditions. Being pregnant or otherwise being significantly overweight may cause LBP. A mattress that does not provide adequate support may cause back pain in the morning. Working in an environment lacking good ergonomic design may also cause back pain. In these instances, the back pain may be cured by eliminating the underlying cause. Whether it is excess body weight, a bad mattress, or a bad office chair, these forms of back pain are readily treated.
  • disc related pain Some forms of back pain are the result of disorders directly related to the spinal column, which disorders are not readily treated. While some pain-causing spinal disorders may be due to facet joint degradation or degradation of individual vertebral masses, disorders associated with the intervertebral discs are predominantly affiliated with chronic back pain (referred to as disc related pain). The exact origin of disc related pain is often uncertain, and although some episodes of disc related pain may be eased with conservative treatments such as bed-rest and physical therapy, future episodes of disc related pain are likely to occur periodically.
  • DDD degenerative disc disease
  • a commonly suspected source of disc related pain is physical impingement of the nerve roots emanating from the spinal cord.
  • Such nerve root impingement may have a number of different underlying causes, but nerve root impingement generally results from either a disc protrusion or a narrowing of the intervertebral foramina (which surround the nerve roots).
  • the annulus fibrosus of a disc may tear, forming one or more fissures (also referred to as fractures). Such fissures may progress to larger tears, which allow the gelatinous material of the nucleus pulposus to flow out of the nucleus and into the outer aspects of the annulus. The flow of the nucleus pulposus to the outer aspects of the annulus may cause a localized bulge or herniation.
  • the condition may be referred to as a disc stenosis, a disc bulge, a herniated disc, a prolapsed disc, a ruptured disc, or, if the protrusion separates from the disc, a sequestered disc.
  • Nerve root impingement most often occurs in the lumbar region of the spinal column since the lumbar discs bear significant vertical loads relative to discs in other regions of the spine.
  • disc protrusions in the lumbar region typically occur posteriorly because the annulus fibrosus is radially thinner on the posterior side than on the anterior side and because normal posture places more compression on the posterior side.
  • Posterior protrusions are particularly problematic since the nerve roots are posteriorly positioned relative to the intervertebral discs.
  • Lower back pain due to nerve root irritation not only results in strong pain in the region of the back adjacent the disc, but may also cause sciatica, or pain radiating down one or both legs. Such pain may also be aggravated by such subtle movements as coughing, bending over, or remaining in a sitting position for an extended period of time.
  • fissures Another suspected source of disc related back pain is damage and irritation to the small nerve endings which lie in close proximity to or just within the outer aspects of the annulus of the discs.
  • the annulus fibrosus may be damaged and form fissures. While these fissures can lead to pain via the mechanisms described above, they may also lead to pain emanating from the small nerve endings in or near the annulus, due to mechanical or chemical irritation at the sites of the fissures.
  • the fissures may continue to irritate the small nerve endings, as their presence causes the disc to become structurally weaker, allowing for more localized straining around the fissures. This results in more relative motion of edges of the fissures, increasing mechanical irritation. Because it is believed that these fissures have only limited healing ability once formed, such irritation may only become progressively worse.
  • a common treatment for a disc herniation is a discectomy, a procedure wherein the protruding portion of the degenerated disc is surgically removed.
  • discectomy procedures have an inherent risk since the portion of the disc to be removed is immediately adjacent the nerve root, and any damage to the nerve root is clearly undesirable.
  • discectomy procedures are not always successful long term because scar tissue may form and/or additional disc material may subsequently protrude or reherniate from the disc space as the disc deteriorates further.
  • the recurrence of a disc herniation may necessitate a repeat discectomy procedure, along with its inherent clinical risks and less than perfect long term success rate.
  • a discectomy procedure at least as a stand-alone procedure, is clearly not an optimal solution.
  • Discectomy is also not a viable solution for DDD when no disc/nuclear herniation is involved.
  • DDD causes the entire disc to degenerate, narrowing the intervertebral space and shifting the load to the facet joints. If the facet joints carry a substantial load, the joints may degrade over time and be a different cause of back pain.
  • the narrowed disc space can result in the intervertebral foramina surrounding the nerve roots directly impinging on one or more nerve roots. Such nerve impingement is very painful and cannot be corrected by a discectomy procedure.
  • a discectomy does not address pain caused by annular fissures or post-surgical defects, which may cause direct mechanical irritation to the small nerve endings near or just within the outer aspect of the annulus of a damaged disc.
  • spinal fusion has become a preferred secondary procedure, and in some instances, a preferred primary procedure.
  • Spinal fusion involves permanently fusing or fixing adjacent vertebrae.
  • Hardware in the form of bars, plates, screws, and cages may be utilized in combination with bone graft material to fuse adjacent vertebrae.
  • Spinal fusion may be performed as a stand-alone procedure, or it may be performed in combination with a discectomy procedure.
  • spinal fusion procedures are invasive to the disc, risk nerve damage, and, dependent upon the procedural approach, are technically complicated (endoscopic anterior approach), invasive to the bowel (surgical anterior approach), and/or invasive to the musculature of the back (surgical posterior approach).
  • Another procedure that has been less than clinically successful is total disc replacement with a prosthetic disc.
  • This procedure is also very invasive to the disc, and, dependent upon the procedural approach, either invasive to the bowel (surgical anterior approach) or invasive to the musculature of the back (surgical posterior approach).
  • the procedure may actually complicate matters by creating instability in the spine, and the long-term mechanical reliability of prosthetic discs has yet to be demonstrated.
  • a substantially cylindrical member is inserted through an opening in the spinal annulus to the extent that the distal portion of the substantially cylindrical member extends into the spinal nuclear defect.
  • the substantially cylindrical member is comprised of a biodurable reticulated elastomeric material that expands to seal the opening.
  • the cylindrical member can comprise one or more metal or polymer components that open or re-align after insertion to assist in maintaining the sealing ability of the substantially cylindrical member.
  • the present invention addresses this need by providing improved devices and methods for the treatment of spinal disorders.
  • the improved devices and methods of the present invention specifically address disc related pain, progressive disc degeneration, and/or reherniation of nuclear material, particularly in the lumbar region, but may have other significant applications not specifically mentioned herein.
  • the present invention is discussed in detail with reference to the treatment of damaged discs in the lumbar region of the adult human spinal column.
  • the device may be used for damaged discs in the thoracic and cervical region of the adult human spinal column
  • the improved devices and methods of the present invention reduce, if not eliminate, back pain while maintaining near normal anatomical motion.
  • the present invention provides an annular repair and/or annulo-nucleoplasty regeneration mechanism, while permitting relative movement of the vertebrae adjacent the damaged disc.
  • the devices of the present invention are particularly well suited for minimally invasive methods of implantation.
  • the devices of the present invention provide three distinct functions.
  • the reinforcement devices mechanically stabilize and strengthen the annular portion of the spinal disc to minimize, if not eliminate, chronic irritation of local nerve roots and nerve endings adjacent to the periphery of the disc annulus.
  • the devices radially and/or circumferentially conform to the surgical and/or pathologic present fissures, fractures,and tears of the disc, thereby preventing the prolapse of extra spinal disc tissue such as nerves and muscle, thereby potentially facilitating healing.
  • the devices may be used to stabilize the nuclear portion of the disc after a discectomy procedure to reduce the need for a subsequent operation or treatment due to reherniation.
  • the present invention provides disc reinforcement in which a device of the invention is implanted into the annulus of an intervertebral disc.
  • the implantation method may be performed by a percutaneous procedure or by a minimally invasive surgical procedure or by the use of trocar, cannula, or through an endoscopic instrument such as an arthroscope, laproscope, or cystoscope.
  • the present invention provides a number or tools to facilitate percutaneous implantation.
  • One or more reinforcement members may be implanted, for example, posteriorly, anteriorly, and/or laterally, and may be oriented circumferentially or radially. As such, the reinforcement members may be used to stabilize the annulus and/or a portion of the annulus so as to reduce recurrent bulges and/or obliterate annular tracts.
  • the implant device may be sized to pass through a trocar and/or may have a tubular cross-section to facilitate advancement over a stylet.
  • the implant device preferably includes a body portion sized to fit in an opening in the annulus and an anchor for engaging the annulus and limiting relative movement therebetween.
  • the anchor may be disposed at the distal portions of the implant body, or may extend over the entire length of the body.
  • the anchoring part to engage in the annulus can be shaped as expanded cylinder, spherical, mushroom-shaped, etc.
  • the anchor portion may comprise threads or wings which may have a variable pitch to facilitate compression of the annulus during implantation.
  • the implant device may incorporate chemical and/or biological agents.
  • the implant device may comprise a biocompatible metal such as stainless steel or a super elastic (nickel titanium) alloy.
  • the implant device may comprise a polymer or a reinforced polymeric structure.
  • the implant device may comprise a bioabsorbable material.
  • Fig. 1 illustrates a superior (top) view of a healthy disc
  • FIGs. 2 and 3 each illustrate a superior (top) view of a degenerated disc
  • Fig. 4 is a partially cross-sectional view of an embodiment of a substantially cylindrical member according to the invention.
  • Fig. 5 is a partially cross-sectional view of an embodiment of an at least partially cylindrical member according to the invention.
  • Fig. 6 is a partially cross-sectional view of a further embodiment of another at least partially cylindrical member according to the invention.
  • Fig. 7 is a cross-sectional view across the line 7-7 of the embodiment of the invention shown in Fig. 6;
  • Fig. 8 is a partially cross-sectional view of another embodiment of the invention in position in the annulus
  • Fig. 9 is a partially cross-sectional view of a variation of the embodiment shown in Fig. 8;
  • Fig. 10 is a lateral view of an embodiment of the invention having radial projections
  • Fig. 11 is a cross-sectional view along the line 11-11 in Fig. 10;
  • Figs. 12 to 14 represent cross-sectional views of delivery of the embodiment of the invention set forth in Figs. 10 and 11;
  • Figs. 15 and 16 are each a micrograph of material prepared according to
  • Figs. 17 and 18 are each a micrograph of material prepared according to
  • Fig. 19 is a micrograph of an embodiment of the invention four weeks after placement.
  • Fig. 20 is a detailed view of a section of the micrograph in Fig. 19. DETAILED DESCRIPTION OF THE INVENTION
  • Figure 1 is a simplified representation of a spinal disc 10 that comprises an annulus fibrosis or annulus 12 surrounding a nucleus pulposus or nucleus 14.
  • the posterior annulus 16 is generally thinner than the anterior annulus 18, which may account for the higher incidence of posterior disc protrusions.
  • each intervertebral disc 10 forms one support point and the facet joints of the spinal column (not shown) form two support points of what may be characterized as a three-point support structure between adjacent vertebrae 20.
  • the facet joints are substantially vertical, leaving the disc 10 to carry the vast majority of the load.
  • the nucleus 14 bears the majority of the load. This belief is based on the theory that the disc 10 behaves much like a balloon or tire and the nucleus 14 bears the somewhat of the majority of the load wherein the annulus 12 merely serves to contain the pressurized nucleus 14 and supports a somewhat smaller proportion of the total load.
  • the annulus 12 comprises 60% of the total disc 10 cross-sectional area and is made of 40-60% organized collagen in the form of a laminated structure.
  • the nucleus 14 only comprises 40% of the total disc 10 cross-section and is made of 18-30% collagen in the form of a relatively homogenous gel. In reality, both the nucleus 14 and annulus 12 play important and critical roles in the load bearing mechanism of the disc 10.
  • the intervertebral disc 10 becomes progressively dehydrated and malnourished with age, as shown in Figures 2 and 3.
  • the disc begins to degenerate.
  • the annulus of the disc may tear, forming one or more radial fissures 23 or tracts 24 or circumferential fissures 26, which may progress to larger tears. Larger tears may allow the gelatinous material of the nucleus pulposus 14 to flow out of the nucleus through a fissure 24 and into the outer aspects of the annulus 12. Nuclear material that escapes through an advanced tear may cause further mechanical irritation and additionally cause chemical irritation of a nerve root.
  • the flow of the nucleus 14 to the outer aspects of the annulus 12 may cause a localized bulge 28.
  • a posterior bulge 28 may result in direct impingement of a nerve root (not shown).
  • a nerve root may also be compressed or tethered by a narrowing of the intervertebral foraminae, resulting from a loss in disc height caused by sustained degeneration of the disc 10.
  • Small nerve endings (not shown) in or near the perimeter of the annulus 12 may also be mechanically or chemically irritated at the sites of the fissures 24, 26. In all cases, degeneration of the disc eventually leads to disc related pain of some origin.
  • a partially cylindrical device 30 comprises a cylindrical portion 32 and an attached expanded, at least partially spherical portion 34.
  • Portion 34 may be entirely spherical or it may optionally have a substantially flat surface 36 bordered by edge 38.
  • the attached expanded portion 34 may be entirely cylindrical.
  • the attached expanded portion 34 may be any other suitable shape that has at least one transverse dimension larger than the diameter of the cylindrical portion 32.
  • Portions 32 and 34 are both solid, although optionally each may contain a longitudinal lumen (not shown) to facilitate threading member 30 over a wire or stylet (not shown).
  • device 30 may optionally contain a retainer or anchor 40, comprising a longitudinal member or shaft 42 and collapsible/expandable spokes or radial members 44.
  • a retainer or anchor 40 comprising a longitudinal member or shaft 42 and collapsible/expandable spokes or radial members 44.
  • the proximal end of each member 44 has a tissue fixation member 46 that contacts the inner portion of the annulus when members 44 expand, to hold or fix device 30 in position.
  • the umbrella anchor 40 is has three or four, preferably four, members
  • the members 44 can be partially collapsed within a trocar or endoscope during delivery and contact the inner portion of the annulus when they expand after delivery to hold or fix elastomeric reticulated device 30 or device 48 in position.
  • Anchor 40 can have a range of dimensions depending on specific applications.
  • the range of dimensions of the different parts are as follows: the angle between central shaft 42 and spokes 44 is from about 15° to about 60°, when the spokes are fully opened.
  • the length of each spoke 44 ranges from about 3 mm to about 10 mm, preferably from about 4 mm to about 7 mm.
  • the cross-section of spokes 44 can be cylindrical, elliptical, square, rectangular, or any other polygonal shape.
  • the diameter of spokes' 44 cross-section or one side of the spoke 44 cross- section ranges from about 2 mm to about 5 mm.
  • the end-to-end distance of the spokes 44 when the spokes 44 are fully opened ranges from about 6 mm to about 15 mm.
  • the cross-section of central shaft 42 can be cylindrical, elliptical, square, rectangular, or any other polygonal shape with the diameter of the central shaft 42 cross-section or one side of the of the central shaft cross-section ranging from about 2 mm to about 5 mm.
  • the overall length of central shaft 42 of the umbrella anchor (including the head and the stem) can range from about 8 mm to about 15 mm.
  • Spokes 44 can be regularly spaced from each other or they could be
  • spokes 44 could be separated by 60° and 120° to form an "X" pattern.
  • shaft 42 could extend in the direction from spokes 44 opposite to the direction shown in Fig. 4.
  • spokes 44 may be arcuate, pointing in the proximal direction, rather than straight as shown in Fig. 4.
  • Anchor 40 is comprised of a physiologically acceptable metal such as nitinol or stainless steel and, after compression, expands to form an umbrella-like shape.
  • anchor 40 preferably is comprised of a degradable or non-degradable polymer such as polypropylene and, after compression, expands to form an umbrella-like shape.
  • a partially cylindrical device 48 comprises a cylindrical portion 50 and a goblet- or mushroom- shaped distal portion 52.
  • the mushroom-shaped distal portion 52 can also be cylindrical in shape.
  • the mushroom-shaped distal portion 52 can also be partially spherical in shape or any other suitable shape that has at least one transverse dimension larger than the diameter of the cylindrical portion 50. In general, the diameter or the largest transverse dimensions of the distal portion 52 is greater than the diameter of the cylindrical portion 50.
  • cylindrical portion 50 has ridges or projections 54 that aid in fixedly positioning device 48 in an annular fissure, especially at the inner portion of the fissure.
  • device 48 has a lumen 56 to facilitate positioning device 48 over a stylet or wire (not shown).
  • FIG. 6 and 7 The embodiment of the invention shown in Figures 6 and 7 is an at least partially cylindrical member 64 that comprises a cylindrical member 66 and a distal semi-spherical portion 68 that comprises distally extending projections 70.
  • projections 70 comprise spaghetti-like shapes suitable for cell propagation.
  • FIG. 8 represents an embodiment of the invention where anchor 74 has one or more crossmembers 76 that have projections 78, intended to engage annular tissue 80.
  • Crossmember 76 can have integral projections 78, so that the crossmember 76 and a projection 78 are inserted, preferably at an angle, into anchor 74 prior to delivery, where preferably projection 78 collapses slightly to permit insertion.
  • projections 78 are attached by glue, "fit", or other suitable fixtation after crossmember 76 is positioned within anchor 74.
  • an anchor 94 is shown in uncompressed condition with a mushroom-shaped distal tip portion 96 and a cylindrical portion 98.
  • Cylindrical portion 98 has radially-extending projections or prongs 102.
  • anchor 94 has six projections 102. However, there could be from 2 to as many as 16 or more projections 102, preferably from about 4 to 12. Optionally there could be projections 102 on more than one plane of cylindrical portion 98, preferably 2 or 3 planes altogether, such as proximal neck and/or mid-shaft and/or distal shaft.
  • Anchor 94 Delivery of anchor 94 is shown in Figs. 12 to 14.
  • Anchor 94 in a compressed state is preloaded into a rigid or substantially rigid tubular member 104.
  • Projections 102 fold around cylindrical portion 98, and the distal portion 106 of a pushing rod or member 108 is positioned adjacent to the proximal surface 110 of cylindrical portion 98.
  • the distal tip 114 of tubular member 104 is positioned in or adjacent to an opening 116 in annulus 120.
  • the material for the attachment device can be degradable or non- degradable materials or fiber-reinforced composites using degradable or non- degradable materials.
  • the list of non-degradable materials for attachment device include polypropylene, polyethylene, polyethylene terepthalate (PET), Nylon 6, Nylon 6-6, poly imide, polyether imide, PEEK, or their mixtures and copolymers thereof.
  • the list of non-degradable materials for attachment devices includes Teflon, ceramics, stainless steel, platinum or nitinol.
  • degradable materials for attachment device include polymers such as polyglycolic acid (“PGA”), polylactic acid (“PLA”), polycaprolactic acid (“PCL”), poly-p-dioxanone (“PDO”), PGA/PLA copolymers, PGA/PCL copolymers, PGA/PDO copolymers, PLA/PCL copolymers, or their mixtures and copolymers thereof, PLA/PDO copolymers, PCL/PDO copolymers or combinations of any two or more of the foregoing.
  • polymers such as polyglycolic acid (“PGA”), polylactic acid (“PLA”), polycaprolactic acid (“PCL”), poly-p-dioxanone (“PDO”), PGA/PLA copolymers, PGA/PCL copolymers, PGA/PDO copolymers, PLA/PCL copolymers, or their mixtures and copolymers thereof, PLA/PDO copolymers, PCL/PDO copolymers or
  • the inventive implantable device is reticulated, i.e., comprises an interconnected network of pores and channels and voids that provides fluid permeability throughout the implantable device and permits cellular and tissue ingrowth and proliferation into the interior of the implantable device.
  • the inventive implantable device is reticulated, i.e., comprises an interconnected and/or intercommunicating network of pores and channels and voids that provides fluid permeability throughout the implantable device and permits cellular and tissue ingrowth and proliferation into the interior of the implantable device.
  • the inventive implantable device is reticulated, i.e., comprises an interconnected and/or intercommunicating network of pores and/or voids and/or channels that provides fluid permeability throughout the implantable device and permits cellular and tissue ingrowth and proliferation into the interior of the implantable device.
  • the biodurable elastomeric matrix or material is considered to be reticulated because its microstructure or the interior structure comprises inter- connected and intercommunicating pores and/or voids bounded by configuration of the struts and intersections that constitute the solid structure.
  • the continuous interconnected void phase is the principle feature of a reticulated structure.
  • Preferred scaffold materials for the implants have a reticulated structure with sufficient and required liquid permeability and thus selected to permit blood, or other appropriate bodily fluid, and cells and tissues to access interior surfaces of the implants. This happens due to the presence of inter-connected and intercommunicating, reticulated open pores and or voids and/or channels that form fluid passageways or fluid permeability providing fluid access all through.
  • Preferred materials are at least partially hydrophobic reticulated, elastomeric polymeric matrix for fabricating implants according to the invention are flexible and resilient in recovery, so that the implants are also compressible materials enabling the implants to be compressed and, once the compressive force is released, to then recover to, or toward, substantially or fully to their original size and shape.
  • an implant can be compressed from a relaxed configuration or a size and shape to a compressed size and shape under ambient conditions, e.g., at 25°C to fit into the introducer instrument for insertion into the target orthopedic repair or regeneration site.
  • an implant may be supplied to the medical practitioner performing the implantation operation, in a compressed configuration, for example, contained in a package, preferably a sterile package.
  • the resiliency of the reticulated elastomeric matrix that is used to fabricate the implant causes it to recover to a working size and configuration in situ, at the implantation site, after being released from its compressed state within the introducer instrument.
  • the working size and shape or configuration can be substantially similar to original size and shape after the in situ recovery.
  • the working size and shape or configuration can be the original size and shape after the in situ recovery.
  • the implant can be delivered in an uncompressed original size and shape by the introducer instrument.
  • Preferred scaffolds are reticulated elastomeric polymeric materials having sufficient structural integrity and durability to endure the intended biological environment, for the intended period of implantation.
  • at least partially hydrophobic polymeric scaffold materials are preferred although other materials may be employed if they meet the requirements described herein.
  • Useful materials are preferably elastomeric in that they can be compressed and can resiliently recover to substantially or completely to the pre-compression state.
  • the implant can be delivered in an uncompressed original size and shape by the introducer instrument.
  • the material once delivered to the target site, the material can stay anchored at the delivery site under compression with or without exerting significant stress to the neighboring tissues.
  • Alternative reticulated polymeric materials with interconnected pores or networks of pores that permit biological fluids to have ready access throughout the interior of an implant may be employed, for example, woven or nonwoven fabrics or networked composites of microstructural elements of various forms.
  • a partially hydrophobic scaffold is preferably constructed of a material selected to be sufficiently biodurable, for the intended period of implantation that the implant will not lose its structural integrity during the implantation time in a biological environment.
  • the biodurable elastomeric matrices forming the scaffold do not exhibit significant symptoms of breakdown, degradation, erosion or significant deterioration of mechanical properties relevant to their use when exposed to biological environments and/or bodily stresses for periods of time commensurate with the use of the implantable device.
  • the desired period of exposure is to be understood to be at least 29 days, preferably several weeks and most preferably 2 to 5 years or more. This measure is intended to avoid scaffold materials that may decompose or degrade into fragments, for example, fragments that could have undesirable effects such as causing an unwanted tissue response.
  • the void phase, preferably continuous and interconnected, of the reticulated polymeric matrix that is used to fabricate the implant of this invention may comprise as little as 50% by volume of the reticulated elastomeric matrix, referring to the volume provided by the interstitial spaces of reticulated elastomeric matrix before any optional interior pore surface coating or layering is applied.
  • the volume of void phase as just defined is from about 70% to about 99% of the volume of reticulated elastomeric matrix.
  • the volume of void phase as just defined is from about 70% to about 88% of the volume of reticulated elastomeric matrix.
  • the volume of void phase is from about 80% to about 88 % of the volume of reticulated elastomeric matrix. In another embodiment, the volume of void phase is from about 80% to about 98% of the volume of reticulated elastomeric matrix. In another embodiment, the volume of void phase is from about 90% to about 98% of the volume of reticulated elastomeric matrix.
  • a pore when a pore is spherical or substantially spherical, its largest transverse dimension is equivalent to the diameter of the pore.
  • a pore when a pore is non-spherical, for example, ellipsoidal or tetrahedral, its largest transverse dimension is equivalent to the greatest distance within the pore from one pore surface to another, e.g., the major axis length for an ellipsoidal pore or the length of the longest side for a tetrahedral pore.
  • the major axis length for an ellipsoidal pore or the length of the longest side for a tetrahedral pore For those skilled in the art, one can routinely estimate the pore frequency from the average cell diameter in microns.
  • the average diameter or other largest transverse dimension of pores is at least about 20 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 50 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 100 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 150 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 250 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than about 250 ⁇ m.
  • the average diameter or other largest transverse dimension of pores is greater than 250 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 275 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than about 275 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than 275 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 300 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than about 300 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than 300 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than 300 ⁇ m.
  • the average diameter or other largest transverse dimension of pores is not greater than about 900 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 750 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 500 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 400 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 300 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 200 ⁇ m. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 100 ⁇ m.
  • the invention comprises an implantable device having sufficient resilient compressibility to be delivered by a "delivery-device", i.e., a device with a chamber for containing an reticulated elastomeric biodurable reticulated implantable device while it is delivered to the desired site then released at the site, e.g., using a trocar, cannula, or through an endoscopic instrument such as an arthroscope, laproscope, or cystoscope.
  • a delivery-device i.e., a device with a chamber for containing an reticulated elastomeric biodurable reticulated implantable device while it is delivered to the desired site then released at the site, e.g., using a trocar, cannula, or through an endoscopic instrument such as an arthroscope, laproscope, or cystoscope.
  • the thus-delivered elastomeric biodurable reticulated implantable device substantially regains its shape after delivery to a biological site and has adequate biodurability and
  • reticulated elastomeric implant which is sufficiently flexible and resilient, i.e., resiliently- compressible, to enable it to be initially compressed under ambient conditions, e.g., at 25°C, from a relaxed configuration to a first, compact configuration for delivery via a delivery-device, e.g., an endoscopic instrument such as an arthroscope, laproscope, cystoscope, or endoscope, or other suitable introducer instrument such as syringe, trocar, etc., for delivery in vitro and, thereafter, to expand to a second, working configuration in situ.
  • reticulated elastomeric implant is delivered in an uncompressed state via a delivery-device.
  • an reticulated elastomeric matrix has the herein described resilient- compressibility after being compressed about 5-95% of an original dimension (e.g., compressed about 19/20th - 1/20th of an original dimension).
  • an reticulated elastomeric matrix has the herein described resilient-compressibility after being compressed about 10-90% of an original dimension (e.g., compressed about 9/10th - 1/10th of an original dimension).
  • reticulated elastomeric implant has "resilient-compressibility", i.e., is “resiliently-compressible", when the second, working configuration, in vitro, is at least about 50% of the size of the relaxed configuration in at least one dimension.
  • the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vitro, is at least about 80% of the size of the relaxed configuration in at least one dimension. In another embodiment, the resilient- compressibility of reticulated elastomeric implant is such that the second, working configuration, in vitro, is at least about 90% of the size of the relaxed configuration in at least one dimension. In another embodiment, the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vitro, is at least about 97% of the size of the relaxed configuration in at least one dimension.
  • a reticulated elastomeric matrix has the herein described resilient-compressibility after being compressed about 5-95% of its original volume (e.g., compressed about 19/20th - l/20th of its original volume).
  • an reticulated elastomeric matrix has the herein described resilient- compressibility after being compressed about 10-90% of its original volume (e.g., compressed about 9/10th - l/10th of its original volume).
  • volume is the volume swept-out by the outermost three-dimensional contour of the reticulated elastomeric matrix.
  • the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, is at least about 40% of the volume occupied by the relaxed configuration. In another embodiment, the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, is at least about 75 % of the volume occupied by the relaxed configuration. In another embodiment, the resilient- compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, is at least about 90% of the volume occupied by the relaxed configuration.
  • the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, occupies at least about 97% of the volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
  • a reticulated elastomeric matrix has the herein described resilient-compressibility is delivered to the target orthopedic or spinal implant but is not compressed during delivery to the target defect site.
  • the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 25% to at least about 40% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
  • the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 40% to at least about 80% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
  • the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 80% to at least about 95% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
  • the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 95% to at least about 98% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
  • the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies the entire volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
  • an individual implanted reticulated elastomeric matrix will, in many cases although not necessarily, have at least one dimension of no more than 75% of the biological site within the entrance thereto or over 75% of the damaged tissue that is being repaired or replaced.
  • an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of no more than 95% of the biological site within the entrance thereto or over 95% of the damaged tissue that is being repaired or replaced.
  • an individual implanted reticulated elastomeric matrix will, in many cases, although not necessarily, have at least one dimension of no more than about 98% of the biological site within the entrance thereto or cover 98% of the damaged tissue that is being repaired or replaced.
  • an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of no more than about 100% of the biological site within the entrance thereto or cover 100% of the damaged tissue that is being repaired or replaced.
  • an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of no more than about 102% of the biological site within the entrance thereto or cover 102% of the damaged tissue that is being repaired or replaced.
  • an individual implanted reticulated elastomeric matrix will, in many cases, although not necessarily, have at least one dimension of more than about 125% of the biological site within the entrance thereto or cover 125% of the damaged tissue that is being repaired or replaced.
  • an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 200% of the biological site within the entrance thereto or cover 200% of the damaged tissue that is being repaired or replaced.
  • an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 150% of the biological site within the entrance thereto or cover 150% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 200% of the biological site within the entrance thereto or cover 200% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 300% of the biological site within the entrance thereto or cover 300% of the damaged tissue that is being repaired or replaced.
  • the reticulated elastomeric matrix has sufficient structural integrity to be self-supporting and free-standing in vitro.
  • the elastomeric matrix can be furnished with structural supports such as ribs or struts.
  • the reticulated elastomeric matrix useful according to the invention should have sufficient tensile and compressive properties such that it can withstand normal manual or mechanical handling during its intended application and during post-processing steps that may be required or desired without tearing, breaking, crumbling, fragmenting or otherwise disintegrating, shedding pieces or particles, or otherwise losing its structural integrity.
  • the tensile and compressive properties of the matrix material(s) should not be so high as to interfere with the fabrication or other processing of the reticulated elastomeric matrix.
  • the tensile and compressive properties should be appropriate so that they can withstand the forces, loads, deformations and moments experienced by the implant when placed at the target orthopedic or spinal implant site.
  • the reticulated polymeric matrix that is used to fabricate the implants of this invention has any suitable bulk density, also known as specific gravity, consistent with its other properties.
  • the bulk density may be from about 0.005 to about 0.15 g/cc (from about 0.31 to about 9.4 lb/ft 3 ), preferably from about 0.015 to about 0.115 g/cc (from about 0.93 to about 7.2 lb/ft 3 ) and most preferably from about 0.024 to about 0.104 g/cc (from about 1.5 to about 6.5 lb/ft 3 ).
  • the reticulated elastomeric matrix has sufficient tensile strength such that it can withstand normal manual or mechanical handling during its intended application and during post-processing steps that may be required or desired without tearing, breaking, crumbling, fragmenting or otherwise disintegrating, shedding pieces or particles, or otherwise losing its structural integrity.
  • the tensile strength of the starting material(s) should not be so high as to interfere with the fabrication or other processing of elastomeric matrix.
  • the reticulated polymeric matrix that is used to fabricate the implants of this invention may have a tensile strength of from about 700 to about 70,000 kg/m (from about 1 to about 100 psi).
  • elastomeric matrix may have a tensile strength of from about 7000 to about 52,500 kg/m 2 (from about 10 to about 75 psi). In another embodiment, elastomeric matrix may have a tensile strength of from about 1,400 to about 14,000 kg/m 2 (from about 2 to about 20 psi) at 20 % ultimate tensile elongation strain. Sufficient ultimate tensile elongation is also desirable. For example, in another embodiment, reticulated elastomeric matrix has an ultimate tensile elongation of at least about 50% to at least about 500%. In yet another embodiment, reticulated elastomeric matrix has an ultimate tensile elongation of at least 75% to at least about 300%.
  • reticulated elastomeric matrix that is used to fabricate the implants of this invention has a compressive strength of from about 700 to about 70,000 kg/m (from about 1 to about 100 psi) at 50% compression strain. In another embodiment, reticulated elastomeric matrix has a compressive strength of from about 1,400 to about 105,000 kg/m 2 (from about 2 to about 150 psi) at 75% compression strain.
  • reticulated elastomeric matrix that is used to fabricate the implants of this invention has a compression set, when compressed to 50%) of its thickness at about 25°C, of not more than about 30%. In another embodiment, reticulated elastomeric matrix has a compression set of not more than about 20%. In another embodiment, reticulated elastomeric matrix has a compression set of not more than about 10%. In another embodiment, reticulated elastomeric matrix has a compression set of not more than about 5%.
  • reticulated elastomeric matrix that is used to fabricate the implants of this invention has a tear strength, of from about 0.18 to about 3.6 kg/linear cm (from about 1 to about 20 lbs/linear inch).
  • the reticulated elastomeric matrix that is used to fabricate the implant can be readily permeable to liquids, permitting flow of liquids, including blood, through the composite device of the invention.
  • the water permeability of the reticulated elastomeric matrix is from about 30 l/min./psi/cm 2 to about 500 l/min./psi/cm 2 , preferably from about 50 l/min./psi/cm 2 to about 300 l/min./psi/cm 2 .
  • permeability of the unreticulated elastomeric matrix is below about 1 l/min./psi/cm .
  • the permeability of the unretriculated elastomeric amtrix is below about 5 l/min./psi/cm .
  • suitable biodurable reticulated elastomeric partially hydrophobic polymeric matrix that is used to fabricate the implant of this invention or for use as scaffold material for the implant in the practice of the present invention, in one embodiment sufficiently well characterized, comprise elastomers that have or can be formulated with the desirable mechanical properties described in the present specification and have a chemistry favorable to biodurability such that they provide a reasonable expectation of adequate biodurability.
  • biodurable reticulated hydrophobic polyurethane materials are suitable for this purpose.
  • structural materials for the inventive reticulated elastomers are synthetic polymers, especially, but not exclusively, elastomeric polymers that are resistant to biological degradation, for example, polycarbonate polyurethane-urea, polycarbonate polyurea-urethane, polycarbonate polyurethane, polycarbonate polysiloxane polyurethane, and polysiloxane polyurethane, and the like.
  • Such elastomers are generally hydrophobic but, pursuant to the invention, may be treated to have surfaces that are less hydrophobic or somewhat hydrophilic. In another embodiment, such elastomers may be produced with surfaces that are less hydrophobic or somewhat hydrophilic.
  • the invention can employ, for implanting, a biodurable reticulatable elastomeric partially hydrophobic polymeric scaffold material or matrix for fabricating the implant or a material. More particularly, in one embodiment, the invention provides a biodurable elastomeric polyurethane scaffold material or matrix which is made by synthesizing the scaffold material or matrix preferably from a polycarbonate polyol component and an isocyanate component by polymerization, cross-linking and foaming, thereby forming pores, followed by reticulation of the porous material to provide a biodurable reticulated elastomeric product with interconnected and/or inter-communicating pores and channels.
  • a biodurable elastomeric polyurethane scaffold material or matrix which is made by synthesizing the scaffold material or matrix preferably from a polycarbonate polyol component and an isocyanate component by polymerization, cross-linking and foaming, thereby forming pores, followed by reticulation of the porous material to provide a biodur
  • the product is designated as a polycarbonate polyurethane, being a polymer comprising urethane groups formed from, e.g., the hydroxyl groups of the polycarbonate polyol component and the isocyanate groups of the isocyanate component.
  • the invention provides a biodurable elastomeric polyurethane scaffold material or matrix which is made by synthesizing the scaffold material or matrix preferably from a polycarbonate polyol component and an isocyanate component by polymerization, cross-linking and foaming, thereby forming pores, and using water as a blowing agent and/or foaming agent during the synthesis, followed by reticulation of the porous material to provide a biodurable reticulated elastomeric product with inter-connected and/or inter-communicating pores and channels.
  • This product is designated as a polycarbonate polyurethane-urea or polycarbonate polyurea-urethane, being a polymer comprising urethane groups formed from, e.g., the hydroxyl groups of the polycarbonate polyol component and the isocyanate groups of the isocyanate component and also comprising urea groups formed from reaction of water with the isocyanate groups.
  • the process employs controlled chemistry to provide a reticulated elastomeric matrix or product with good biodurability characteristics.
  • the matrix or product employing chemistry that avoids biologically undesirable or nocuous constituents therein.
  • the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one polyol component to provide the so-called soft segement.
  • polyol component includes molecules comprising, on the average, about 2 hydroxyl groups per molecule, i.e., a difunctional polyol or a diol, as well as those molecules comprising, on the average, greater than about 2 hydroxyl groups per molecule, i.e., a polyol or a multi-functional polyol.
  • this soft segment polyol is terminated with hydroxyl groups, either primary or secondary.
  • Exemplary polyols can comprise, on the average, from about 2 to about 5 hydroxyl groups per molecule.
  • the process employs a difunctional polyol component in which the hydroxyl group functionality of the diol is about 2.
  • the soft segment is composed of a polyol component that is generally of a relatively low molecular weight, typically from about 500 to about 6,000 daltons and preferably between 1000 to 2500 daltons.
  • suitable polyol components include but not limited to polycarbonate polyol, hydrocarbon polyol, polysiloxane polyol, poly(carbonate-co- hydrocarbon) polyol, poly(carbonate-co-siloxane) polyol, poly(hydrocarbon-co- siloxane) polyol, polysiloxane polyol and copolymers and mixtures thereof.
  • the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one isocyanate component and, optionally, at least one chain extender component to provide the so-called "hard segment".
  • the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one isocyanate component.
  • isocyanate component includes molecules comprising, on the average, about 2 isocyanate groups per molecule as well as those molecules comprising, on the average, greater than about 2 isocyanate groups per molecule.
  • the isocyanate groups of the isocyanate component are reactive with reactive hydrogen groups of the other ingredients, e.g., with hydrogen bonded to oxygen in hydroxyl groups of the polyol component, with hydrogen bonded to nitrogen in amine groups, chain extender, crosslinker and/or water.
  • the average number of isocyanate groups per molecule in the isocyanate component is about 2. In another embodiment, the average number of isocyanate groups per molecule in the isocyanate component is greater than about 2.
  • the isocyanate index is the mole ratio of the number of isocyanate groups in a formulation available for reaction to the number of groups in the formulation that are able to react with those isocyanate groups, e.g., the reactive groups of diol(s), polyol component(s), chain extender(s) and water, when present.
  • the isocyanate index is from about 0.9 to about 1.1.
  • the isocyanate index is from about 0.9 to about 1.02.
  • the isocyanate index is from about 0.98 to about 1.02.
  • the isocyanate index is from about 0.9 to about 1.0.
  • the isocyanate index is from about 0.9 to about 0.98.
  • a small quantity of an optional ingredient such as a multi-functional hydroxyl compound or other cross-linker having a functionality greater than 2, is present to allow crosslinking and/or to achieve a stable foam, i.e., a foam that does not collapse to become non-foamlike.
  • an optional ingredient such as a multi-functional hydroxyl compound or other cross-linker having a functionality greater than 2
  • polyfunctional adducts of aliphatic and cycloaliphatic isocyanates can be used to impart cross-linking in combination with aromatic diisocyanates.
  • polyfunctional adducts of aliphatic and cycloaliphatic isocyanates can be used to impart cross-linking in combination with aliphatic diisocyanates.
  • polymeric aromatic diisocyanates can be used to impart cross-linking.
  • the presence of these components and adducts with functionality higher than 2 in the hard segment component allows for cross-linking to occur.
  • additional cross-linking arises out of hydrogen bonding in and between both the hard and soft phases of the matrix and is termed as physical cross-linking.
  • Exemplary diisocyanates include aliphatic diisocyanates, isocyanates comprising aromatic groups, the so-called “aromatic diisocyanates", and mixtures thereof.
  • Aliphatic diisocyanates include tetramethylene diisocyanate, cyclohexane- 1,2-diisocyanate, cyclohexane-l,4-diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, methylene-bis-(p-cyclohexyl isocyanate) ("HI 2 MDI”), and mixtures thereof.
  • Aromatic diisocyanates include p-phenylene diisocyanate, 4,4'- diphenylmethane diisocyanate (“4,4'-MDI”), 2,4'-diphenylmethane diisocyanate (“2,4'-MDI”), polymeric MDI, and mixtures thereof.
  • optional chain extenders include diols, diamines, alkanol amines or a mixture thereof.
  • the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one blowing agent such as water.
  • blowing agents include the physical blowing agents, e.g., volatile organic chemicals such as hydrocarbons, ethanol and acetone, and various fluorocarbons, hydrofluorocarbons, chlorofluorocarbons, and hydrochlorofluorocarbons.
  • Additional exemplary blowing agents include the physical blowing agents such as gases as nitrogen, helium, etc., that can additionally act as nucleating agent and whose amount and the pressure under which they are introduced during matrix formation can be used to control the density of the biodurable, elastomeric and partially hydrophobic polymeric matrix.
  • the hard segments also contain a urea component formed during foaming reaction with water.
  • the reaction of water with an isocyanate group yields carbon dioxide, which serves as a blowing agent.
  • the amount of blowing agent e.g., water, is adjusted to obtain different densities of non-reticulated foams. A reduced amount of blowing agent such as water may reduce the number of urea linkages in the material.
  • any or all of the processing approaches of the invention may be used to make foam with a density greater than 3.4 lbs/ft (0.054 g/cc).
  • crosslinker(s) such as glycerol
  • the functionality of the isocyanate component is from 2.0 to 2.5
  • the isocyanate component consists essentially of 4, 4 diphenylmethane diisocyanate ("4,4'-MDI"), and the remaining components being 2,4'-diphenylmethane diisocyanate (“2,4*-MDI”), polymeric MDI
  • 4,4'-MDI is greater than about 55% by weight of the isocyanate component.
  • the molecular weight of the polyol component is from about 500 to 3000 Daltons but preferably between 1,000 to about 2,000 Daltons.
  • the amount of blowing agent e.g., water, is adjusted to obtain non-reticulated foam with densities greater than 3.4 lbs/ft (0.054 g/cc).
  • a reduced amount of blowing agent may reduce the number of urea linkages in the material. In one embodiment, any reduction in stiffness and/or tensile strength and/or compressive strength caused by fewer urea linkages and/or by lower crosslinking can be compensated for by using di-functional chain extenders, such as butanediol, and/or increasing the density of the foam.
  • any reduction in stiffness and/or tensile strength and/or compressive strength caused by fewer urea linkages and/or lower crosslinking can be compensated for by using or increasing the amount or proportion of 4,4'-MDI of the isocyanate component.
  • 4,4'-MDI of the isocyanate component
  • implantable device can be rendered radiopaque to facilitate in vivo imaging, for example, by adhering to, covalently bonding to and/or incorporating into the elastomeric matrix itself particles of a radio-opaque material.
  • Radio-opaque materials include titanium, tantalum, tungsten, barium sulfate or other suitable material known to those skilled in the art.
  • the starting material of the biodurable reticulated elastomeric partially hydrophobic polymeric matrix is a commercial polyurethane polymers are linear, not crosslinked, polymers, therefore, they are soluble, can be melted, readily analyzable and readily characterizable.
  • the starting polymer provides good biodurability characteristics.
  • the reticulated elastomeric matrix is produced by taking a solution of the commercial polymer such as polyurethane and charging it into a mold that has been fabricated with surfaces defining a microstructural configuration for the final implant or scaffold, solidifying the polymeric material and removing the sacrificial mold by melting, dissolving or subliming- away the sacrificial mold.
  • the solvents can be lyophilized leaving at least a partially or fully reticulated material matrix.
  • the matrix or product employing a foaming process that avoids biologically undesirable or nocuous constituents therein.
  • thermoplastic elastomers such as polyurethanes whose chemistry is associated with good biodurability properties, for example.
  • thermoplastic polyurethane elastomers include polycarbonate polyurethanes, polysiloxane polyurethanes, polyurethanes with so-called "mixed" soft segments, and mixtures thereof.
  • Mixed soft segment polyurethanes are known to those skilled in the art and include, e.g., polycarbonate-polysiloxane polyurethanes.
  • thermoplastic polyurethane elastomer comprises at least one diisocyanate in the isocyanate component, at least one chain extender and at least one diol, and may be formed from any combination of the diisocyanates, difunctional chain extenders and diols described in detail above.
  • suitable thermoplastic polyurethanes for practicing the invention include: polyurethanes with mixed soft segments comprising polysiloxane together with a polycarbonate component.
  • the weight average molecular weight of the thermoplastic elastomer is from about 30,000 to about 500,000 Daltons. In another embodiment, the weight average molecular weight of the thermoplastic elastomer is from about 50,000 to about 250,000 Daltons.
  • thermoplastic elastomers suitable for use in practicing the present invention include the line of polycarbonate polyurethanes supplied under the trademark BIONATE® by The Polymer Technology Group Inc. (Berkeley, CA).
  • BIONATE® 80A, 55 and 90 are soluble in THF, DMF, DMAT, DMSO, or a mixture of two or more thereof, processable, reportedly have good mechanical properties, lack cytotoxicity, lack mutagenicity, lack carcinogenicity and are non-hemolytic.
  • Another commercially-available elastomer suitable for use in practicing the present invention is the CHRONOFLEX® C line of biodurable medical grade polycarbonate aromatic polyurethane thermoplastic elastomers available from CardioTech International, Inc. (Woburn, MA).
  • the elastomeric scaffold may optionally have a simple dip or spray polymer coating, the coating optionally comprising a pharmaceutically-active agent, such as a therapeutic agent or drug.
  • the coating may be a solution and the polymer content in the coating solution is from about 1% to about 40% by weight.
  • the polymer content in the coating solution may be from about 1% to about 20% by weight.
  • the polymer content in the coating solution may be from about 1% to about 10% by weight.
  • a biodurable reticulated elastomeric matrix has a coating comprising material selected to encourage cellular ingrowth and proliferation.
  • the coating material can, for example, comprise a foamed coating of a biodegradable material, optionally, collagen, fibronectin, elastin, hyaluronic acid and mixtures thereof.
  • the coating comprises a biodegradable polymer and an inorganic component.
  • the reticulated biodurable elastomer is coated or impregnated with a material such as, for example, polyglycolic acid (“PGA”), polylactic acid (“PLA”), polycaprolactic acid (“PCL”), poly-p-dioxanone (“PDO”), PGA/PLA copolymers, PGA/PCL copolymers, PGA/PDO copolymers, PLA/PCL copolymers, PLA/PDO copolymers, PCL/PDO copolymers or combinations of any two or more of the foregoing.
  • PGA polyglycolic acid
  • PLA polylactic acid
  • PCL polycaprolactic acid
  • PDO poly-p-dioxanone
  • the solvent or solvent blend for the coating solution is chosen with consideration given to, inter alia, the proper balancing the viscosity, deposition level of the polymer, wetting rate and evaporation rate of the solvent to properly coat solid phase as known to those in the art.
  • the solvent is chosen such the polymer is soluble in the solvent.
  • the solvent is substantially completely removed from the coating.
  • the solvent is non- toxic, non-carcinogenic and environmentally benign. Mixed solvent systems can be advantageous for controlling the viscosity and evaporation rates. In all cases, the solvent should not react with the coating polymer.
  • Solvents include, but are not limited to, acetone, N-methylpyrrolidone ("NMP”), DMSO, toluene, methylene chloride, chloroform, 1,1,2-trichloroethane (“TCE”), various freons, dioxane, ethyl acetate, THF, DMF and DMAC.
  • the film- forming coating polymer is a thermoplastic polymer that is melted, enters the pores of the elastomeric matrix and, upon cooling or solidifying, forms a coating on at least a portion of the solid material of the elastomeric matrix .
  • the processing temperature of the thermoplastic coating polymer in its melted form is above about 60°C.
  • the processing temperature of the thermoplastic coating polymer in its melted form is above about 90°C.
  • the processing temperature of the thermoplastic coating polymer in its melted form is above about 120°C.
  • some or all of the pores of the elastomeric matrix are coated or filled with a cellular ingrowth promoter.
  • the promoter can be foamed.
  • the promoter can be present as a film.
  • the promoter can be a biodegradable material to promote cellular invasion of the elastomeric matrix in vivo.
  • Promoters include naturally occurring materials that can be enzymatically degraded in the human body or are hydrolytically unstable in the human body, such as fibrin, fibrinogen, collagen, elastin, hyaluronic acid and absorbable biocompatible polysaccharides, such as chitosan, starch, fatty acids (and esters thereof), glucoso- glycans and hyaluronic acid.
  • the pore surface of the elastomeric matrix is coated or impregnated, as described above, but substituting the promoter for the biocompatible polymer or adding the promoter to the biocompatible polymer, to encourage cellular ingrowth and proliferation.
  • the coating or impregnating process is conducted so as to ensure that the product "composite elastomeric implantable device", i.e., a reticulated elastomeric matrix and a coating, as used herein, retains sufficient resiliency after compression such that it can be delivery-device delivered, e.g., catheter, syringe or endoscope delivered.
  • a composite elastomeric implantable device i.e., a reticulated elastomeric matrix and a coating, as used herein.
  • Collagen may be infiltrated by forcing, e.g., with pressure, an aqueous collagen slurry, suspension or solution into the pores of an elastomeric matrix.
  • the collagen may be Type I, II or III or mixtures thereof.
  • the collagen type comprises at least 90% collagen I.
  • the concentration of collagen is from about 0.3% to about 2.0% by weight and the pH of the slurry, suspension or solution is adjusted to be from about 2.6 to about 5.0 at the time of lyophilization.
  • collagen may be infiltrated by dipping an elastomeric matrix into a collagen slurry.
  • the composite elastomeric implantable device can have a void phase that is slightly reduced in volume.
  • the composite elastomeric implantable device retains good fluid permeability and sufficient porosity for ingrowth and proliferation of fibroblasts or other cells.
  • the lyophilized collagen can be crosslinked to control the rate of in vivo enzymatic degradation of the collagen coating and to control the ability of the collagen coating to bond to the elastomeric matrix.
  • tissue-forming agents that have a high affinity to collagen, such as fibroblasts, will more readily invade the collagen-impregnated elastomeric matrix than the uncoated matrix.
  • new tissue invades and fills voids left by the degrading collagen while also infiltrating and filling other available spaces in the elastomeric matrix.
  • Such a collagen coated or impregnated elastomeric matrix is thought, without being bound by any particular theory, to be additionally advantageous for the structural integrity provided by the reinforcing effect of the collagen within the pores of the elastomeric matrix which can impart greater rigidity and structural stability to various configurations of the elastomeric matrix .
  • the biodurable reticulated elastomeric matrix useful according to this invention can support cell types including cells secreting structural proteins and cells that produce proteins characterizing organ function.
  • the ability of the elastomeric matrix to facilitate the co-existence of multiple cell types together and its ability to support protein secreting cells demonstrates the applicability of the elastomeric matrix in organ growth in vitro or in vivo and in organ reconstruction.
  • biodurable reticulated elastomeric matrix may also be used in the scale up of human cell lines for implantation to the body for many applications including implantation of fibroblasts, chondrocytes, osteoblasts, osteoclasts, osteocytes, synovial cells, bone marrow stromal cells, stem cells, fibrocartilage cells, endothelial cells, smooth muscle cells, adipocytes, cardiomyocytes, myocytes, keratinocytes, hepatocytes, leukocytes, macrophages, endocrine cells, genitourinary cells, lymphatic vessel cells, pancreatic islet cells, muscle cells, intestinal cells, kidney cells, blood vessel cells, thyroid cells, parathyroid cells, cells of the adrenal-hypothalamic pituitary axis, bile duct cells, ovarian or testicular cells, salivary secretory cells, renal cells, epithelial cells, nerve cells, stem cells, progenitor cells, myoblasts, stem
  • New tissue can be obtained through implantation of cells seeded in elastomeric matrices (either prior to or concurrent to or subsequent to implantation).
  • the elastomeric matrices may be configured either in a closed manner to protect the implanted cells from the body's immune system, or in an open manner so that the new cells can be incorporated into the body.
  • the cells may be incorporated, i.e., cultured and proliferated, onto the elastomeric matrix prior, concurrent or subsequent to implantation of the elastomeric matrix in the patient.
  • the implantable device made from biodurable reticulated elastomeric matrix can be seeded with a type of cell and cultured before being inserted into the patient, optionally using a delivery-device, for the explicit purpose of tissue repair or tissue regeneration. It is necessary to perform the tissue or cell culture in a suitable culture medium with or without stimulus such as stress or orientation.
  • the cells include fibroblasts, chondrocytes, osteoblasts, osteoclasts, osteocytes, synovial cells, bone marrow stromal cells, stem cells, fibrocartilage cells, endothelial cells and smooth muscle cells.
  • Biodurable reticulated elastomeric matrix possessing different pore morphology, size, shape and orientation may be cultured with different type of cells to develop cellular tissue engineering implantable devices that are specifically targeted towards orthopedic applications, especially in soft tissue attachment, repair, re-generation, augmentation and/or support encompassing spine, shoulder, knee, hand, joints, and in the growth of a prosthetic organ.
  • all the surfaces on the biodurable reticulated elastomeric matrix possessing similar pore morphology, size, shape and orientation may be so cultured.
  • the film- forming polymer used to coat the reticulated elastomeric matrix can provide a vehicle for the delivery of and/or the controlled release of a pharmaceutically-active agent, for example, a drug, such as is described in the copending applications.
  • a pharmaceutically-active agent for example, a drug, such as is described in the copending applications.
  • the pharmaceutically-active agent is admixed with, covalently bonded to and/or adsorbed in or on the coating of the elastomeric matrix to provide a pharmaceutical composition.
  • the components, polymers and/or blends used to form the foam comprise a pharmaceutically-active agent. To form these foams, the previously described components, polymers and/or blends are admixed with the pharmaceutically-active agent prior to forming the foam or the pharmaceutically- active agent is loaded into the foam after it is formed.
  • the coating polymer and pharmaceutically-active agent have a common solvent. This can provide a coating that is a solution.
  • the pharmaceutically-active agent can be present as a solid dispersion in a solution of the coating polymer in a solvent.
  • a reticulated elastomeric matrix comprising a pharmaceutically-active agent may be formulated by mixing one or more pharmaceutically-active agent with the polymer used to make the foam, with the solvent or with the polymer-solvent mixture and foamed.
  • a pharmaceutically-active agent can be coated onto the foam, in one embodiment, using a pharmaceutically-acceptable carrier. If melt-coating isemployed, then, in another embodiment, the pharmaceutically-active agent withstands melt processing temperatures without substantial diminution of its efficacy.
  • Formulations comprising a pharmaceutically-active agent can be prepared by admixing, covalently bonding and/or adsorbing one or more pharmaceutically-active agents with the coating of the reticulated elastomeric matrix or by incorporating the pharmaceutically-active agent into additional hydrophobic or hydrophilic coatings.
  • the pharmaceutically-active agent may be present as a liquid, a finely divided solid or another appropriate physical form.
  • the matrix can include one or more conventional additives, such as diluents, carriers, excipients, stabilizers and the like.
  • a top coating can be applied to delay release of the pharmaceutically-active agent.
  • a top coating can be used as the matrix for the delivery of a second pharmaceutically-active agent.
  • a layered coating comprising respective layers of fast- and slow-hydrolyzing polymer, can be used to stage release of the pharmaceutically-active agent or to control release of different pharmaceutically-active agents placed in the different layers.
  • Polymer blends may also be used to control the release rate of different pharmaceutically-active agents or to provide a desirable balance of coating characteristics (e.g., elasticity, toughness) and drug delivery characteristics (e.g., release profile).
  • Polymers with differing solvent solubilities can be used to build-up different polymer layers that may be used to deliver different pharmaceutically-active agents or to control the release profile of a pharmaceutically-active agents.
  • the amount of pharmaceutically-active agent present depends upon the particular pharmaceutically-active agent employed and medical condition being treated. In one embodiment, the pharmaceutically-active agent is present in an effective amount. In another embodiment, the amount of pharmaceutically-active agent represents from about 0.01% to about 60% of the coating by weight. In another embodiment, the amount of pharmaceutically-active agent represents from about 0.01% to about 40% of the coating by weight. In another embodiment, the amount of pharmaceutically-active agent represents from about 0.1% to about 20% of the coating by weight.
  • pharmaceutically-active agents can be used in conjunction with the reticulated elastomeric matrix.
  • pharmaceutically- active agents that may be administered via pharmaceutical compositions of this invention include, without limitation, any therapeutic or pharmaceutically-active agent (including but not limited to nucleic acids, proteins, lipids, and carbohydrates) that possesses desirable physiologic characteristics for application to the implant site or administration via a pharmaceutical compositions of the invention.
  • Therapeutics include, without limitation, antiinfectives such as antibiotics and antiviral agents; chemotherapeutic agents (e.g., anticancer agents); anti-rejection agents; analgesics and analgesic combinations; anti-inflammatory agents; hormones such as steroids; growth factors (including but not limited to cytokines, chemokines, and interleukins) and other naturally derived or genetically engineered proteins, polysaccharides, glycoproteins and lipoproteins. These growth factors are described in The Cellular and Molecular Basis of Bone Formation and Repair by Vicki Rosen and R. Scott Thies, published by R. G. Landes Company, hereby incorporated herein by reference.
  • Additional therapeutics include thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroids, non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, angiotensin-converting enzyme (ACE) inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents and gene therapy agents.
  • ACE angiotensin-converting
  • various proteins including short chain peptides
  • growth agents including short chain peptides
  • chemotatic agents growth factor receptors or ceramic particles
  • the pores of the foam may be partially or completely filled with biocompatible resorbable synthetic polymers or biopolymers (such as collagen or elastin), biocompatible ceramic materials (such as hydroxyapatite), and combinations thereof, and may optionally contain materials that promote tissue growth through the device.
  • tissue-growth materials include but are not limited to autograft, allograft or xenograft bone, bone marrow and morphogenic proteins.
  • Biopolymers can also be used as conductive or chemotactic materials, or as delivery vehicles for growth factors. Examples include recombinant collagen, animal-derived collagen, elastin and hyaluronic acid. Pharmaceutically-active coatings or surface treatments could also be present on the surface of the materials. For example, bioactive peptide sequences (RGD's) could be attached to the surface to facilitate protein adsorption and subsequent cell tissue attachment.
  • RGD's bioactive peptide sequences
  • the pores of biodurable reticulated elastomeric matrix that are used to fabricate the implants of this invention are coated or filled with a cellular ingrowth promoter.
  • the promoter can be foamed.
  • the promoter can be present as a film.
  • the promoter can be a biodegradable material to promote cellular invasion of pores biodurable reticulated elastomeric matrix that are used to fabricate the implants of this invention in vivo.
  • Promoters include naturally occurring materials that can be enzymatically degraded in the human body or are hydrolytically unstable in the human body, such as fibrin, fibrinogen, collagen, elastin, hyaluronic acid and absorbable biocompatible polysaccharides, such as chitosan, starch, fatty acids (and esters thereof), glucoso-glycans and hyaluronic acid.
  • the pore surface of the biodurable reticulated elastomeric matrix that are used to fabricate the implants of this invention is coated or impregnated, as described in the previous section but substituting the promoter for the biocompatible polymer or adding the promoter to the biocompatible polymer, to encourage cellular ingrowth and proliferation.
  • Bioactive molecules include, without limitation, proteins, collagens
  • fibrillar collagens including types I, II, III, V, XI
  • FACIT collagens types IX, XII, XIV
  • other collagens types VI, VII, XIII
  • short chain collagens types VIII, X
  • elastin entactin-1, fibrillin, fibronectin, fibrin, fibrinogen, fibroglycan, fibromodulin, fibulin, glypican, vitronectin, laminin, nidogen, matrilin, perlecan, heparin, heparan sulfate proteoglycans, decorin, filaggrin, keratin, syndecan, agrin, integrins, aggrecan, biglycan, bone sialoprotein, cartilage matrix protein, Cat-301 proteoglycan, CD44, cholinesterase, HB-GAM, hyaluronan, hyaluronan binding proteins,
  • Additional bioactive molecules include, without limitation, cell adhesion molecules and matricellular proteins, including those of the immunoglobulin (Ig; including monoclonal and polyclonal antibodies), cadherin, integrin, selectin, and H- CAM superfamilies.
  • immunoglobulin Ig; including monoclonal and polyclonal antibodies
  • cadherin including monoclonal and polyclonal antibodies
  • integrin including monoclonal and polyclonal antibodies
  • selectin include H- CAM superfamilies.
  • Examples include, without limitation, AMOG, CD2, CD4, CD8, C-CAM (CELL-CAM 105), cell surface galactosyltransferase, connexins, desmocollins, desmoglein, fasciclins, FI 1, GP Ib-IX complex, intercellular adhesion molecules, leukocyte common antigen protein tyrosine phosphate (LCA, CD45), LFA- 1, LFA-3, mannose binding proteins (MBP), MTJC18, myelin associated glycoprotein (MAG), neural cell adhesion molecule (NCAM), neurofascin, neruoglian, neurotactin, netrin, PECAM-1, PH-20, semaphorin, TAG-1, VCAM-1, SPARC/osteonectin, CCN1 (CYR61), CCN2 (CTGF; Connective Tissue Growth Factor), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), CCN6 (WISP-3),
  • Growth factors include, without limitation, BMP's (1-7), BMP-like Proteins (GFD-5, -7, -8), epidermal growth factor (EGF), erythropoietin (EPO), fibroblast growth factor (FGF), growth hormone (GH), growth hormone releasing factor (GHRF), granulocyte colony-stimulating factor (G-CSF), granulocyte- macrophage colony- stimulating factor (GM-CSF), insulin, insulin-like growth factors (IGF-I, IGF-II), insulin-like growth factor binding proteins (IGFBP), macrophage colony-stimulating factor (M-CSF), Multi-CSF (II-3), platelet-derived growth factor (PDGF), tumor growth factors (TGF-alpha, TGF-beta), tumor necrosis factor (TNF- alpha), vascular endothelial growth factors (VEGF's), angiopoietins, placenta growth factor (PIGF), interleukins, and receptor proteins or other molecules that
  • Short-chain peptides include, without limitation (designated by single letter amino acid code), RGD, EILDV, RGDS, RGES, RFDS, GRDGS, GRGS, GRGDTP and QPPRARI.
  • One possible material for use in the present invention comprises a resiliently compressible composite polyurethane material comprising a hydrophilic foam coated on and throughout the pore surfaces of a hydrophobic foam scaffold.
  • One suitable such material is the composite foam disclosed in co-pending, commonly assigned U.S. patent applications Serial No. 10/692,055, filed October 22, 2003, Serial No. 10/749,742, filed December 30, 2003, Serial No. 10/848,624, filed May 17, 2004, and Serial No. 10/900,982, filed July 27, 2004, each of which is incorporated herein by reference in its entirety.
  • the hydrophobic foam provides support and resilient compressibility enabling the desired collapsing of the implant for delivery and reconstitution in situ.
  • the elastomeric matrix useful according to the invention may be molded into any of a wide variety of shapes and sizes during its formation or production.
  • the shape may be a working configuration, such as any of the shapes and configurations described above, or the shape may be for bulk stock. Stock items may subsequently be cut, trimmed, punched or otherwise shaped for end use.
  • the sizing and shaping can be carried out by, for example, using a blade, punch, drill or laser.
  • the processing temperature or temperatures of the cutting tools for shaping and sizing can be greater than about 100°C. In another embodiment, the processing temperature(s) of the cutting tools for shaping and sizing can be greater than about 130°C.
  • Finishing steps can include, in one embodiment, trimming of macrostructural surface protrusions, such as struts or the like, which can irritate biological tissues.
  • finishing steps can include heat annealing. Annealing can be carried out before or after final cutting and shaping.
  • the dimensions of the shaped and sized devices made from the elastomeric matrix can vary depending on the application.
  • major dimensions of a device, such as device 30 or device 48, prior to being compressed and delivered are from about 5 mm to about 30 mm in one direction and from about 5mm to about 30 mm in another direction.
  • major dimensions of a device, such as device 30 or device 48, prior to being compressed and delivered are from about 8 mm to about 25 mm in one direction and from about 8 mm to about 25 mm in another direction.
  • the length of a cylindrical portion of a device, such as device 30 or device 48, according to the invention is expected to be from about 6 mm to about 14 mm, since that is approximately the typical radial thickness of a patient's annulus.
  • the diameter or the largest transverse dimension of the cylindrical portion of a device, such as cylindrical part 32 or cylindrical part 50, according to the invention is expected to be from about 5 mm to about 30 mm, preferably from about 8 mm to about 20 mm.
  • the diameter or the largest transverse dimension of the partial cylindrical or partial spherical portion of a device, such as expanded portion 34 or mushrrom- shape distal portion 52, according to the invention is expected to be from about 8 mm to about 40 mm, preferably from about 10 mm to about 30 mm.
  • the elastomeric matrix can exhibit compression set upon being compressed and transported through a delivery-device, e.g., a trocar, cannula, or catheter, with assisted visualization.
  • compression set and its standard deviation are taken into consideration when designing the pre-compression dimensions of the device.
  • Biodurable reticulated elastomeric matrices can be sterilized by any method known to the art including gamma irradiation, autoclaving, ethylene oxide sterilization, infrared irradiation and electron beam irradiation.
  • biodurable elastomers used to fabricate the elastomeric matrix tolerate such sterilization without loss of useful physical and mechanical properties.
  • the use of gamma irradiation can potentially provide additional crosslinking to enhance the performance of the device.
  • the sterilized products may be packaged in uncompressed state in sterile packages of paper, polymer or other suitable material.
  • the elastomeric matrix remains uncompressed in such a package for typical commercial storage and distribution times, which will commonly exceed 3 months and may be up to 1 or 5 years from manufacture to use.
  • the elastomeric matrix is compressed within a retaining member to facilitate its loading into a delivery-device, such as a catheter or endoscope, in a compressed configuration.
  • the elastomeric matrix comprises an elastomer with a compression set enabling it to expand to a substantial proportion of its pre-compressed volume, e.g., at 25 °C, to at least 50% of its pre-compressed volume.
  • expansion occurs after the elastomeric matrix remains compressed in such a package for typical commercial storage and distribution times, which will commonly exceed 3 months and may be up to 1 or 5 years from manufacture to use.
  • the reticulated elastomeric implants or implants can be rendered radiopaque to allow for visualization of the implants in situ by the clinician during and after the procedure, employing radioimaging.
  • radiopaque agent that can be covalently bound, adhered or otherwise attached to the reticulated polymeric implants may be employed including without limitation, tantalum, titanium and barium sulfate or other suitable material known to those skilled in the art.
  • a further embodiment of the invention encompasses the use of radiopaque metallic components to impart radiopacity to the implant.
  • thin filaments comprised of metals with or without shape memory properties such as platinum or nitinol can be embedded into the implant and may be in the form of a straight or curved wire, helical or coil-like structure, umbrella structure, or other structure generally known to those skilled in the art.
  • a metallic frame around the implant may also be used to impart radiopacity.
  • the metallic frame may be in the form of a tubular structure, a helical or coil-like structure, an umbrella structure, or other structure generally known to those skilled in the art.
  • the metallic implants incorporated in or surrounding the orthopedic or spinal implant for gripping or attachment or positioning or fastening of the implant at the target site can be used to impart radiopacity. Attachment of radiopaque metallic components to the implant can be accomplished by means including but not limited to chemical bonding or adhesion, suturing, pressure fitting, compression fitting, and other physical methods.
  • the reticulated elastomeric matrix can be appropriately shaped to form a closure device to seal the access opening in the annulus resulting from a discotomy to reinforce and stabilize the disc annulus in case of herniated disc, also known as disc prolapse or a slipped or bulging disc.
  • the implantable device is compressed and delivered into the annulus opening by a trocar, cannula, or catheter with assisted visualization through an endoscopic intrument such as a laproscope, arthroscope, or cystoscope, preferably the cannula used during the discectomy procedure.
  • the implantable device is not compressed and delivered into the annulus opening by a trocar, cannula, or catheter with assisted visualization through an endoscopic intrument such as a laproscope, arthroscope, or cystoscope, preferably the cannula used during the discectomy procedure.
  • the device can be secured into the opening by at least the following two mechanisms: first, the outwardly resilient nature of the reticulated solid phase can provide a mechanical means for preventing migration; and, second, the reticulated solid phase can serve as a scaffold to support fibrocartilage growth into the interconnected void phase of the elastomeric matrix. Additional securing may be obtained by the use of anchors, sutures or biological glues and adhesives, as known to those in the art.
  • the closure device can support fibrocartilage ingrowth into the elastomeric matrix of the implantable device. Once released at the site, the reticulated elastomeric matrix expands resiliently to about its original, relaxed size and shape subject, of course, to its compression set limitation and any desired flexing, draping or other conformation to the site anatomy that the implantable device may adopt.
  • cellular entities such as fibroblasts and tissues can invade and grow into the reticulated elastomeric matrix.
  • ingrowth can extend into the interior pores and interstices of the inserted reticulated elastomeric matrix.
  • the elastomeric matrix can become substantially filled with proliferating cellular ingrowth that provides a mass that can occupy the site or the void spaces in it.
  • tissue ingrowth possible include, but are not limited to, fibrous tissues and endothelial tissues.
  • the implantable device or device system causes cellular ingrowth and proliferation throughout the site, throughout the site boundary, or through some of the exposed surfaces, thereby sealing the site. Over time, this induced fibrovascular entity resulting from tissue ingrowth can cause the implantable device to be incorporated into the conduit. Tissue ingrowth can lead to very effective resistance to migration of the implantable device over time. It may also prevent recanalization of the conduit. In another embodiment, over the course of time, for example, for 2 weeks to 3 months to 1 year, the implanted reticulated elastomeric matrix becomes completely filled and/or encapsulated by tissue, fibrous tissue, scar tissue or the like.
  • the properties of the reticulated elastomeric matrix can be engineered to match the application by, e.g., controlling the amount of crosslinking, amount of crystallinity, chemical composition, chemical type of the solvent or solvent blend (when a solvent is used in processing), annealing conditions, curing conditions, and degree of reticulation.
  • the reticulated elastomeric matrix maintains its physical characteristics and performance in vivo over long periods of time. Thus, it does not initiate undesirable tissue response as is observed for biodegradable implants when they break down and degrade.
  • the high void content and degree of reticulation of the reticulated elastomeric matrix allows tissue ingrowth and proliferation of cells within the matrix.
  • the ingrown tissue and/or proliferated cells occupy from about 51% to about 99% of the volume of interconnected void phase of the original implantable device, thereby providing functionality, such as load bearing capability, of the original tissue that is being repaired or replaced.
  • Aromatic isocyanates RUBINATE 9258 (from Huntsman; comprising a mixture of 4,4'-MDI and 2,4'-MDI), were used as the isocyanate component.
  • RUBINATE 9258 contains about 68% by weight 4,4'-MDI, about 32% by weight 2,4'- MDI and has an isocyanate functionality of about 2.33 and is a liquid at at 25°C.
  • a polyol - 1,6-hexamethylene carbonate i.e., a diol, with a molecular weight of about 1,000 Daltons, was used as the polyol component and is a solid at 25°C.
  • Glycerol was the chain extender,and water was used as the blowing agent.
  • the blowing catalyst were tertiary amine 33% tri ethyl enediamine in dipropylene glycol (DABCO 33LV supplied by Air Products) and Niax-Al (supplied by Air Products).
  • a silicone-based surfactant was used (TEGOSTAB® BF 2370, supplied by Goldschmidt).
  • the cell-opener was ORTEGOL® 501 (supplied by Goldschmidt).
  • a viscosity depressant Propylene carbonate supplied by Sigma- Aldrich was also used. The proportions of the components that were used is given in the following table:
  • the polyol was liquefied at 70 °C in an air circulation oven, and was weighed into a polyethylene cup.
  • Viscosity depressant (propylene carbonate) was added to the polyol and mixed with a drill mixer equipped with a mixing shaft at 3100 m for 15 seconds (mix-1).
  • Surfactant (Tegostab BF-2370) was added to mix-1 and mixed for additional 15 seconds (mix-2).
  • Cell opener (Ortogel 501) was added to mix-2 and mixed for 15 seconds (mix-3).
  • Isocyanate (Rubinate 9258) was added to mix-3 and mixed for 60 ⁇ 10 seconds (system A).
  • System B Niax Al) and glycerine in a small plastic cup by using a tiny glass rod for 60 seconds.
  • System B was poured into System A as quickly as possible without spilling and with vigorous mixing with a drill mixer for 10 seconds and poured into cardboard box of 9 in. x 8 in. x 5 in., which is covered inside with aluminum foil.
  • the foaming profile was as follows: mixing time of 10 sec, cream time of 18 sec. and rise time of 75 sec.
  • the average pore diameter of the foam was between 150 and 300 ⁇ m.
  • Aromatic isocyanates RUBINATE 9258 (from Huntsman; comprising a mixture of 4,4'-MDI and 2,4'-MDI), were used as the isocyanate component.
  • RUBINATE 9258 contains about 68% by weight 4,4'-MDI, about 32% by weight 2,4'- MDI and has an isocyanate functionality of about 2.33 and is a liquid at at 25°C.
  • a polyol - 1,6-hexamethylene carbonate (Desmophen LS 2391, Bayer Polymers), i.e., a diol, with a molecular weight of about 2,000 Daltons, was used as the polyol component and is a solid at 25°C. Water was used as the blowing agent.
  • the blowing catalyst was the tertiary amine 33% triethylenediamine in dipropylene glycol (DABCO 33LV supplied by Air Products).
  • a silicone-based surfactant was used (TEGOSTAB® BF 2370, supplied by Goldschmidt).
  • the cell-opener was ORTEGOL® 501 (supplied by Goldschmidt).
  • a viscosity depressant (Propylene carbonate supplied by Sigma- Aldrich) was also used. The proportions of the components that were used is given the following table:
  • the polyol Desmophen LS 2391 was liquefied at 70 °C in an air circulation oven, and 150 gms of it was weighed into a polyethylene cup.
  • 8.7 g of viscosity depressant (propylene carbonate) was added to the polyol and mixed with a drill mixer equipped with a mixing shaft at 3100 ⁇ m for 15 seconds (mix-1).
  • 3.3 g of surfactant (Tegostab BF-2370) was added to mix-1 and mixed for additional 15 seconds (mix-2).
  • 0.75 g of cell opener (Ortogel 501) was added to mix-2 and mixed for 15 seconds (mix-3).
  • 80.9 g of isocyanate (Rubinate 9258) is added to mix-3 and mixed for 60 ⁇ 10 seconds (System A).
  • System B was poured into System A as quickly as possible without spilling and with vigorous mixing with a drill mixer for 10 seconds and poured into cardboard box of 9 in. x 8 in. x 5 in., which was covered inside with aluminum foil.
  • the foaming profile was as follows: mixing time of 10 sec, cream time of 18 sec. and rise time of 85 sec.
  • the foam was placed in the oven at 100 - 105°C for curing for 60minutes.
  • the foam is taken from the oven and cooled for 15 minutes at room temperature.
  • the skin is cut with the band saw, and the foamwais pressed by hand from all sides to open the cell windows.
  • the foam was put back in an air-circulation oven for postcuring at 100° - 105°C for additional 5 hours.
  • the average pore diameter of the foam was between 150 and 450 ⁇ m.
  • Compressive strengths of the foam were measured with specimens measuring 50 mm x 50 mm x 25 mm. The tests were conducted using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 10 mm/min (0.4 inches /min). The compressive strength at 50% was about 12 + 3 psi. The compression set after subjecting the sample to 50 % compression for 22 hours at 40 °C and releasing the stress was 2 %.
  • Tear resistance strength of the foam was measured with specimens measuring approximately 152 mm x 25 mm x 12.7 mm. A 40 mm cut was made on one side of each specimen. The tear strength was measured using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 500 mm/min (19.6 inches/minute). The tear strength was determined to be about 2.9 + 0. libs/inch.
  • Extrusion Porosimeter manufactured by Porous Materials, Inc. (Ithaca, NY).
  • a wetting fluid having a surface tension of 19 dynes/cm and loaded in a sample chamber with a 27 micron diameter pore membrane being placed under the sample .
  • the pressure of air in the chamber space above the wetted sample is increased slowly so that the liquid is extruded from the pores of the sample.
  • the contact angle is taken to be zero and the wetting liquid that spontaneously fills the pore of the test sample also spontaneously fill the pores of the membranes when the former is emptied under pressure with larger pores emptying out at lower pressures and smaller pores emptying out at higher pressure.
  • the displaced liquid passes through the membrane and its volume measured.
  • the gas pressure gives the pore diameter and the volume of the displaced liquid gives the pore volume or the intrusion volume accessible to the low surface tension liquid.
  • the liquid intrusion volume for the foam is 4 cc/gm and permeability of water through the foam is 1 lit/min/psi/sq cm.
  • Post reticulation compressive strengths of the foam were measured with specimens measuring 50 mm x 50 mm x 25 mm. The tests were conducted using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 10 mm/min (0.4 inches /min). The compressive strength at 50% was about 6.5 psi.
  • RUBINATE 9258 (from Huntsman) was used as the isocyanate component.
  • a diol, poly(l,6-hexanecarbonate)diol (POLY-CD CD220 from Arch Chemicals) with a molecular weight of about 2,000 Daltons was used as the polyol component and was a solid at 25°C. Distilled water was used as the blowing agent.
  • the blowing catalyst used was the tertiary amine triethylenediamine (33% in dipropylene glycol; DABCO 33LV from Air Products).
  • a silicone-based surfactant was used (TEGOSTAB® BF 2370 from Goldschmidt).
  • a cell-opener was used (ORTEGOL® 501 from Goldschmidt).
  • the viscosity modifier propylene carbonate was present to reduce the viscosity. The proportions of the components that were used are set forth in the following table: Table 3
  • the polyol component was liquefied at 70°C in a circulating-air oven, and 100 g thereof was weighed out into a polyethylene cup. 5.8 g of viscosity modifier was added to the polyol component to reduce the viscosity, and the ingredients were mixed at 3100 ⁇ m for 15 seconds with the mixing shaft of a drill mixer to form "Mix-1". 0.66 g of surfactant was added to Mix-1, and the ingredients were mixed as described above for 15 seconds to form "Mix-2". Thereafter, 1.00 g of cell opener was added to Mix-2, and the ingredients were mixed as described above for 15 seconds to form "Mix-3". 47.25 g of isocyanate component were added to Mix- 3, and the ingredients were mixed for 60 ⁇ 10 seconds to form "System A”.
  • System B was poured into System A as quickly as possible while avoiding spillage.
  • the ingredients were mixed vigorously with the drill mixer as described above for 10 seconds and then poured into a 22.9 cm x 20.3 cm x 12.7 cm (9 in. x 8 in. x 5 in.) cardboard box with its inside surfaces covered by aluminum foil.
  • the foaming profile was as follows: 10 seconds mixing time, 17 seconds cream time, and 85 seconds rise time.
  • the foam was placed into a circulating-air oven maintained at 100-105°C for curing for from about 55 to about 60 minutes. Then, the foam was removed from the oven and cooled for 15 minutes at about 25°C. The skin was removed from each side using a band saw. Thereafter, hand pressure was applied to each side of the foam to open the cell windows. The foam was replaced into the circulating-air oven and postcured at 100-105°C for an additional four hours.
  • the average pore diameter of the foam was greater than about 275 ⁇ m.
  • the measurement of the liquid flow through the material is measured in the following way using a iquid permeability apparatus or Liquid Permeaeter (Porous Materials, Inc., Ithaca, NY).
  • the foam sample was 8.5 mm in thickness and covered a hole 6.6 mm in diameter in the center of a metal plate that was placed at the bottom of the Liquid Permeaeter filled with water. Thereafter, the air pressure above the sample was increased slowly to extrude the liquid from the sample and the permeability of water through the foam was determined to be 0.11 L/min/psi/cm .
  • Reticulation of the foam described in Example 3 was carried out by the following procedure: A block of foam measuring approximately 15.25 cm x 15.25 cm x 7.6 cm (6 in. x 6 in. x 3 in.) was placed into a pressure chamber, the doors of the chamber were closed, and an airtight seal to the surrounding atmosphere was maintained. The pressure within the chamber was reduced to below about 100 millitorr by evacuation for at least about two minutes to remove substantially all of the air in the foam. A mixture of hydrogen and oxygen gas, present at a ratio sufficient to support combustion, was charged into the chamber over a period of at least about three minutes. The gas in the chamber was then ignited by a spark plug. The ignition exploded the gas mixture within the foam. The explosion was believed to have at least partially removed many of the cell walls between adjoining pores, thereby forming a reticulated elastomeric matrix structure.
  • the average pore diameter of the reticulated elastomeric matrix was greater than about 275 ⁇ m.
  • a scanning electron micrograph image of the reticulated elastomeric matrix of this example (not shown here) demonstrated, e.g., the communication and interconnectivity of pores therein.
  • a comparable foam with little to no reticulation typically has t-90 values of greater than about 60-90 seconds after 10 minutes of compression.
  • the measurement of the liquid flow through the material was measured in the following way using a Liquid permeability apparatus or Liquid Permeaeter (Porous Materials, Inc., Ithaca, NY).
  • the foam samples were between 7.0 and 7.7 mm in thickness and covered a hole 8.2 mm in diameter in the center of a metal plate that was placed at the bottom of the Liquid Permeaeter filled with water.
  • the water was allowed to extrude through the sample under gravity and the permeability of water through the foam was determined to be 180 L/min/psi/cm 2 in the direction of foam nse and 160 L/min/psi/cm in the pe ⁇ endicular to foam rise.
  • reaction profile is as follows:
  • the average pore diameter of the foam was greater than about 225 ⁇ m.
  • Tensile tests were conducted on samples that were cut pe ⁇ endicular to the direction of foam rise.
  • the dog-bone shaped tensile specimens were cut from blocks of foam. Each test specimen measured about 12.5 mm thick, about 25.4 mm wide, and about 140 mm long; the gage length of each specimen was 35 mm and the gage width of each specimen was 6.5 mm.
  • Tensile properties (tensile strength and elongation at break) were measured using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 500 mm/min (19.6 inches/minute). The average tensile strength pe ⁇ endicular to the direction of foam rise was determined as 37.8 psi (26,500 kg/m 2 ). The elongation to break pe ⁇ endicular to the direction of foam rise was determined to be 141%.
  • Reticulation of the foam described above was carried out by the following procedure: A block of foam measuring approximately 15.25 cm x 15.25 cm x 7.6 cm (6 in. x 6 in. x 3 in.) was placed into a pressure chamber, the doors of the chamber were closed, and an airtight seal to the surrounding atmosphere was maintained. The pressure within the chamber was reduced to below about 100 millitorr by evacuation for at least about two minutes to remove substantially all of the air in the foam. A mixture of hydrogen and oxygen gas, present at a ratio sufficient to support combustion, was charged into the chamber over a period of at least about three minutes. The gas in the chamber was then ignited by a spark plug. The ignition exploded the gas mixture within the foam. The explosion was believed to have at least partially removed many of the cell walls between adjoining pores, thereby forming a reticulated elastomeric matrix structure.
  • a scanning electron micrograph image of the reticulated elastomeric matrix of this example (not shown here) demonstrated, e.g., the communication and interconnectivity of pores therein.
  • the density of the reticulated foam was determined as described above and a value of 4.00 lbs/ft (0.0656 g/cc) was obtained.
  • This model is considered a standard model to evaluate the vertebral disc. See, for example, H.S. An et al., "Biological Repair of Intervertebral Disc,” Spine, 2003 Aug. 1; 28 (15 Suppl.); D.G. Anderson et al., "Comparative Gene Expression Profiling of Normal and degenerative Discs: Analysis of a Rabbit Annular Laceration Mode," Spine. 2002 Jun 15; 27(12): 1291-96; and M.W.
  • the ARDX implant was well integrated with good tissue in-growth, as is shown in the micrograph (No2L45 SO stain lOOx) of Fig. 19 and the closeup view in Fig. 20, where the implant 130 abuts nucleus 132 adjacent to annulus 134. Annulus 134 is in turn adjacent to vertebral end plate 136. In the detail shown in Fig. 20 new tissue growth 138 can be seen. A strut or projection 140 from implant 130 can be seen. The early regeneration of matrix secretion and organized collagen fibers preserved the disc space and prevented degeneration when compared to control samples.

Abstract

The invention relates to the repair of spinal annular defects. An appartatus comprises a scaffold comprised of a biodurable, resiliently compressible, elastomeric reticulated composition to obliterate spinal/vertabral connective tissue defects, to obliterate spinal-annular nuclear tissue defects, and for spinal annulo­nucleoplasty regeneration. The apparatus comprises an at least partially cylindrical member.

Description

REPAIR OF SPINAL ANNULAR DEFECTS AND ANNULO-NUCLEOPLASTY REGENERATION
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is based upon co-pending, commonly assigned U.S.
Patent Application Serial No. 10/746,563, filed December 24, 2003, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the repair of spinal annular defects. More particularly, this invention relates to a method and composition for the repair of spinal annular defects and annulo-nucleoplasty regeneration.
BACKGROUND OF THE INVENTION
[0003] Back pain is one of the most common and often debilitating conditions affecting millions of people. Some forms of back pain are muscular in nature and may be simply treated by rest, posture adjustments and painkillers. For example, lower back pain (LBP) is a very common condition that may be caused by unusual exertion or injury. Unusual exertion such as heavy lifting or strenuous exercise may result in back pain due to a pulled muscle, a sprained muscle, a sprained ligament, a muscle spasm, or a combination thereof. An injury caused by falling down or a blow to the back may cause bruising. These forms of back pain are typically non-chronic and may be self-treated and cured in a few days or weeks.
[0004] Other types of non-chronic back pain may be treated by improvements in physical condition, posture and/or work conditions. Being pregnant or otherwise being significantly overweight may cause LBP. A mattress that does not provide adequate support may cause back pain in the morning. Working in an environment lacking good ergonomic design may also cause back pain. In these instances, the back pain may be cured by eliminating the underlying cause. Whether it is excess body weight, a bad mattress, or a bad office chair, these forms of back pain are readily treated.
[0005] It is estimated that over ten million people in the United States alone suffer from persistent back pain. Approximately half of those suffering from persistent back pain are afflicted with chronic disabling pain, which seriously compromises a person's quality of life and is the second most common cause of worker absenteeism. Further, the cost of treating chronic back pain is very high, even though the majority of sufferers do not receive treatment due to health risks, limited treatment options, and/or inadequate therapeutic results. Thus, chronic back pain has a significantly adverse effect on a person's quality of life, on industrial productivity, and on heath care expenditures.
[0006] Some forms of back pain are the result of disorders directly related to the spinal column, which disorders are not readily treated. While some pain-causing spinal disorders may be due to facet joint degradation or degradation of individual vertebral masses, disorders associated with the intervertebral discs are predominantly affiliated with chronic back pain (referred to as disc related pain). The exact origin of disc related pain is often uncertain, and although some episodes of disc related pain may be eased with conservative treatments such as bed-rest and physical therapy, future episodes of disc related pain are likely to occur periodically.
[0007] There are a number of suspected causes of disc related pain, and in any given patient, one or more of these causes may be present. However, the ability to accurately diagnose a specific cause or locus of pain is currently difficult. Because of this uncertainty, many of the causes of disc related pain are often lumped together and referred to as degenerative disc disease (DDD).
[0008] A commonly suspected source of disc related pain is physical impingement of the nerve roots emanating from the spinal cord. Such nerve root impingement may have a number of different underlying causes, but nerve root impingement generally results from either a disc protrusion or a narrowing of the intervertebral foramina (which surround the nerve roots).
[0009] As a person ages, their intervertebral discs become progressively dehydrated and malnourished. Due to the combination of aging and continued stressing, the discs begin to degenerate. With continued degeneration, or an excessive stressing event, or both, the annulus fibrosus of a disc may tear, forming one or more fissures (also referred to as fractures). Such fissures may progress to larger tears, which allow the gelatinous material of the nucleus pulposus to flow out of the nucleus and into the outer aspects of the annulus. The flow of the nucleus pulposus to the outer aspects of the annulus may cause a localized bulge or herniation.
[0010] When herniation of the nucleus/annulus occurs in the posterior portions of the disc, nerve roots may be directly and physically impinged by the bulge. In more extreme or progressed instances of annular tears, the nuclear material may escape, additionally causing chemical irritation of the nerve roots. Dependent upon the cause and nature of the disc protrusion, the condition may be referred to as a disc stenosis, a disc bulge, a herniated disc, a prolapsed disc, a ruptured disc, or, if the protrusion separates from the disc, a sequestered disc.
[0011] Dehydration and progressive degeneration of a disc also leads to thinning of the disc. As the thickness of the disc reduces, the intervertebral foraminae become narrow. Because the nerve roots pass through the intervertebral foraminae, such narrowing may mechanically entrap the nerve roots. This entrapment can cause direct mechanical compression or it may tether the roots, causing excessive tension to the roots during body movement.
[0012] Nerve root impingement most often occurs in the lumbar region of the spinal column since the lumbar discs bear significant vertical loads relative to discs in other regions of the spine. In addition, disc protrusions in the lumbar region typically occur posteriorly because the annulus fibrosus is radially thinner on the posterior side than on the anterior side and because normal posture places more compression on the posterior side. Posterior protrusions are particularly problematic since the nerve roots are posteriorly positioned relative to the intervertebral discs. Lower back pain due to nerve root irritation not only results in strong pain in the region of the back adjacent the disc, but may also cause sciatica, or pain radiating down one or both legs. Such pain may also be aggravated by such subtle movements as coughing, bending over, or remaining in a sitting position for an extended period of time.
[0013] Another suspected source of disc related back pain is damage and irritation to the small nerve endings which lie in close proximity to or just within the outer aspects of the annulus of the discs. Again, as the disc degenerates and is subjected to stressing events, the annulus fibrosus may be damaged and form fissures. While these fissures can lead to pain via the mechanisms described above, they may also lead to pain emanating from the small nerve endings in or near the annulus, due to mechanical or chemical irritation at the sites of the fissures. The fissures may continue to irritate the small nerve endings, as their presence causes the disc to become structurally weaker, allowing for more localized straining around the fissures. This results in more relative motion of edges of the fissures, increasing mechanical irritation. Because it is believed that these fissures have only limited healing ability once formed, such irritation may only become progressively worse.
[0014] A common treatment for a disc herniation is a discectomy, a procedure wherein the protruding portion of the degenerated disc is surgically removed. However, discectomy procedures have an inherent risk since the portion of the disc to be removed is immediately adjacent the nerve root, and any damage to the nerve root is clearly undesirable. Furthermore, discectomy procedures are not always successful long term because scar tissue may form and/or additional disc material may subsequently protrude or reherniate from the disc space as the disc deteriorates further. The recurrence of a disc herniation may necessitate a repeat discectomy procedure, along with its inherent clinical risks and less than perfect long term success rate. Thus, a discectomy procedure, at least as a stand-alone procedure, is clearly not an optimal solution.
[0015] Discectomy is also not a viable solution for DDD when no disc/nuclear herniation is involved. As mentioned above, DDD causes the entire disc to degenerate, narrowing the intervertebral space and shifting the load to the facet joints. If the facet joints carry a substantial load, the joints may degrade over time and be a different cause of back pain. Furthermore, the narrowed disc space can result in the intervertebral foramina surrounding the nerve roots directly impinging on one or more nerve roots. Such nerve impingement is very painful and cannot be corrected by a discectomy procedure. Furthermore, a discectomy does not address pain caused by annular fissures or post-surgical defects, which may cause direct mechanical irritation to the small nerve endings near or just within the outer aspect of the annulus of a damaged disc.
[0016] As a result of the limitations of a discetomy, spinal fusion, particularly with the assistance of interbody fusion cages, has become a preferred secondary procedure, and in some instances, a preferred primary procedure. Spinal fusion involves permanently fusing or fixing adjacent vertebrae. Hardware in the form of bars, plates, screws, and cages may be utilized in combination with bone graft material to fuse adjacent vertebrae. Spinal fusion may be performed as a stand-alone procedure, or it may be performed in combination with a discectomy procedure. By placement of the adjacent vertebrae in their normal position and fixing them in place, relative movement therebetween may be significantly reduced and the disc space may be restored to its normal condition. Thus, theoretically, aggravation caused by relative movement between adjacent vertebrae may be reduced if not eliminated.
[0017] The success rate of spinal fusion procedures is certainly less than perfect for a number of different reasons, none of which are well understood. In addition, even if spinal fusion procedures are initially successful, they may cause accelerated degeneration of adjacent discs since the adjacent discs must accommodate a greater degree of motion. The degeneration of adjacent discs simply leads to the same problem at a different anatomical location, which is clearly not an optimal solution. Furthermore, spinal fusion procedures are invasive to the disc, risk nerve damage, and, dependent upon the procedural approach, are technically complicated (endoscopic anterior approach), invasive to the bowel (surgical anterior approach), and/or invasive to the musculature of the back (surgical posterior approach).
[0018] Another procedure that has been less than clinically successful is total disc replacement with a prosthetic disc. This procedure is also very invasive to the disc, and, dependent upon the procedural approach, either invasive to the bowel (surgical anterior approach) or invasive to the musculature of the back (surgical posterior approach). In addition, the procedure may actually complicate matters by creating instability in the spine, and the long-term mechanical reliability of prosthetic discs has yet to be demonstrated.
[0019] Many other medical procedures have been proposed to solve the problems associated with degenerative discs or disc protrusions. However, many of the proposed procedures have not been clinically proven, and some of the allegedly beneficial procedures have controversial clinical data. There is a substantial need for improvements in the treatment of spinal disorders, particularly in the treatment of disc related pain associated with a damaged or otherwise unhealthy disc, specifically the repair of disc defects or annulo-nucleoplasty regeneration.
OBJECTS OF THE INVENTION
[0020] It is an object of the invention to provide a method for the repair of spinal annular defects.
[0021] It is also an object of the invention to provide a composition for the repair of spinal annular defects.
[0022] It is a further object of the invention to provide a method and composition for annulo-nucleoplasty regeneration.
[0023] It is a yet further object of the invention to provide a method of repairing spinal annular defects where a polymeric or metallic substantially cylindrical member is inserted into the spinal annulus.
[0024] It is a yet further object of the invention where a polymeric or metallic substantially cylindrical member is inserted into the spinal annulus to promote annulo- nucleoplasty regeneration.
[0025] These and other objects of the invention will become more apparent from the discussion below.
SUMMARY OF THE INVENTION
[0026] The invention described and claimed below relates to the repair of spinal annular defects. According to the invention, a substantially cylindrical member is inserted through an opening in the spinal annulus to the extent that the distal portion of the substantially cylindrical member extends into the spinal nuclear defect. The substantially cylindrical member is comprised of a biodurable reticulated elastomeric material that expands to seal the opening. Optionally the cylindrical member can comprise one or more metal or polymer components that open or re-align after insertion to assist in maintaining the sealing ability of the substantially cylindrical member.
[0027] The present invention addresses this need by providing improved devices and methods for the treatment of spinal disorders. The improved devices and methods of the present invention specifically address disc related pain, progressive disc degeneration, and/or reherniation of nuclear material, particularly in the lumbar region, but may have other significant applications not specifically mentioned herein. For purposes of illustration only, and without limitation, the present invention is discussed in detail with reference to the treatment of damaged discs in the lumbar region of the adult human spinal column. Optionally, the device may be used for damaged discs in the thoracic and cervical region of the adult human spinal column
[0028] As will become apparent from the detailed description below, the improved devices and methods of the present invention reduce, if not eliminate, back pain while maintaining near normal anatomical motion. Specifically, the present invention provides an annular repair and/or annulo-nucleoplasty regeneration mechanism, while permitting relative movement of the vertebrae adjacent the damaged disc. The devices of the present invention are particularly well suited for minimally invasive methods of implantation.
[0029] The devices of the present invention provide three distinct functions.
First, the reinforcement devices mechanically stabilize and strengthen the annular portion of the spinal disc to minimize, if not eliminate, chronic irritation of local nerve roots and nerve endings adjacent to the periphery of the disc annulus. Second, the devices radially and/or circumferentially conform to the surgical and/or pathologic present fissures, fractures,and tears of the disc, thereby preventing the prolapse of extra spinal disc tissue such as nerves and muscle, thereby potentially facilitating healing. And third, the devices may be used to stabilize the nuclear portion of the disc after a discectomy procedure to reduce the need for a subsequent operation or treatment due to reherniation.
[0030] In an exemplary embodiment, the present invention provides disc reinforcement in which a device of the invention is implanted into the annulus of an intervertebral disc. The implantation method may be performed by a percutaneous procedure or by a minimally invasive surgical procedure or by the use of trocar, cannula, or through an endoscopic instrument such as an arthroscope, laproscope, or cystoscope. The present invention provides a number or tools to facilitate percutaneous implantation. One or more reinforcement members may be implanted, for example, posteriorly, anteriorly, and/or laterally, and may be oriented circumferentially or radially. As such, the reinforcement members may be used to stabilize the annulus and/or a portion of the annulus so as to reduce recurrent bulges and/or obliterate annular tracts.
[0031] The implant device may be sized to pass through a trocar and/or may have a tubular cross-section to facilitate advancement over a stylet. The implant device preferably includes a body portion sized to fit in an opening in the annulus and an anchor for engaging the annulus and limiting relative movement therebetween. The anchor may be disposed at the distal portions of the implant body, or may extend over the entire length of the body. The anchoring part to engage in the annulus can be shaped as expanded cylinder, spherical, mushroom-shaped, etc. The anchor portion may comprise threads or wings which may have a variable pitch to facilitate compression of the annulus during implantation. The implant device may incorporate chemical and/or biological agents. The implant device may comprise a biocompatible metal such as stainless steel or a super elastic (nickel titanium) alloy. Alternatively, the implant device may comprise a polymer or a reinforced polymeric structure. As a further alternative, the implant device may comprise a bioabsorbable material.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Fig. 1 illustrates a superior (top) view of a healthy disc;
[0033] Figs. 2 and 3 each illustrate a superior (top) view of a degenerated disc;
[0034] Fig. 4 is a partially cross-sectional view of an embodiment of a substantially cylindrical member according to the invention;
[0035] Fig. 5 is a partially cross-sectional view of an embodiment of an at least partially cylindrical member according to the invention;
[0036] Fig. 6 is a partially cross-sectional view of a further embodiment of another at least partially cylindrical member according to the invention; [0037] Fig. 7 is a cross-sectional view across the line 7-7 of the embodiment of the invention shown in Fig. 6;
[0038] Fig. 8 is a partially cross-sectional view of another embodiment of the invention in position in the annulus;
[0039] Fig. 9 is a partially cross-sectional view of a variation of the embodiment shown in Fig. 8;
[0040] Fig. 10 is a lateral view of an embodiment of the invention having radial projections;
[0041] Fig. 11 is a cross-sectional view along the line 11-11 in Fig. 10;
[0042] Figs. 12 to 14 represent cross-sectional views of delivery of the embodiment of the invention set forth in Figs. 10 and 11;
[0043] Figs. 15 and 16 are each a micrograph of material prepared according to
Example 1;
[0044] Figs. 17 and 18 are each a micrograph of material prepared according to
Example 2;
[0045] Fig. 19 is a micrograph of an embodiment of the invention four weeks after placement; and
[0046] Fig. 20 is a detailed view of a section of the micrograph in Fig. 19. DETAILED DESCRIPTION OF THE INVENTION
[0047] The invention can perhaps be better appreciated from the drawings.
Figure 1 is a simplified representation of a spinal disc 10 that comprises an annulus fibrosis or annulus 12 surrounding a nucleus pulposus or nucleus 14. The posterior annulus 16 is generally thinner than the anterior annulus 18, which may account for the higher incidence of posterior disc protrusions.
[0048] A common theory is that each intervertebral disc 10 forms one support point and the facet joints of the spinal column (not shown) form two support points of what may be characterized as a three-point support structure between adjacent vertebrae 20. However, in the lumbar region, the facet joints are substantially vertical, leaving the disc 10 to carry the vast majority of the load. As between the annulus 12 and the nucleus 14 of the disc 10, it is commonly believed that the nucleus 14 bears the majority of the load. This belief is based on the theory that the disc 10 behaves much like a balloon or tire and the nucleus 14 bears the somewhat of the majority of the load wherein the annulus 12 merely serves to contain the pressurized nucleus 14 and supports a somewhat smaller proportion of the total load. The annulus 12 comprises 60% of the total disc 10 cross-sectional area and is made of 40-60% organized collagen in the form of a laminated structure. By contrast, the nucleus 14 only comprises 40% of the total disc 10 cross-section and is made of 18-30% collagen in the form of a relatively homogenous gel. In reality, both the nucleus 14 and annulus 12 play important and critical roles in the load bearing mechanism of the disc 10.
[0049] The intervertebral disc 10 becomes progressively dehydrated and malnourished with age, as shown in Figures 2 and 3. In combination with continued stressing from load bearing and/or resisting outward pressure from the nucleus, the disc begins to degenerate. With continued degeneration, or an excessive stressing event, the annulus of the disc may tear, forming one or more radial fissures 23 or tracts 24 or circumferential fissures 26, which may progress to larger tears. Larger tears may allow the gelatinous material of the nucleus pulposus 14 to flow out of the nucleus through a fissure 24 and into the outer aspects of the annulus 12. Nuclear material that escapes through an advanced tear may cause further mechanical irritation and additionally cause chemical irritation of a nerve root.
[0050] The flow of the nucleus 14 to the outer aspects of the annulus 12 may cause a localized bulge 28. A posterior bulge 28 may result in direct impingement of a nerve root (not shown).
[0051] A nerve root may also be compressed or tethered by a narrowing of the intervertebral foraminae, resulting from a loss in disc height caused by sustained degeneration of the disc 10. Small nerve endings (not shown) in or near the perimeter of the annulus 12 may also be mechanically or chemically irritated at the sites of the fissures 24, 26. In all cases, degeneration of the disc eventually leads to disc related pain of some origin.
[0052] In an embodiment of the invention shown in Figure 4, a partially cylindrical device 30 comprises a cylindrical portion 32 and an attached expanded, at least partially spherical portion 34. Portion 34 may be entirely spherical or it may optionally have a substantially flat surface 36 bordered by edge 38. Optionally, the attached expanded portion 34 may be entirely cylindrical. In one embodiment, the attached expanded portion 34 may be any other suitable shape that has at least one transverse dimension larger than the diameter of the cylindrical portion 32. Portions 32 and 34 are both solid, although optionally each may contain a longitudinal lumen (not shown) to facilitate threading member 30 over a wire or stylet (not shown). Also, device 30 may optionally contain a retainer or anchor 40, comprising a longitudinal member or shaft 42 and collapsible/expandable spokes or radial members 44. Preferably the proximal end of each member 44 has a tissue fixation member 46 that contacts the inner portion of the annulus when members 44 expand, to hold or fix device 30 in position. [0053] The umbrella anchor 40 is has three or four, preferably four, members
44 and a central shaft 42 as shown in Fig. 4. The members 44 can be partially collapsed within a trocar or endoscope during delivery and contact the inner portion of the annulus when they expand after delivery to hold or fix elastomeric reticulated device 30 or device 48 in position.
[0054] Anchor 40 can have a range of dimensions depending on specific applications. The range of dimensions of the different parts are as follows: the angle between central shaft 42 and spokes 44 is from about 15° to about 60°, when the spokes are fully opened. The length of each spoke 44 ranges from about 3 mm to about 10 mm, preferably from about 4 mm to about 7 mm. The cross-section of spokes 44 can be cylindrical, elliptical, square, rectangular, or any other polygonal shape. The diameter of spokes' 44 cross-section or one side of the spoke 44 cross- section ranges from about 2 mm to about 5 mm. The end-to-end distance of the spokes 44 when the spokes 44 are fully opened ranges from about 6 mm to about 15 mm. The cross-section of central shaft 42 can be cylindrical, elliptical, square, rectangular, or any other polygonal shape with the diameter of the central shaft 42 cross-section or one side of the of the central shaft cross-section ranging from about 2 mm to about 5 mm. The overall length of central shaft 42 of the umbrella anchor (including the head and the stem) can range from about 8 mm to about 15 mm.
[0055] Spokes 44 can be regularly spaced from each other or they could be
"paired" as cross-pieces. For example, adjacent spokes 44 could be separated by 60° and 120° to form an "X" pattern. Also, in another embodiment, shaft 42 could extend in the direction from spokes 44 opposite to the direction shown in Fig. 4. In yet another embodiment spokes 44 may be arcuate, pointing in the proximal direction, rather than straight as shown in Fig. 4.
[0056] Anchor 40 is comprised of a physiologically acceptable metal such as nitinol or stainless steel and, after compression, expands to form an umbrella-like shape. In another embodiment, anchor 40 preferably is comprised of a degradable or non-degradable polymer such as polypropylene and, after compression, expands to form an umbrella-like shape.
[0057] In the embodiment of the invention shown in Figure 5, a partially cylindrical device 48 comprises a cylindrical portion 50 and a goblet- or mushroom- shaped distal portion 52. In one embodiment, the mushroom-shaped distal portion 52. can also be cylindrical in shape. In another embodiment, the mushroom-shaped distal portion 52 can also be partially spherical in shape or any other suitable shape that has at least one transverse dimension larger than the diameter of the cylindrical portion 50. In general, the diameter or the largest transverse dimensions of the distal portion 52 is greater than the diameter of the cylindrical portion 50. Optionally, cylindrical portion 50 has ridges or projections 54 that aid in fixedly positioning device 48 in an annular fissure, especially at the inner portion of the fissure. Optionally device 48 has a lumen 56 to facilitate positioning device 48 over a stylet or wire (not shown).
[0058] The embodiment of the invention shown in Figures 6 and 7 is an at least partially cylindrical member 64 that comprises a cylindrical member 66 and a distal semi-spherical portion 68 that comprises distally extending projections 70. Preferably projections 70 comprise spaghetti-like shapes suitable for cell propagation.
[0059] Fig. 8 represents an embodiment of the invention where anchor 74 has one or more crossmembers 76 that have projections 78, intended to engage annular tissue 80. Crossmember 76 can have integral projections 78, so that the crossmember 76 and a projection 78 are inserted, preferably at an angle, into anchor 74 prior to delivery, where preferably projection 78 collapses slightly to permit insertion. Alternatively, projections 78 are attached by glue, "fit", or other suitable fixtation after crossmember 76 is positioned within anchor 74. As is shown in the uncompressed anchor 82 depicted in Fig. 9, there could be two or more sets of crossmembers 84 and projections 86. [0060] In Fig. 10 an anchor 94 is shown in uncompressed condition with a mushroom-shaped distal tip portion 96 and a cylindrical portion 98. Cylindrical portion 98 has radially-extending projections or prongs 102. As shown in the cross- sectional view of Fig. 11, anchor 94 has six projections 102. However, there could be from 2 to as many as 16 or more projections 102, preferably from about 4 to 12. Optionally there could be projections 102 on more than one plane of cylindrical portion 98, preferably 2 or 3 planes altogether, such as proximal neck and/or mid-shaft and/or distal shaft.
[0061] Delivery of anchor 94 is shown in Figs. 12 to 14. Anchor 94 in a compressed state is preloaded into a rigid or substantially rigid tubular member 104. Projections 102 fold around cylindrical portion 98, and the distal portion 106 of a pushing rod or member 108 is positioned adjacent to the proximal surface 110 of cylindrical portion 98. The distal tip 114 of tubular member 104 is positioned in or adjacent to an opening 116 in annulus 120.
[0062] As shown in Figs. 13 and 14, pushing member 108 pushes anchor 94 distally so that anchor 92 fills and engages opening 116. Anchor distal portion 96 expends into the cavity 122 of annulus 120 and seals opening 116. Projections 102 are designed so that tubular member 104 can be rotated or twisted to cause projections 102 to expand into the tissue of annulus 120 to secure anchor 94 in position. When tubular member 104 is withdrawn from opening 116, the bottom portion 124 of cylindrical member 98 fills out the remainder of opening 116. It is within the scope of the invention that when anchor 92 is twisted or rotated in the opposite direction, projections 102 will disengage so that anchor 92 could be revived or repositioned. It is also within the scope of the invention that an anchor can be held, maintained, or retained in position by other retaining means, such as sutures, staples, clips, or the like.
[0063] The material for the attachment device can be degradable or non- degradable materials or fiber-reinforced composites using degradable or non- degradable materials. The list of non-degradable materials for attachment device include polypropylene, polyethylene, polyethylene terepthalate (PET), Nylon 6, Nylon 6-6, poly imide, polyether imide, PEEK, or their mixtures and copolymers thereof. Aditionally, the list of non-degradable materials for attachment devices includes Teflon, ceramics, stainless steel, platinum or nitinol. The list of degradable materials for attachment device include polymers such as polyglycolic acid ("PGA"), polylactic acid ("PLA"), polycaprolactic acid ("PCL"), poly-p-dioxanone ("PDO"), PGA/PLA copolymers, PGA/PCL copolymers, PGA/PDO copolymers, PLA/PCL copolymers, or their mixtures and copolymers thereof, PLA/PDO copolymers, PCL/PDO copolymers or combinations of any two or more of the foregoing.
[0064] The inventive implantable device is reticulated, i.e., comprises an interconnected network of pores and channels and voids that provides fluid permeability throughout the implantable device and permits cellular and tissue ingrowth and proliferation into the interior of the implantable device. The inventive implantable device is reticulated, i.e., comprises an interconnected and/or intercommunicating network of pores and channels and voids that provides fluid permeability throughout the implantable device and permits cellular and tissue ingrowth and proliferation into the interior of the implantable device. The inventive implantable device is reticulated, i.e., comprises an interconnected and/or intercommunicating network of pores and/or voids and/or channels that provides fluid permeability throughout the implantable device and permits cellular and tissue ingrowth and proliferation into the interior of the implantable device. The biodurable elastomeric matrix or material is considered to be reticulated because its microstructure or the interior structure comprises inter- connected and intercommunicating pores and/or voids bounded by configuration of the struts and intersections that constitute the solid structure. The continuous interconnected void phase is the principle feature of a reticulated structure. [0065] Preferred scaffold materials for the implants have a reticulated structure with sufficient and required liquid permeability and thus selected to permit blood, or other appropriate bodily fluid, and cells and tissues to access interior surfaces of the implants. This happens due to the presence of inter-connected and intercommunicating, reticulated open pores and or voids and/or channels that form fluid passageways or fluid permeability providing fluid access all through.
[0066] Preferred materials are at least partially hydrophobic reticulated, elastomeric polymeric matrix for fabricating implants according to the invention are flexible and resilient in recovery, so that the implants are also compressible materials enabling the implants to be compressed and, once the compressive force is released, to then recover to, or toward, substantially or fully to their original size and shape. For example, an implant can be compressed from a relaxed configuration or a size and shape to a compressed size and shape under ambient conditions, e.g., at 25°C to fit into the introducer instrument for insertion into the target orthopedic repair or regeneration site. Alternatively, an implant may be supplied to the medical practitioner performing the implantation operation, in a compressed configuration, for example, contained in a package, preferably a sterile package. The resiliency of the reticulated elastomeric matrix that is used to fabricate the implant causes it to recover to a working size and configuration in situ, at the implantation site, after being released from its compressed state within the introducer instrument. The working size and shape or configuration can be substantially similar to original size and shape after the in situ recovery. In one embodiment, the working size and shape or configuration can be the original size and shape after the in situ recovery. In another embodiment, the implant can be delivered in an uncompressed original size and shape by the introducer instrument.
[0067] Preferred scaffolds are reticulated elastomeric polymeric materials having sufficient structural integrity and durability to endure the intended biological environment, for the intended period of implantation. For structure and durability, at least partially hydrophobic polymeric scaffold materials are preferred although other materials may be employed if they meet the requirements described herein. Useful materials are preferably elastomeric in that they can be compressed and can resiliently recover to substantially or completely to the pre-compression state. In one embodiment, the implant can be delivered in an uncompressed original size and shape by the introducer instrument. In one embodiment once delivered to the target site, the material can stay anchored at the delivery site under compression with or without exerting significant stress to the neighboring tissues. Alternative reticulated polymeric materials with interconnected pores or networks of pores that permit biological fluids to have ready access throughout the interior of an implant may be employed, for example, woven or nonwoven fabrics or networked composites of microstructural elements of various forms.
[0068] A partially hydrophobic scaffold is preferably constructed of a material selected to be sufficiently biodurable, for the intended period of implantation that the implant will not lose its structural integrity during the implantation time in a biological environment. The biodurable elastomeric matrices forming the scaffold do not exhibit significant symptoms of breakdown, degradation, erosion or significant deterioration of mechanical properties relevant to their use when exposed to biological environments and/or bodily stresses for periods of time commensurate with the use of the implantable device. In one embodiment, the desired period of exposure is to be understood to be at least 29 days, preferably several weeks and most preferably 2 to 5 years or more. This measure is intended to avoid scaffold materials that may decompose or degrade into fragments, for example, fragments that could have undesirable effects such as causing an unwanted tissue response.
[0069] The void phase, preferably continuous and interconnected, of the reticulated polymeric matrix that is used to fabricate the implant of this invention may comprise as little as 50% by volume of the reticulated elastomeric matrix, referring to the volume provided by the interstitial spaces of reticulated elastomeric matrix before any optional interior pore surface coating or layering is applied. In one embodiment, the volume of void phase as just defined, is from about 70% to about 99% of the volume of reticulated elastomeric matrix. In another embodiment, the volume of void phase as just defined, is from about 70% to about 88% of the volume of reticulated elastomeric matrix. In another embodiment, the volume of void phase is from about 80% to about 88 % of the volume of reticulated elastomeric matrix. In another embodiment, the volume of void phase is from about 80% to about 98% of the volume of reticulated elastomeric matrix. In another embodiment, the volume of void phase is from about 90% to about 98% of the volume of reticulated elastomeric matrix.
[0070] As used herein, when a pore is spherical or substantially spherical, its largest transverse dimension is equivalent to the diameter of the pore. When a pore is non-spherical, for example, ellipsoidal or tetrahedral, its largest transverse dimension is equivalent to the greatest distance within the pore from one pore surface to another, e.g., the major axis length for an ellipsoidal pore or the length of the longest side for a tetrahedral pore. For those skilled in the art, one can routinely estimate the pore frequency from the average cell diameter in microns.
[0071] In one embodiment relating to orthopedic and spinal implant applications and the like, to encourage cellular ingrowth and proliferation and to provide adequate fluid permeability, the average diameter or other largest transverse dimension of pores is at least about 20 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 50 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 100 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 150 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 250 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than about 250 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than 250 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 275 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than about 275 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than 275 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is at least about 300 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than about 300 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is greater than 300 μm.
[0072] In another embodiment relating to orthopedic and spinal implant applications and the like, the average diameter or other largest transverse dimension of pores is not greater than about 900 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 750 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 500 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 400 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 300 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 200 μm. In another embodiment, the average diameter or other largest transverse dimension of pores is not greater than about 100 μm.
[0073] In one embodiment, the invention comprises an implantable device having sufficient resilient compressibility to be delivered by a "delivery-device", i.e., a device with a chamber for containing an reticulated elastomeric biodurable reticulated implantable device while it is delivered to the desired site then released at the site, e.g., using a trocar, cannula, or through an endoscopic instrument such as an arthroscope, laproscope, or cystoscope. In another embodiment, the thus-delivered elastomeric biodurable reticulated implantable device substantially regains its shape after delivery to a biological site and has adequate biodurability and biocompatibility characteristics to be suitable for long-term implantation.
[0074] One embodiment for use in the practice of the invention is a reticulated elastomeric implant which is sufficiently flexible and resilient, i.e., resiliently- compressible, to enable it to be initially compressed under ambient conditions, e.g., at 25°C, from a relaxed configuration to a first, compact configuration for delivery via a delivery-device, e.g., an endoscopic instrument such as an arthroscope, laproscope, cystoscope, or endoscope, or other suitable introducer instrument such as syringe, trocar, etc., for delivery in vitro and, thereafter, to expand to a second, working configuration in situ. In another embodiment, reticulated elastomeric implant is delivered in an uncompressed state via a delivery-device. Furthermore, in another embodiment, an reticulated elastomeric matrix has the herein described resilient- compressibility after being compressed about 5-95% of an original dimension (e.g., compressed about 19/20th - 1/20th of an original dimension). In another embodiment, an reticulated elastomeric matrix has the herein described resilient-compressibility after being compressed about 10-90% of an original dimension (e.g., compressed about 9/10th - 1/10th of an original dimension). As used herein, reticulated elastomeric implant has "resilient-compressibility", i.e., is "resiliently-compressible", when the second, working configuration, in vitro, is at least about 50% of the size of the relaxed configuration in at least one dimension. In another embodiment, the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vitro, is at least about 80% of the size of the relaxed configuration in at least one dimension. In another embodiment, the resilient- compressibility of reticulated elastomeric implant is such that the second, working configuration, in vitro, is at least about 90% of the size of the relaxed configuration in at least one dimension. In another embodiment, the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vitro, is at least about 97% of the size of the relaxed configuration in at least one dimension. [0075] In another embodiment, a reticulated elastomeric matrix has the herein described resilient-compressibility after being compressed about 5-95% of its original volume (e.g., compressed about 19/20th - l/20th of its original volume). In another embodiment, an reticulated elastomeric matrix has the herein described resilient- compressibility after being compressed about 10-90% of its original volume (e.g., compressed about 9/10th - l/10th of its original volume). As used herein, "volume" is the volume swept-out by the outermost three-dimensional contour of the reticulated elastomeric matrix. In another embodiment, the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, is at least about 40% of the volume occupied by the relaxed configuration. In another embodiment, the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, is at least about 75 % of the volume occupied by the relaxed configuration. In another embodiment, the resilient- compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, is at least about 90% of the volume occupied by the relaxed configuration. In another embodiment, the resilient-compressibility of reticulated elastomeric implant is such that the second, working configuration, in vivo, occupies at least about 97% of the volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
[0076] In another embodiment, a reticulated elastomeric matrix has the herein described resilient-compressibility is delivered to the target orthopedic or spinal implant but is not compressed during delivery to the target defect site. In another embodiment, after being delivered in an uncompressed state, the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 25% to at least about 40% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration. In another embodiment, after being delivered in an uncompressed state, the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 40% to at least about 80% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration. In another embodiment, after being delivered in an uncompressed state, the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 80% to at least about 95% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration. In another embodiment, after being delivered in an uncompressed state, the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies at least about 95% to at least about 98% of the of volume occupied by the reticulated elastomeric matrix in its relaxed configuration. In another embodiment, after being delivered in an uncompressed state, the resilient- compressibility of reticulated elastomeric implant is such that the second working configuration, in vivo, occupies the entire volume occupied by the reticulated elastomeric matrix in its relaxed configuration.
[0077] It is contemplated, in another embodiment, that upon implantation, before their pores become filled with biological fluids, bodily fluids and/or tissue, such implantable devices for orthopedic applications and the like do not entirely fill, cover or span the biological site in which they reside and that an individual implanted reticulated elastomeric matrix will, in many cases although not necessarily, have at least one dimension of no more than 75% of the biological site within the entrance thereto or over 75% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of no more than 95% of the biological site within the entrance thereto or over 95% of the damaged tissue that is being repaired or replaced.
[0078] In another embodiment, that upon implantation, before their pores become filled with biological fluids, bodily fluids and/or tissue, such implantable devices for orthopedic applications and the like substantially fill, cover or span the biological site in which they reside and an individual implanted reticulated elastomeric matrix will, in many cases, although not necessarily, have at least one dimension of no more than about 98% of the biological site within the entrance thereto or cover 98% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of no more than about 100% of the biological site within the entrance thereto or cover 100% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of no more than about 102% of the biological site within the entrance thereto or cover 102% of the damaged tissue that is being repaired or replaced.
[0079] In another embodiment, that upon implantation, before their pores become filled with biological fluids, bodily fluids and/or tissue, such implantable devices for orthopedic applications and the like overfill, cover or span the biological site in which they reside and an individual implanted reticulated elastomeric matrix will, in many cases, although not necessarily, have at least one dimension of more than about 125% of the biological site within the entrance thereto or cover 125% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 200% of the biological site within the entrance thereto or cover 200% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 150% of the biological site within the entrance thereto or cover 150% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 200% of the biological site within the entrance thereto or cover 200% of the damaged tissue that is being repaired or replaced. In another embodiment, an individual implanted reticulated elastomeric matrix as described above will have at least one dimension of more than about 300% of the biological site within the entrance thereto or cover 300% of the damaged tissue that is being repaired or replaced.
[0080] Without being bound by any particular theory, it is believed that the absence or substantial absence of cell walls in reticulated implants when compressed to very high degree will allow them to demonstrate resilient recovery in somewhat shorter time (such as recovery time of under 45 seconds when compressed to 75% of their relaxed configuration for 10 minutes and recovery time of under 60 seconds when compressed to 90% of their relaxed configuration for 10 minutes) as compared to un-reticulated porous foams.
[0081] In one embodiment, the reticulated elastomeric matrix has sufficient structural integrity to be self-supporting and free-standing in vitro. However, in another embodiment, the elastomeric matrix can be furnished with structural supports such as ribs or struts.
[0082] The reticulated elastomeric matrix useful according to the invention should have sufficient tensile and compressive properties such that it can withstand normal manual or mechanical handling during its intended application and during post-processing steps that may be required or desired without tearing, breaking, crumbling, fragmenting or otherwise disintegrating, shedding pieces or particles, or otherwise losing its structural integrity. The tensile and compressive properties of the matrix material(s) should not be so high as to interfere with the fabrication or other processing of the reticulated elastomeric matrix. The tensile and compressive properties should be appropriate so that they can withstand the forces, loads, deformations and moments experienced by the implant when placed at the target orthopedic or spinal implant site. In one embodiment, the reticulated polymeric matrix that is used to fabricate the implants of this invention has any suitable bulk density, also known as specific gravity, consistent with its other properties. For example, in one embodiment, the bulk density may be from about 0.005 to about 0.15 g/cc (from about 0.31 to about 9.4 lb/ft3), preferably from about 0.015 to about 0.115 g/cc (from about 0.93 to about 7.2 lb/ft3) and most preferably from about 0.024 to about 0.104 g/cc (from about 1.5 to about 6.5 lb/ft3).
[0083] The reticulated elastomeric matrix has sufficient tensile strength such that it can withstand normal manual or mechanical handling during its intended application and during post-processing steps that may be required or desired without tearing, breaking, crumbling, fragmenting or otherwise disintegrating, shedding pieces or particles, or otherwise losing its structural integrity. The tensile strength of the starting material(s) should not be so high as to interfere with the fabrication or other processing of elastomeric matrix. Thus, for example, in one embodiment, the reticulated polymeric matrix that is used to fabricate the implants of this invention may have a tensile strength of from about 700 to about 70,000 kg/m (from about 1 to about 100 psi). In another embodiment, elastomeric matrix may have a tensile strength of from about 7000 to about 52,500 kg/m2 (from about 10 to about 75 psi). In another embodiment, elastomeric matrix may have a tensile strength of from about 1,400 to about 14,000 kg/m2 (from about 2 to about 20 psi) at 20 % ultimate tensile elongation strain. Sufficient ultimate tensile elongation is also desirable. For example, in another embodiment, reticulated elastomeric matrix has an ultimate tensile elongation of at least about 50% to at least about 500%. In yet another embodiment, reticulated elastomeric matrix has an ultimate tensile elongation of at least 75% to at least about 300%.
[0084] In one embodiment, reticulated elastomeric matrix that is used to fabricate the implants of this invention has a compressive strength of from about 700 to about 70,000 kg/m (from about 1 to about 100 psi) at 50% compression strain. In another embodiment, reticulated elastomeric matrix has a compressive strength of from about 1,400 to about 105,000 kg/m2 (from about 2 to about 150 psi) at 75% compression strain.
[0085] In another embodiment, reticulated elastomeric matrix that is used to fabricate the implants of this invention has a compression set, when compressed to 50%) of its thickness at about 25°C, of not more than about 30%. In another embodiment, reticulated elastomeric matrix has a compression set of not more than about 20%. In another embodiment, reticulated elastomeric matrix has a compression set of not more than about 10%. In another embodiment, reticulated elastomeric matrix has a compression set of not more than about 5%.
[0086] In another embodiment, reticulated elastomeric matrix that is used to fabricate the implants of this invention has a tear strength, of from about 0.18 to about 3.6 kg/linear cm (from about 1 to about 20 lbs/linear inch).
[0087] In another embodiment of the invention the reticulated elastomeric matrix that is used to fabricate the implant can be readily permeable to liquids, permitting flow of liquids, including blood, through the composite device of the invention. The water permeability of the reticulated elastomeric matrix is from about 30 l/min./psi/cm2 to about 500 l/min./psi/cm2, preferably from about 50 l/min./psi/cm2 to about 300 l/min./psi/cm2. In contrast, permeability of the unreticulated elastomeric matrix is below about 1 l/min./psi/cm . In another embodiment, the permeability of the unretriculated elastomeric amtrix is below about 5 l/min./psi/cm .
[0088] In general, suitable biodurable reticulated elastomeric partially hydrophobic polymeric matrix that is used to fabricate the implant of this invention or for use as scaffold material for the implant in the practice of the present invention, in one embodiment sufficiently well characterized, comprise elastomers that have or can be formulated with the desirable mechanical properties described in the present specification and have a chemistry favorable to biodurability such that they provide a reasonable expectation of adequate biodurability.
[0089] Various biodurable reticulated hydrophobic polyurethane materials are suitable for this purpose. In one embodiment, structural materials for the inventive reticulated elastomers are synthetic polymers, especially, but not exclusively, elastomeric polymers that are resistant to biological degradation, for example, polycarbonate polyurethane-urea, polycarbonate polyurea-urethane, polycarbonate polyurethane, polycarbonate polysiloxane polyurethane, and polysiloxane polyurethane, and the like. Such elastomers are generally hydrophobic but, pursuant to the invention, may be treated to have surfaces that are less hydrophobic or somewhat hydrophilic. In another embodiment, such elastomers may be produced with surfaces that are less hydrophobic or somewhat hydrophilic.
[0090] The invention can employ, for implanting, a biodurable reticulatable elastomeric partially hydrophobic polymeric scaffold material or matrix for fabricating the implant or a material. More particularly, in one embodiment, the invention provides a biodurable elastomeric polyurethane scaffold material or matrix which is made by synthesizing the scaffold material or matrix preferably from a polycarbonate polyol component and an isocyanate component by polymerization, cross-linking and foaming, thereby forming pores, followed by reticulation of the porous material to provide a biodurable reticulated elastomeric product with interconnected and/or inter-communicating pores and channels. The product is designated as a polycarbonate polyurethane, being a polymer comprising urethane groups formed from, e.g., the hydroxyl groups of the polycarbonate polyol component and the isocyanate groups of the isocyanate component. In another embodiment, the invention provides a biodurable elastomeric polyurethane scaffold material or matrix which is made by synthesizing the scaffold material or matrix preferably from a polycarbonate polyol component and an isocyanate component by polymerization, cross-linking and foaming, thereby forming pores, and using water as a blowing agent and/or foaming agent during the synthesis, followed by reticulation of the porous material to provide a biodurable reticulated elastomeric product with inter-connected and/or inter-communicating pores and channels. This product is designated as a polycarbonate polyurethane-urea or polycarbonate polyurea-urethane, being a polymer comprising urethane groups formed from, e.g., the hydroxyl groups of the polycarbonate polyol component and the isocyanate groups of the isocyanate component and also comprising urea groups formed from reaction of water with the isocyanate groups. In all of these embodiments, the process employs controlled chemistry to provide a reticulated elastomeric matrix or product with good biodurability characteristics. The matrix or product employing chemistry that avoids biologically undesirable or nocuous constituents therein.
[0091] In one embodiment, the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one polyol component to provide the so-called soft segement. For the purposes of this application, the term "polyol component" includes molecules comprising, on the average, about 2 hydroxyl groups per molecule, i.e., a difunctional polyol or a diol, as well as those molecules comprising, on the average, greater than about 2 hydroxyl groups per molecule, i.e., a polyol or a multi-functional polyol. In one embodiment, this soft segment polyol is terminated with hydroxyl groups, either primary or secondary. Exemplary polyols can comprise, on the average, from about 2 to about 5 hydroxyl groups per molecule. In one embodiment, as one starting material, the process employs a difunctional polyol component in which the hydroxyl group functionality of the diol is about 2. In another embodiment, the soft segment is composed of a polyol component that is generally of a relatively low molecular weight, typically from about 500 to about 6,000 daltons and preferably between 1000 to 2500 daltons. Examples of suitable polyol components include but not limited to polycarbonate polyol, hydrocarbon polyol, polysiloxane polyol, poly(carbonate-co- hydrocarbon) polyol, poly(carbonate-co-siloxane) polyol, poly(hydrocarbon-co- siloxane) polyol, polysiloxane polyol and copolymers and mixtures thereof.
[0092] In one embodiment, the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one isocyanate component and, optionally, at least one chain extender component to provide the so-called "hard segment". In one embodiment, the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one isocyanate component. For the purposes of this application, the term "isocyanate component" includes molecules comprising, on the average, about 2 isocyanate groups per molecule as well as those molecules comprising, on the average, greater than about 2 isocyanate groups per molecule. The isocyanate groups of the isocyanate component are reactive with reactive hydrogen groups of the other ingredients, e.g., with hydrogen bonded to oxygen in hydroxyl groups of the polyol component, with hydrogen bonded to nitrogen in amine groups, chain extender, crosslinker and/or water. In one embodiment, the average number of isocyanate groups per molecule in the isocyanate component is about 2. In another embodiment, the average number of isocyanate groups per molecule in the isocyanate component is greater than about 2.
[0093] The isocyanate index, a quantity well known to those in the art, is the mole ratio of the number of isocyanate groups in a formulation available for reaction to the number of groups in the formulation that are able to react with those isocyanate groups, e.g., the reactive groups of diol(s), polyol component(s), chain extender(s) and water, when present. In one embodiment, the isocyanate index is from about 0.9 to about 1.1. In another embodiment, the isocyanate index is from about 0.9 to about 1.02. In another embodiment, the isocyanate index is from about 0.98 to about 1.02. In another embodiment, the isocyanate index is from about 0.9 to about 1.0. In another embodiment, the isocyanate index is from about 0.9 to about 0.98.
[0094] In one embodiment, a small quantity of an optional ingredient, such as a multi-functional hydroxyl compound or other cross-linker having a functionality greater than 2, is present to allow crosslinking and/or to achieve a stable foam, i.e., a foam that does not collapse to become non-foamlike. Alternatively, or in addition, polyfunctional adducts of aliphatic and cycloaliphatic isocyanates can be used to impart cross-linking in combination with aromatic diisocyanates. Alternatively, or in addition, polyfunctional adducts of aliphatic and cycloaliphatic isocyanates can be used to impart cross-linking in combination with aliphatic diisocyanates. Alternatively, or in addition, polymeric aromatic diisocyanates can be used to impart cross-linking. The presence of these components and adducts with functionality higher than 2 in the hard segment component allows for cross-linking to occur. In distinction to the cross-linking described above which is termed chemical cross- linking, additional cross-linking arises out of hydrogen bonding in and between both the hard and soft phases of the matrix and is termed as physical cross-linking.
[0095] Exemplary diisocyanates include aliphatic diisocyanates, isocyanates comprising aromatic groups, the so-called "aromatic diisocyanates", and mixtures thereof. Aliphatic diisocyanates include tetramethylene diisocyanate, cyclohexane- 1,2-diisocyanate, cyclohexane-l,4-diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, methylene-bis-(p-cyclohexyl isocyanate) ("HI 2 MDI"), and mixtures thereof. Aromatic diisocyanates include p-phenylene diisocyanate, 4,4'- diphenylmethane diisocyanate ("4,4'-MDI"), 2,4'-diphenylmethane diisocyanate ("2,4'-MDI"), polymeric MDI, and mixtures thereof. Examples of optional chain extenders include diols, diamines, alkanol amines or a mixture thereof.
[0096] In one embodiment, the starting material for synthesizing the biodurable reticulated elastomeric partially hydrophobic polymeric matrix contains at least one blowing agent such as water. Other exemplary blowing agents include the physical blowing agents, e.g., volatile organic chemicals such as hydrocarbons, ethanol and acetone, and various fluorocarbons, hydrofluorocarbons, chlorofluorocarbons, and hydrochlorofluorocarbons. Additional exemplary blowing agents include the physical blowing agents such as gases as nitrogen, helium, etc., that can additionally act as nucleating agent and whose amount and the pressure under which they are introduced during matrix formation can be used to control the density of the biodurable, elastomeric and partially hydrophobic polymeric matrix. In one embodiment, the hard segments also contain a urea component formed during foaming reaction with water. In one embodiment, the reaction of water with an isocyanate group yields carbon dioxide, which serves as a blowing agent. The amount of blowing agent, e.g., water, is adjusted to obtain different densities of non-reticulated foams. A reduced amount of blowing agent such as water may reduce the number of urea linkages in the material.
[0097] In another embodiment, any or all of the processing approaches of the invention may be used to make foam with a density greater than 3.4 lbs/ft (0.054 g/cc). In this embodiment, optionally some amount of crosslinker(s), such as glycerol, are used; the functionality of the isocyanate component is from 2.0 to 2.5; the isocyanate component consists essentially of 4, 4 diphenylmethane diisocyanate ("4,4'-MDI"), and the remaining components being 2,4'-diphenylmethane diisocyanate ("2,4*-MDI"), polymeric MDI; and the amount of 4,4'-MDI is greater than about 55% by weight of the isocyanate component. It may also include additional amount of 4,4'- MDI. The molecular weight of the polyol component is from about 500 to 3000 Daltons but preferably between 1,000 to about 2,000 Daltons. The amount of blowing agent, e.g., water, is adjusted to obtain non-reticulated foam with densities greater than 3.4 lbs/ft (0.054 g/cc). A reduced amount of blowing agent may reduce the number of urea linkages in the material. In one embodiment, any reduction in stiffness and/or tensile strength and/or compressive strength caused by fewer urea linkages and/or by lower crosslinking can be compensated for by using di-functional chain extenders, such as butanediol, and/or increasing the density of the foam. In another embodiment, any reduction in stiffness and/or tensile strength and/or compressive strength caused by fewer urea linkages and/or lower crosslinking can be compensated for by using or increasing the amount or proportion of 4,4'-MDI of the isocyanate component. Although not bound by any particular theory, it is believed that by controlling the degree of cross-linking in the hard phase, amount of 4,4 MDI and by controlling density of the foam material, it is possible to increase the foam's toughness and/or elongation to break. This consequently should allow for more efficient reticulation because the higher density, higher amount of 4,4 MDI and lighter cross-linking results in tougher matrix material which can better withstand the sudden impact a reticulation process can provide with minimal, if any, damage to struts. [0098] In one embodiment, implantable device can be rendered radiopaque to facilitate in vivo imaging, for example, by adhering to, covalently bonding to and/or incorporating into the elastomeric matrix itself particles of a radio-opaque material. Radio-opaque materials include titanium, tantalum, tungsten, barium sulfate or other suitable material known to those skilled in the art.
[0099] In one embodiment, the starting material of the biodurable reticulated elastomeric partially hydrophobic polymeric matrix is a commercial polyurethane polymers are linear, not crosslinked, polymers, therefore, they are soluble, can be melted, readily analyzable and readily characterizable. In this embodiment, the starting polymer provides good biodurability characteristics. The reticulated elastomeric matrix is produced by taking a solution of the commercial polymer such as polyurethane and charging it into a mold that has been fabricated with surfaces defining a microstructural configuration for the final implant or scaffold, solidifying the polymeric material and removing the sacrificial mold by melting, dissolving or subliming- away the sacrificial mold. In one embodiment, the solvents can be lyophilized leaving at least a partially or fully reticulated material matrix. The matrix or product employing a foaming process that avoids biologically undesirable or nocuous constituents therein.
[00100] Of particular interest are thermoplastic elastomers such as polyurethanes whose chemistry is associated with good biodurability properties, for example. In one embodiment, such thermoplastic polyurethane elastomers include polycarbonate polyurethanes, polysiloxane polyurethanes, polyurethanes with so-called "mixed" soft segments, and mixtures thereof. Mixed soft segment polyurethanes are known to those skilled in the art and include, e.g., polycarbonate-polysiloxane polyurethanes. In another embodiment, the thermoplastic polyurethane elastomer comprises at least one diisocyanate in the isocyanate component, at least one chain extender and at least one diol, and may be formed from any combination of the diisocyanates, difunctional chain extenders and diols described in detail above. Some suitable thermoplastic polyurethanes for practicing the invention, in one embodiment suitably characterized as described herein, include: polyurethanes with mixed soft segments comprising polysiloxane together with a polycarbonate component.
[00101] In one embodiment, the weight average molecular weight of the thermoplastic elastomer is from about 30,000 to about 500,000 Daltons. In another embodiment, the weight average molecular weight of the thermoplastic elastomer is from about 50,000 to about 250,000 Daltons.
[00102] Some commercially-available thermoplastic elastomers suitable for use in practicing the present invention include the line of polycarbonate polyurethanes supplied under the trademark BIONATE® by The Polymer Technology Group Inc. (Berkeley, CA). For example, the very well-characterized grades of polycarbonate polyurethane polymer BIONATE® 80A, 55 and 90 are soluble in THF, DMF, DMAT, DMSO, or a mixture of two or more thereof, processable, reportedly have good mechanical properties, lack cytotoxicity, lack mutagenicity, lack carcinogenicity and are non-hemolytic. Another commercially-available elastomer suitable for use in practicing the present invention is the CHRONOFLEX® C line of biodurable medical grade polycarbonate aromatic polyurethane thermoplastic elastomers available from CardioTech International, Inc. (Woburn, MA).
[00103] Other possible embodiments of the materials used to fabricate the implants of this invention are described in co-pending, commonly assigned U.S. patent applications Serial No. 10/749,742, filed December 30, 2003, titled "Reticulated Elastomeric Matrices, Their Manufacture and Use in Implantable Devices", Serial No. 10/848,624, filed May 17, 2004, titled "Reticulated Elastomeric Matrices, Their Manufacture and Use In Implantable Devices", and Serial No. 10/990,982, filed July 27, 2004, titled "Endovascular Treatment Devices and Methods", each of which is incorporated herein by reference in its entirely. [00104] It is within the scope of this invention that the elastomeric scaffold may optionally have a simple dip or spray polymer coating, the coating optionally comprising a pharmaceutically-active agent, such as a therapeutic agent or drug. In one embodiment the coating may be a solution and the polymer content in the coating solution is from about 1% to about 40% by weight. In another embodiment, the polymer content in the coating solution may be from about 1% to about 20% by weight. In another embodiment, the polymer content in the coating solution may be from about 1% to about 10% by weight.
[00105] In one embodiment of the invention, a biodurable reticulated elastomeric matrix has a coating comprising material selected to encourage cellular ingrowth and proliferation. The coating material can, for example, comprise a foamed coating of a biodegradable material, optionally, collagen, fibronectin, elastin, hyaluronic acid and mixtures thereof. Alternatively, the coating comprises a biodegradable polymer and an inorganic component.
[00106] In another embodiment, the reticulated biodurable elastomer is coated or impregnated with a material such as, for example, polyglycolic acid ("PGA"), polylactic acid ("PLA"), polycaprolactic acid ("PCL"), poly-p-dioxanone ("PDO"), PGA/PLA copolymers, PGA/PCL copolymers, PGA/PDO copolymers, PLA/PCL copolymers, PLA/PDO copolymers, PCL/PDO copolymers or combinations of any two or more of the foregoing.
[00107] The solvent or solvent blend for the coating solution is chosen with consideration given to, inter alia, the proper balancing the viscosity, deposition level of the polymer, wetting rate and evaporation rate of the solvent to properly coat solid phase as known to those in the art. In one embodiment, the solvent is chosen such the polymer is soluble in the solvent. In another embodiment, the solvent is substantially completely removed from the coating. In another embodiment, the solvent is non- toxic, non-carcinogenic and environmentally benign. Mixed solvent systems can be advantageous for controlling the viscosity and evaporation rates. In all cases, the solvent should not react with the coating polymer. Solvents include, but are not limited to, acetone, N-methylpyrrolidone ("NMP"), DMSO, toluene, methylene chloride, chloroform, 1,1,2-trichloroethane ("TCE"), various freons, dioxane, ethyl acetate, THF, DMF and DMAC.
[00108] In another embodiment, the film- forming coating polymer is a thermoplastic polymer that is melted, enters the pores of the elastomeric matrix and, upon cooling or solidifying, forms a coating on at least a portion of the solid material of the elastomeric matrix . In another embodiment, the processing temperature of the thermoplastic coating polymer in its melted form is above about 60°C. In another embodiment, the processing temperature of the thermoplastic coating polymer in its melted form is above about 90°C. In another embodiment, the processing temperature of the thermoplastic coating polymer in its melted form is above about 120°C.
[00109] In a further embodiment of the invention, described in more detail below, some or all of the pores of the elastomeric matrix are coated or filled with a cellular ingrowth promoter. In another embodiment, the promoter can be foamed. In another embodiment, the promoter can be present as a film. The promoter can be a biodegradable material to promote cellular invasion of the elastomeric matrix in vivo. Promoters include naturally occurring materials that can be enzymatically degraded in the human body or are hydrolytically unstable in the human body, such as fibrin, fibrinogen, collagen, elastin, hyaluronic acid and absorbable biocompatible polysaccharides, such as chitosan, starch, fatty acids (and esters thereof), glucoso- glycans and hyaluronic acid. In some embodiments, the pore surface of the elastomeric matrix is coated or impregnated, as described above, but substituting the promoter for the biocompatible polymer or adding the promoter to the biocompatible polymer, to encourage cellular ingrowth and proliferation.
[00110] In one embodiment, the coating or impregnating process is conducted so as to ensure that the product "composite elastomeric implantable device", i.e., a reticulated elastomeric matrix and a coating, as used herein, retains sufficient resiliency after compression such that it can be delivery-device delivered, e.g., catheter, syringe or endoscope delivered. Some embodiments of such a composite elastomeric implantable device will now be described with reference to collagen, by way of non-limiting example, with the understanding that other materials may be employed in place of collagen, as described above.
[00111] Collagen may be infiltrated by forcing, e.g., with pressure, an aqueous collagen slurry, suspension or solution into the pores of an elastomeric matrix. The collagen may be Type I, II or III or mixtures thereof. In one embodiment, the collagen type comprises at least 90% collagen I. The concentration of collagen is from about 0.3% to about 2.0% by weight and the pH of the slurry, suspension or solution is adjusted to be from about 2.6 to about 5.0 at the time of lyophilization. Alternatively, collagen may be infiltrated by dipping an elastomeric matrix into a collagen slurry.
[00112] As compared with the uncoated reticulated elastomer, the composite elastomeric implantable device can have a void phase that is slightly reduced in volume. In one embodiment, the composite elastomeric implantable device retains good fluid permeability and sufficient porosity for ingrowth and proliferation of fibroblasts or other cells.
[00113] Optionally, the lyophilized collagen can be crosslinked to control the rate of in vivo enzymatic degradation of the collagen coating and to control the ability of the collagen coating to bond to the elastomeric matrix. Without being bound by any particular theory, it is thought that when the composite elastomeric implantable device is implanted, tissue-forming agents that have a high affinity to collagen, such as fibroblasts, will more readily invade the collagen-impregnated elastomeric matrix than the uncoated matrix. It is further thought, again without being bound by any particular theory, that as the collagen enzymatically degrades, new tissue invades and fills voids left by the degrading collagen while also infiltrating and filling other available spaces in the elastomeric matrix. Such a collagen coated or impregnated elastomeric matrix is thought, without being bound by any particular theory, to be additionally advantageous for the structural integrity provided by the reinforcing effect of the collagen within the pores of the elastomeric matrix which can impart greater rigidity and structural stability to various configurations of the elastomeric matrix .
[00114] The biodurable reticulated elastomeric matrix useful according to this invention can support cell types including cells secreting structural proteins and cells that produce proteins characterizing organ function. The ability of the elastomeric matrix to facilitate the co-existence of multiple cell types together and its ability to support protein secreting cells demonstrates the applicability of the elastomeric matrix in organ growth in vitro or in vivo and in organ reconstruction. In addition, the biodurable reticulated elastomeric matrix may also be used in the scale up of human cell lines for implantation to the body for many applications including implantation of fibroblasts, chondrocytes, osteoblasts, osteoclasts, osteocytes, synovial cells, bone marrow stromal cells, stem cells, fibrocartilage cells, endothelial cells, smooth muscle cells, adipocytes, cardiomyocytes, myocytes, keratinocytes, hepatocytes, leukocytes, macrophages, endocrine cells, genitourinary cells, lymphatic vessel cells, pancreatic islet cells, muscle cells, intestinal cells, kidney cells, blood vessel cells, thyroid cells, parathyroid cells, cells of the adrenal-hypothalamic pituitary axis, bile duct cells, ovarian or testicular cells, salivary secretory cells, renal cells, epithelial cells, nerve cells, stem cells, progenitor cells, myoblasts and intestinal cells.
[00115] New tissue can be obtained through implantation of cells seeded in elastomeric matrices (either prior to or concurrent to or subsequent to implantation). In this case, the elastomeric matrices may be configured either in a closed manner to protect the implanted cells from the body's immune system, or in an open manner so that the new cells can be incorporated into the body. Thus, in another embodiment, the cells may be incorporated, i.e., cultured and proliferated, onto the elastomeric matrix prior, concurrent or subsequent to implantation of the elastomeric matrix in the patient.
[00116] In one embodiment, the implantable device made from biodurable reticulated elastomeric matrix can be seeded with a type of cell and cultured before being inserted into the patient, optionally using a delivery-device, for the explicit purpose of tissue repair or tissue regeneration. It is necessary to perform the tissue or cell culture in a suitable culture medium with or without stimulus such as stress or orientation. The cells include fibroblasts, chondrocytes, osteoblasts, osteoclasts, osteocytes, synovial cells, bone marrow stromal cells, stem cells, fibrocartilage cells, endothelial cells and smooth muscle cells.
[00117] Surfaces on the biodurable reticulated elastomeric matrix possessing different pore morphology, size, shape and orientation may be cultured with different type of cells to develop cellular tissue engineering implantable devices that are specifically targeted towards orthopedic applications, especially in soft tissue attachment, repair, re-generation, augmentation and/or support encompassing spine, shoulder, knee, hand, joints, and in the growth of a prosthetic organ. In another embodiment, all the surfaces on the biodurable reticulated elastomeric matrix possessing similar pore morphology, size, shape and orientation may be so cultured.
[00118] In another embodiment, the film- forming polymer used to coat the reticulated elastomeric matrix can provide a vehicle for the delivery of and/or the controlled release of a pharmaceutically-active agent, for example, a drug, such as is described in the copending applications. In another embodiment, the pharmaceutically-active agent is admixed with, covalently bonded to and/or adsorbed in or on the coating of the elastomeric matrix to provide a pharmaceutical composition. In another embodiment, the components, polymers and/or blends used to form the foam comprise a pharmaceutically-active agent. To form these foams, the previously described components, polymers and/or blends are admixed with the pharmaceutically-active agent prior to forming the foam or the pharmaceutically- active agent is loaded into the foam after it is formed.
[00119] In one embodiment, the coating polymer and pharmaceutically-active agent have a common solvent. This can provide a coating that is a solution. In another embodiment, the pharmaceutically-active agent can be present as a solid dispersion in a solution of the coating polymer in a solvent.
[00120] A reticulated elastomeric matrix comprising a pharmaceutically-active agent may be formulated by mixing one or more pharmaceutically-active agent with the polymer used to make the foam, with the solvent or with the polymer-solvent mixture and foamed. Alternatively, a pharmaceutically-active agent can be coated onto the foam, in one embodiment, using a pharmaceutically-acceptable carrier. If melt-coating isemployed, then, in another embodiment, the pharmaceutically-active agent withstands melt processing temperatures without substantial diminution of its efficacy.
[00121] Formulations comprising a pharmaceutically-active agent can be prepared by admixing, covalently bonding and/or adsorbing one or more pharmaceutically-active agents with the coating of the reticulated elastomeric matrix or by incorporating the pharmaceutically-active agent into additional hydrophobic or hydrophilic coatings. The pharmaceutically-active agent may be present as a liquid, a finely divided solid or another appropriate physical form. Typically, but optionally, the matrix can include one or more conventional additives, such as diluents, carriers, excipients, stabilizers and the like.
[00122] In another embodiment, a top coating can be applied to delay release of the pharmaceutically-active agent. In another embodiment, a top coating can be used as the matrix for the delivery of a second pharmaceutically-active agent. A layered coating, comprising respective layers of fast- and slow-hydrolyzing polymer, can be used to stage release of the pharmaceutically-active agent or to control release of different pharmaceutically-active agents placed in the different layers. Polymer blends may also be used to control the release rate of different pharmaceutically-active agents or to provide a desirable balance of coating characteristics (e.g., elasticity, toughness) and drug delivery characteristics (e.g., release profile). Polymers with differing solvent solubilities can be used to build-up different polymer layers that may be used to deliver different pharmaceutically-active agents or to control the release profile of a pharmaceutically-active agents.
[00123] The amount of pharmaceutically-active agent present depends upon the particular pharmaceutically-active agent employed and medical condition being treated. In one embodiment, the pharmaceutically-active agent is present in an effective amount. In another embodiment, the amount of pharmaceutically-active agent represents from about 0.01% to about 60% of the coating by weight. In another embodiment, the amount of pharmaceutically-active agent represents from about 0.01% to about 40% of the coating by weight. In another embodiment, the amount of pharmaceutically-active agent represents from about 0.1% to about 20% of the coating by weight.
[00124] Many different pharmaceutically-active agents can be used in conjunction with the reticulated elastomeric matrix. In general, pharmaceutically- active agents that may be administered via pharmaceutical compositions of this invention include, without limitation, any therapeutic or pharmaceutically-active agent (including but not limited to nucleic acids, proteins, lipids, and carbohydrates) that possesses desirable physiologic characteristics for application to the implant site or administration via a pharmaceutical compositions of the invention. Therapeutics include, without limitation, antiinfectives such as antibiotics and antiviral agents; chemotherapeutic agents (e.g., anticancer agents); anti-rejection agents; analgesics and analgesic combinations; anti-inflammatory agents; hormones such as steroids; growth factors (including but not limited to cytokines, chemokines, and interleukins) and other naturally derived or genetically engineered proteins, polysaccharides, glycoproteins and lipoproteins. These growth factors are described in The Cellular and Molecular Basis of Bone Formation and Repair by Vicki Rosen and R. Scott Thies, published by R. G. Landes Company, hereby incorporated herein by reference. Additional therapeutics include thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, anti metabolites, antiproliferatives, anticancer chemotherapeutic agents, anti-inflammatory steroids, non-steroidal anti-inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, angiotensin-converting enzyme (ACE) inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, antiviral agents, photodynamic therapy agents and gene therapy agents.
[00125] Additionally, various proteins (including short chain peptides), growth agents, chemotatic agents, growth factor receptors or ceramic particles can be added to the foams during processing, adsorbed onto the surface or back-filled into the foams after the foams are made. For example, in one embodiment, the pores of the foam may be partially or completely filled with biocompatible resorbable synthetic polymers or biopolymers (such as collagen or elastin), biocompatible ceramic materials (such as hydroxyapatite), and combinations thereof, and may optionally contain materials that promote tissue growth through the device. Such tissue-growth materials include but are not limited to autograft, allograft or xenograft bone, bone marrow and morphogenic proteins. Biopolymers can also be used as conductive or chemotactic materials, or as delivery vehicles for growth factors. Examples include recombinant collagen, animal-derived collagen, elastin and hyaluronic acid. Pharmaceutically-active coatings or surface treatments could also be present on the surface of the materials. For example, bioactive peptide sequences (RGD's) could be attached to the surface to facilitate protein adsorption and subsequent cell tissue attachment. In a further embodiment of the invention, the pores of biodurable reticulated elastomeric matrix that are used to fabricate the implants of this invention are coated or filled with a cellular ingrowth promoter. In another embodiment, the promoter can be foamed. In another embodiment, the promoter can be present as a film. The promoter can be a biodegradable material to promote cellular invasion of pores biodurable reticulated elastomeric matrix that are used to fabricate the implants of this invention in vivo. Promoters include naturally occurring materials that can be enzymatically degraded in the human body or are hydrolytically unstable in the human body, such as fibrin, fibrinogen, collagen, elastin, hyaluronic acid and absorbable biocompatible polysaccharides, such as chitosan, starch, fatty acids (and esters thereof), glucoso-glycans and hyaluronic acid. In some embodiments, the pore surface of the biodurable reticulated elastomeric matrix that are used to fabricate the implants of this invention is coated or impregnated, as described in the previous section but substituting the promoter for the biocompatible polymer or adding the promoter to the biocompatible polymer, to encourage cellular ingrowth and proliferation.
[00126] Bioactive molecules include, without limitation, proteins, collagens
(including types IV and XVIII), fibrillar collagens (including types I, II, III, V, XI), FACIT collagens (types IX, XII, XIV), other collagens (types VI, VII, XIII), short chain collagens (types VIII, X), elastin, entactin-1, fibrillin, fibronectin, fibrin, fibrinogen, fibroglycan, fibromodulin, fibulin, glypican, vitronectin, laminin, nidogen, matrilin, perlecan, heparin, heparan sulfate proteoglycans, decorin, filaggrin, keratin, syndecan, agrin, integrins, aggrecan, biglycan, bone sialoprotein, cartilage matrix protein, Cat-301 proteoglycan, CD44, cholinesterase, HB-GAM, hyaluronan, hyaluronan binding proteins, mucins, osteopontin, plasminogen, plasminogen activator inhibitors, restrictin, serglycin, tenascin, thrombospondin, tissue-type plasminogen activator, urokinase type plasminogen activator, versican, von Willebrand factor, dextran, arabinogalactan, chitosan, polyactide-glycolide, alginates, pullulan, gelatin and albumin. [00127] Additional bioactive molecules include, without limitation, cell adhesion molecules and matricellular proteins, including those of the immunoglobulin (Ig; including monoclonal and polyclonal antibodies), cadherin, integrin, selectin, and H- CAM superfamilies. Examples include, without limitation, AMOG, CD2, CD4, CD8, C-CAM (CELL-CAM 105), cell surface galactosyltransferase, connexins, desmocollins, desmoglein, fasciclins, FI 1, GP Ib-IX complex, intercellular adhesion molecules, leukocyte common antigen protein tyrosine phosphate (LCA, CD45), LFA- 1, LFA-3, mannose binding proteins (MBP), MTJC18, myelin associated glycoprotein (MAG), neural cell adhesion molecule (NCAM), neurofascin, neruoglian, neurotactin, netrin, PECAM-1, PH-20, semaphorin, TAG-1, VCAM-1, SPARC/osteonectin, CCN1 (CYR61), CCN2 (CTGF; Connective Tissue Growth Factor), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), CCN6 (WISP-3), occludin and claudin. Growth factors include, without limitation, BMP's (1-7), BMP-like Proteins (GFD-5, -7, -8), epidermal growth factor (EGF), erythropoietin (EPO), fibroblast growth factor (FGF), growth hormone (GH), growth hormone releasing factor (GHRF), granulocyte colony-stimulating factor (G-CSF), granulocyte- macrophage colony- stimulating factor (GM-CSF), insulin, insulin-like growth factors (IGF-I, IGF-II), insulin-like growth factor binding proteins (IGFBP), macrophage colony-stimulating factor (M-CSF), Multi-CSF (II-3), platelet-derived growth factor (PDGF), tumor growth factors (TGF-alpha, TGF-beta), tumor necrosis factor (TNF- alpha), vascular endothelial growth factors (VEGF's), angiopoietins, placenta growth factor (PIGF), interleukins, and receptor proteins or other molecules that are known to bind with the aforementioned factors. Short-chain peptides include, without limitation (designated by single letter amino acid code), RGD, EILDV, RGDS, RGES, RFDS, GRDGS, GRGS, GRGDTP and QPPRARI. One possible material for use in the present invention comprises a resiliently compressible composite polyurethane material comprising a hydrophilic foam coated on and throughout the pore surfaces of a hydrophobic foam scaffold. One suitable such material is the composite foam disclosed in co-pending, commonly assigned U.S. patent applications Serial No. 10/692,055, filed October 22, 2003, Serial No. 10/749,742, filed December 30, 2003, Serial No. 10/848,624, filed May 17, 2004, and Serial No. 10/900,982, filed July 27, 2004, each of which is incorporated herein by reference in its entirety. The hydrophobic foam provides support and resilient compressibility enabling the desired collapsing of the implant for delivery and reconstitution in situ.
[00128] The elastomeric matrix useful according to the invention may be molded into any of a wide variety of shapes and sizes during its formation or production. The shape may be a working configuration, such as any of the shapes and configurations described above, or the shape may be for bulk stock. Stock items may subsequently be cut, trimmed, punched or otherwise shaped for end use. The sizing and shaping can be carried out by, for example, using a blade, punch, drill or laser. In each of these embodiments, the processing temperature or temperatures of the cutting tools for shaping and sizing can be greater than about 100°C. In another embodiment, the processing temperature(s) of the cutting tools for shaping and sizing can be greater than about 130°C. Finishing steps can include, in one embodiment, trimming of macrostructural surface protrusions, such as struts or the like, which can irritate biological tissues. In another embodiment, finishing steps can include heat annealing. Annealing can be carried out before or after final cutting and shaping.
[00129] The dimensions of the shaped and sized devices made from the elastomeric matrix can vary depending on the application. In one embodiment, major dimensions of a device, such as device 30 or device 48, prior to being compressed and delivered, are from about 5 mm to about 30 mm in one direction and from about 5mm to about 30 mm in another direction. In another embodiment, major dimensions of a device, such as device 30 or device 48, prior to being compressed and delivered are from about 8 mm to about 25 mm in one direction and from about 8 mm to about 25 mm in another direction. The length of a cylindrical portion of a device, such as device 30 or device 48, according to the invention is expected to be from about 6 mm to about 14 mm, since that is approximately the typical radial thickness of a patient's annulus. The diameter or the largest transverse dimension of the cylindrical portion of a device, such as cylindrical part 32 or cylindrical part 50, according to the invention is expected to be from about 5 mm to about 30 mm, preferably from about 8 mm to about 20 mm. The diameter or the largest transverse dimension of the partial cylindrical or partial spherical portion of a device, such as expanded portion 34 or mushrrom- shape distal portion 52, according to the invention is expected to be from about 8 mm to about 40 mm, preferably from about 10 mm to about 30 mm. The elastomeric matrix can exhibit compression set upon being compressed and transported through a delivery-device, e.g., a trocar, cannula, or catheter, with assisted visualization. In another embodiment, compression set and its standard deviation are taken into consideration when designing the pre-compression dimensions of the device.
[00130] Biodurable reticulated elastomeric matrices, or an implantable device system comprising such matrices, can be sterilized by any method known to the art including gamma irradiation, autoclaving, ethylene oxide sterilization, infrared irradiation and electron beam irradiation. In one embodiment, biodurable elastomers used to fabricate the elastomeric matrix tolerate such sterilization without loss of useful physical and mechanical properties. The use of gamma irradiation can potentially provide additional crosslinking to enhance the performance of the device.
[00131] In one embodiment, the sterilized products may be packaged in uncompressed state in sterile packages of paper, polymer or other suitable material. In embodiment, the elastomeric matrix remains uncompressed in such a package for typical commercial storage and distribution times, which will commonly exceed 3 months and may be up to 1 or 5 years from manufacture to use. In another embodiment, within such packages, the elastomeric matrix is compressed within a retaining member to facilitate its loading into a delivery-device, such as a catheter or endoscope, in a compressed configuration. In another embodiment, the elastomeric matrix comprises an elastomer with a compression set enabling it to expand to a substantial proportion of its pre-compressed volume, e.g., at 25 °C, to at least 50% of its pre-compressed volume. In another embodiment, expansion occurs after the elastomeric matrix remains compressed in such a package for typical commercial storage and distribution times, which will commonly exceed 3 months and may be up to 1 or 5 years from manufacture to use. If desired, the reticulated elastomeric implants or implants can be rendered radiopaque to allow for visualization of the implants in situ by the clinician during and after the procedure, employing radioimaging. Any suitable radiopaque agent that can be covalently bound, adhered or otherwise attached to the reticulated polymeric implants may be employed including without limitation, tantalum, titanium and barium sulfate or other suitable material known to those skilled in the art. In addition to incorporating radiopaque agents such as tantalum into the implant material itself, a further embodiment of the invention encompasses the use of radiopaque metallic components to impart radiopacity to the implant. For example, thin filaments comprised of metals with or without shape memory properties such as platinum or nitinol can be embedded into the implant and may be in the form of a straight or curved wire, helical or coil-like structure, umbrella structure, or other structure generally known to those skilled in the art. Alternatively, a metallic frame around the implant may also be used to impart radiopacity. The metallic frame may be in the form of a tubular structure, a helical or coil-like structure, an umbrella structure, or other structure generally known to those skilled in the art. In one embodiment, the metallic implants incorporated in or surrounding the orthopedic or spinal implant for gripping or attachment or positioning or fastening of the implant at the target site can be used to impart radiopacity. Attachment of radiopaque metallic components to the implant can be accomplished by means including but not limited to chemical bonding or adhesion, suturing, pressure fitting, compression fitting, and other physical methods.
[00132] According to the invention the reticulated elastomeric matrix can be appropriately shaped to form a closure device to seal the access opening in the annulus resulting from a discotomy to reinforce and stabilize the disc annulus in case of herniated disc, also known as disc prolapse or a slipped or bulging disc. The implantable device is compressed and delivered into the annulus opening by a trocar, cannula, or catheter with assisted visualization through an endoscopic intrument such as a laproscope, arthroscope, or cystoscope, preferably the cannula used during the discectomy procedure. In another embodiment, the implantable device is not compressed and delivered into the annulus opening by a trocar, cannula, or catheter with assisted visualization through an endoscopic intrument such as a laproscope, arthroscope, or cystoscope, preferably the cannula used during the discectomy procedure. The device can be secured into the opening by at least the following two mechanisms: first, the outwardly resilient nature of the reticulated solid phase can provide a mechanical means for preventing migration; and, second, the reticulated solid phase can serve as a scaffold to support fibrocartilage growth into the interconnected void phase of the elastomeric matrix. Additional securing may be obtained by the use of anchors, sutures or biological glues and adhesives, as known to those in the art. The closure device can support fibrocartilage ingrowth into the elastomeric matrix of the implantable device. Once released at the site, the reticulated elastomeric matrix expands resiliently to about its original, relaxed size and shape subject, of course, to its compression set limitation and any desired flexing, draping or other conformation to the site anatomy that the implantable device may adopt.
[00133] In one embodiment, cellular entities such as fibroblasts and tissues can invade and grow into the reticulated elastomeric matrix. In due course, such ingrowth can extend into the interior pores and interstices of the inserted reticulated elastomeric matrix. Eventually, the elastomeric matrix can become substantially filled with proliferating cellular ingrowth that provides a mass that can occupy the site or the void spaces in it. The types of tissue ingrowth possible include, but are not limited to, fibrous tissues and endothelial tissues.
[00134] In another embodiment, the implantable device or device system causes cellular ingrowth and proliferation throughout the site, throughout the site boundary, or through some of the exposed surfaces, thereby sealing the site. Over time, this induced fibrovascular entity resulting from tissue ingrowth can cause the implantable device to be incorporated into the conduit. Tissue ingrowth can lead to very effective resistance to migration of the implantable device over time. It may also prevent recanalization of the conduit. In another embodiment, over the course of time, for example, for 2 weeks to 3 months to 1 year, the implanted reticulated elastomeric matrix becomes completely filled and/or encapsulated by tissue, fibrous tissue, scar tissue or the like.
[00135] The properties of the reticulated elastomeric matrix can be engineered to match the application by, e.g., controlling the amount of crosslinking, amount of crystallinity, chemical composition, chemical type of the solvent or solvent blend (when a solvent is used in processing), annealing conditions, curing conditions, and degree of reticulation. Unlike biodegradable polymers, when used as a scaffold, the reticulated elastomeric matrix maintains its physical characteristics and performance in vivo over long periods of time. Thus, it does not initiate undesirable tissue response as is observed for biodegradable implants when they break down and degrade. The high void content and degree of reticulation of the reticulated elastomeric matrix allows tissue ingrowth and proliferation of cells within the matrix. In one embodiment, the ingrown tissue and/or proliferated cells occupy from about 51% to about 99% of the volume of interconnected void phase of the original implantable device, thereby providing functionality, such as load bearing capability, of the original tissue that is being repaired or replaced. E X A M P L E S
[00136] Example 1- Fabrication of a Crosslinked Reticulated Polyurethane
Matrix
[00137] Aromatic isocyanates, RUBINATE 9258 (from Huntsman; comprising a mixture of 4,4'-MDI and 2,4'-MDI), were used as the isocyanate component. RUBINATE 9258 contains about 68% by weight 4,4'-MDI, about 32% by weight 2,4'- MDI and has an isocyanate functionality of about 2.33 and is a liquid at at 25°C. A polyol - 1,6-hexamethylene carbonate (PC 1733, Stahl Chemicals) i.e., a diol, with a molecular weight of about 1,000 Daltons, was used as the polyol component and is a solid at 25°C. Glycerol was the chain extender,and water was used as the blowing agent. The blowing catalyst were tertiary amine 33% tri ethyl enediamine in dipropylene glycol (DABCO 33LV supplied by Air Products) and Niax-Al (supplied by Air Products). A silicone-based surfactant was used (TEGOSTAB® BF 2370, supplied by Goldschmidt). The cell-opener was ORTEGOL® 501 (supplied by Goldschmidt). A viscosity depressant (Propylene carbonate supplied by Sigma- Aldrich) was also used. The proportions of the components that were used is given in the following table:
Table 1 Ingredient Parts by Weight
Polyol Component -PC 1733 , Stahl 100 Chemicals Glycerine 4.92 Viscosity Depressant - Propylene carbonate ^ " Surfactant - TEGOSTAB® BF 2370 4-40 Cell Opener - ORTEGOL® 501 4-° Isocyanate Component RUBINATE 99-78 9258 1.00 Isocyanate Index 3.36 Distilled Water 1.0 Blowing Catalyst Dabco 33 LV 0.06 Blowing Catalyst Niax-Al
[00138] The polyol was liquefied at 70 °C in an air circulation oven, and was weighed into a polyethylene cup. Viscosity depressant (propylene carbonate) was added to the polyol and mixed with a drill mixer equipped with a mixing shaft at 3100 m for 15 seconds (mix-1). Surfactant (Tegostab BF-2370) was added to mix-1 and mixed for additional 15 seconds (mix-2). Cell opener (Ortogel 501) was added to mix-2 and mixed for 15 seconds (mix-3). Isocyanate (Rubinate 9258) was added to mix-3 and mixed for 60±10 seconds (system A).
[00139] Distilled water was mixed with both blowing catalyst (Dabco 33LV and
Niax Al) and glycerine in a small plastic cup by using a tiny glass rod for 60 seconds (System B). [00140] System B was poured into System A as quickly as possible without spilling and with vigorous mixing with a drill mixer for 10 seconds and poured into cardboard box of 9 in. x 8 in. x 5 in., which is covered inside with aluminum foil. The foaming profile was as follows: mixing time of 10 sec, cream time of 18 sec. and rise time of 75 sec.
[00141] Two minutes after beginning of foam mixing, the foam was placed in the oven at 100 - 105°C for curing for 65 minutes. The foam is taken from the oven and cooled for 15 minutes at room temperature. The skin was cut with the band saw, and the foam was pressed by hand from all sides to open the cell windows. The foam was put back into an air-circulation oven for post-curing at 100° - 105°C for an additional 5 hours.
[00142] The average pore diameter of the foam, as observed by optical microscopy, as shown in the micrographs of Figures 15 and 16, was between 150 and 300 μm.
[00143] The subsequent foam testing was carried out in accordance with ASTM
D3574. Density was measured with specimens measuring 50 mm x 50 mm x 25 mm. The density was calculated by dividing the weight of the sample by the volume of the specimen; a value of 2.75 lbs/ft3 was obtained.
[00144] Tensile tests were conducted on samples that were cut both parallel and peφendicular to the direction of foam rise. The dog-bone shaped tensile specimens were cut from blocks of foam each about 12.5 mm thick, about 25.4 mm wide and about 140 mm long. Tensile properties (strength and elongation at break) were measured using an INSTRON Universal Testing Instrument Model 1122 with a cross- head speed of 500 mm/min (19.6 inches/minute). The average tensile strength, measured from two orthogonal directions parallel and peφendicular with respect to foam rise, were 67.6 psi and 56.44 psi, respectively. The elongation to break was approximately 46 %.
[00145] In the subsequent reticulation procedure, a block of foam was placed into a pressure chamber, the doors of the chamber were closed and an airtight seal was maintained. The pressure was reduced to remove substantially all of the air in the foam. A combustible ratio of hydrogen to oxygen gas was charged into the chamber for enough time to permeate all the samples. The gas in the chamber was then ignited by a spark plug. The ignition exploded the gasses within the foam cell structure. This explosion blew out many of the foam cell windows, thereby creating a reticulated elastomeric matrix structure.
[00146] Example 2 - Fabrication of a Crosslinked Reticulated Polyurethane
Matrix
[00147] Aromatic isocyanates, RUBINATE 9258 (from Huntsman; comprising a mixture of 4,4'-MDI and 2,4'-MDI), were used as the isocyanate component. RUBINATE 9258 contains about 68% by weight 4,4'-MDI, about 32% by weight 2,4'- MDI and has an isocyanate functionality of about 2.33 and is a liquid at at 25°C. A polyol - 1,6-hexamethylene carbonate (Desmophen LS 2391, Bayer Polymers), i.e., a diol, with a molecular weight of about 2,000 Daltons, was used as the polyol component and is a solid at 25°C. Water was used as the blowing agent. The blowing catalyst was the tertiary amine 33% triethylenediamine in dipropylene glycol (DABCO 33LV supplied by Air Products). A silicone-based surfactant was used (TEGOSTAB® BF 2370, supplied by Goldschmidt). The cell-opener was ORTEGOL® 501 (supplied by Goldschmidt). A viscosity depressant (Propylene carbonate supplied by Sigma- Aldrich) was also used. The proportions of the components that were used is given the following table:
Table 2 Ingredient Parts by Weight
Polyol Component - Desmophen LS 100 2391 5.76 Viscosity Depressant - Propylene carbonate 2.16
Surfactant - TEGOSTAB® BF 2370 0.48
Cell Opener - ORTEGOL® 501 53.8
Isocyanate Component RUBINATE 1.00 9258 2.82 Isocyanate Index 0.44 Distilled Water Blowing Catalyst
[00148] The polyol Desmophen LS 2391 was liquefied at 70 °C in an air circulation oven, and 150 gms of it was weighed into a polyethylene cup. 8.7 g of viscosity depressant (propylene carbonate) was added to the polyol and mixed with a drill mixer equipped with a mixing shaft at 3100 φm for 15 seconds (mix-1). 3.3 g of surfactant (Tegostab BF-2370) was added to mix-1 and mixed for additional 15 seconds (mix-2). 0.75 g of cell opener (Ortogel 501) was added to mix-2 and mixed for 15 seconds (mix-3). 80.9 g of isocyanate (Rubinate 9258) is added to mix-3 and mixed for 60±10 seconds (System A).
[00149] 4.2 g of distilled water was mixed with 0.66 g of blowing catalyst
(Dabco 33LV) in a small plastic cup by using a tiny glass rod for 60 seconds (System B).
[00150] System B was poured into System A as quickly as possible without spilling and with vigorous mixing with a drill mixer for 10 seconds and poured into cardboard box of 9 in. x 8 in. x 5 in., which was covered inside with aluminum foil. The foaming profile was as follows: mixing time of 10 sec, cream time of 18 sec. and rise time of 85 sec.
[00151] Two minutes after beginning of foam mixing, the foam was placed in the oven at 100 - 105°C for curing for 60minutes. The foam is taken from the oven and cooled for 15 minutes at room temperature. The skin is cut with the band saw, and the foamwais pressed by hand from all sides to open the cell windows. The foam was put back in an air-circulation oven for postcuring at 100° - 105°C for additional 5 hours.
[00152] The average pore diameter of the foam, as observed by optical microscopy, as shown in Figures 17 and 18, was between 150 and 450 μm.
[00153] Subsequent foam testing was carried out in accordance with ASTM
D3574. Density was measured with specimens measuring 50 mm x 50 mm x 25 mm. The density was calculated by dividing the weight of the sample by the volume of the specimen; a value of 2.5 lbs/ft was obtained.
[00154] Tensile tests were conducted on samples that were cut both parallel and peφendicular to the direction of foam rise. The dog-bone shaped tensile specimens were cut from blocks of foam each about 12.5 mm thick, about 25.4 mm wide and about 140 mm long. Tensile properties (strength and elongation at break) were measured using an INSTRON Universal Testing Instrument Model 1122 with a cross- head speed of 500 mm/min (19.6 inches/minute). The average tensile strength, measured from two orthogonal directions with respect to foam rise, was 24.64 + 2.35 psi. The elongation to break was approximately 215 + 12 %.
[00155] Compressive strengths of the foam were measured with specimens measuring 50 mm x 50 mm x 25 mm. The tests were conducted using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 10 mm/min (0.4 inches /min). The compressive strength at 50% was about 12 + 3 psi. The compression set after subjecting the sample to 50 % compression for 22 hours at 40 °C and releasing the stress was 2 %.
[00156] Tear resistance strength of the foam was measured with specimens measuring approximately 152 mm x 25 mm x 12.7 mm. A 40 mm cut was made on one side of each specimen. The tear strength was measured using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 500 mm/min (19.6 inches/minute). The tear strength was determined to be about 2.9 + 0. libs/inch.
[00157] The pore structure and its inter-connectivity is measured by Liquid
Extrusion Porosimeter (manufactured by Porous Materials, Inc. (Ithaca, NY). In this test, the pores of a 25.4 mm diameter sample is filled with a wetting fluid having a surface tension of 19 dynes/cm and loaded in a sample chamber with a 27 micron diameter pore membrane being placed under the sample . The pressure of air in the chamber space above the wetted sample is increased slowly so that the liquid is extruded from the pores of the sample. For low surface tension fluid, the contact angle is taken to be zero and the wetting liquid that spontaneously fills the pore of the test sample also spontaneously fill the pores of the membranes when the former is emptied under pressure with larger pores emptying out at lower pressures and smaller pores emptying out at higher pressure. The displaced liquid passes through the membrane and its volume measured. The differential pressure p required to displace liquid from a pore is related to its diameter D, surface tension of the liquid γ and the contact angle 0 by the relation p= 4 γ cos Θ/D. The gas pressure gives the pore diameter and the volume of the displaced liquid gives the pore volume or the intrusion volume accessible to the low surface tension liquid. Again measurement of liquid flow (water in this case) without the membrane under the sample and using similar pressure-flow methods yields liquid permeability. The liquid intrusion volume for the foam is 4 cc/gm and permeability of water through the foam is 1 lit/min/psi/sq cm.
[00158] In the subsequent reticulation procedure, a block of foam was placed into a pressure chamber, the doors of the chamber are closed, and an airtight seal was maintained. The pressure is reduced to remove substantially all of the air in the foam. A combustible ratio of hydrogen to oxygen gas was charged into the chamber for enough time to permeate all the samples. The gas in the chamber was then ignited by a spark plug. The ignition explodes the gasses within the foam cell structure. This explosion blew out many of the foam cell windows, thereby creating a reticulated elastomeric matrix structure.
[00159] Tensile tests were conducted on reticulated samples that were cut both parallel and peφendicular to the direction of foam rise. The dog-bone shaped tensile specimens were cut from blocks of foam each about 12.5 mm thick, about 25.4 mm wide and about 140 mm long. Tensile properties (strength and elongation at break) were measured using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 500 mm/min (19.6 inches/minute). The average tensile strength, measured from two orthogonal directions with respect to foam rise, was 23.5 psi. The elongation to break was approximately 194 %. [00160] Post reticulation compressive strengths of the foam were measured with specimens measuring 50 mm x 50 mm x 25 mm. The tests were conducted using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 10 mm/min (0.4 inches /min). The compressive strength at 50% was about 6.5 psi.
[00161] The pore structure and its inter-connectivity is measured by Liquid
Extrusion Porosimeter. The liquid intrusion volume for the reticulated foam is 28 cc/gm and permeability of water through the foam is 413 lit/min psi/sq cm. The results demonstrate the interconnected and continuous pore structure of the reticulated foam compared to the un-reticulated foam.
[00162] Example 3 -Fabrication of a Crosslinked Polyurethane Matrix
[00163] The aromatic isocyanate RUBINATE 9258 (from Huntsman) was used as the isocyanate component. RUBINATE 9258, which is a liquid at 25°C, contains 4,4'-MDI and 2,4'-MDI and has an isocyanate functionality of about 2.33. A diol, poly(l,6-hexanecarbonate)diol (POLY-CD CD220 from Arch Chemicals) with a molecular weight of about 2,000 Daltons was used as the polyol component and was a solid at 25°C. Distilled water was used as the blowing agent. The blowing catalyst used was the tertiary amine triethylenediamine (33% in dipropylene glycol; DABCO 33LV from Air Products). A silicone-based surfactant was used (TEGOSTAB® BF 2370 from Goldschmidt). A cell-opener was used (ORTEGOL® 501 from Goldschmidt). The viscosity modifier propylene carbonate (from Sigma- Aldrich) was present to reduce the viscosity. The proportions of the components that were used are set forth in the following table: Table 3
Ingredient Parts bv Weight Polyol Component 100 Viscosity Modifier 5.80 Surfactant 0.66 Cell Opener 1.00 Isocyanate Component 47.25 Isocyanate Index 1.00 Distilled Water 2.38 Blowing Catalyst 0.53
[00164] The polyol component was liquefied at 70°C in a circulating-air oven, and 100 g thereof was weighed out into a polyethylene cup. 5.8 g of viscosity modifier was added to the polyol component to reduce the viscosity, and the ingredients were mixed at 3100 φm for 15 seconds with the mixing shaft of a drill mixer to form "Mix-1". 0.66 g of surfactant was added to Mix-1, and the ingredients were mixed as described above for 15 seconds to form "Mix-2". Thereafter, 1.00 g of cell opener was added to Mix-2, and the ingredients were mixed as described above for 15 seconds to form "Mix-3". 47.25 g of isocyanate component were added to Mix- 3, and the ingredients were mixed for 60 ± 10 seconds to form "System A".
[00165] 2.38 g of distilled water was mixed with 0.53 g of blowing catalyst in a small plastic cup for 60 seconds with a glass rod to form "System B".
[00166] System B was poured into System A as quickly as possible while avoiding spillage. The ingredients were mixed vigorously with the drill mixer as described above for 10 seconds and then poured into a 22.9 cm x 20.3 cm x 12.7 cm (9 in. x 8 in. x 5 in.) cardboard box with its inside surfaces covered by aluminum foil. The foaming profile was as follows: 10 seconds mixing time, 17 seconds cream time, and 85 seconds rise time. [00167] Two minutes after the beginning of foaming, i.e., the time when
Systems A and B were combined, the foam was placed into a circulating-air oven maintained at 100-105°C for curing for from about 55 to about 60 minutes. Then, the foam was removed from the oven and cooled for 15 minutes at about 25°C. The skin was removed from each side using a band saw. Thereafter, hand pressure was applied to each side of the foam to open the cell windows. The foam was replaced into the circulating-air oven and postcured at 100-105°C for an additional four hours.
[00168] The average pore diameter of the foam, as determined from optical microscopy observations, was greater than about 275 μm.
[00169] The following foam testing was carried out according to ASTM D3574:
Bulk density was measured using specimens of dimensions 50 mm x 50 mm x 25 mm. The density was calculated by dividing the weight of the sample by the volume of the specimen. A density value of 2.81 lbs/ft (0.0450 g/cc) was obtained.
[00170] Tensile tests were conducted on samples that were cut either parallel to or peφendicular to the direction of foam rise. The dog-bone shaped tensile specimens were cut from blocks of foam. Each test specimen measured about 12.5 mm thick, about 25.4 mm wide, and about 140 mm long; the gage length of each specimen was 35 mm and the gage width of each specimen was 6.5 mm. Tensile properties (tensile strength and elongation at break) were measured using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 500 mm/min (19.6 inches/minute). The average tensile strength peφendicular to the direction of foam rise was determined as 29.3 psi (20,630 kg/m2). The elongation to break peφendicular to the direction of foam rise was determined to be 266%.
[00171] The measurement of the liquid flow through the material is measured in the following way using a iquid permeability apparatus or Liquid Permeaeter (Porous Materials, Inc., Ithaca, NY). The foam sample was 8.5 mm in thickness and covered a hole 6.6 mm in diameter in the center of a metal plate that was placed at the bottom of the Liquid Permeaeter filled with water. Thereafter, the air pressure above the sample was increased slowly to extrude the liquid from the sample and the permeability of water through the foam was determined to be 0.11 L/min/psi/cm .
[00172] Example 4 - Reticulation of a Crosslinked Polyurethane Foam
[00173] Reticulation of the foam described in Example 3 was carried out by the following procedure: A block of foam measuring approximately 15.25 cm x 15.25 cm x 7.6 cm (6 in. x 6 in. x 3 in.) was placed into a pressure chamber, the doors of the chamber were closed, and an airtight seal to the surrounding atmosphere was maintained. The pressure within the chamber was reduced to below about 100 millitorr by evacuation for at least about two minutes to remove substantially all of the air in the foam. A mixture of hydrogen and oxygen gas, present at a ratio sufficient to support combustion, was charged into the chamber over a period of at least about three minutes. The gas in the chamber was then ignited by a spark plug. The ignition exploded the gas mixture within the foam. The explosion was believed to have at least partially removed many of the cell walls between adjoining pores, thereby forming a reticulated elastomeric matrix structure.
[00174] The average pore diameter of the reticulated elastomeric matrix, as determined from optical microscopy observations, was greater than about 275 μm. A scanning electron micrograph image of the reticulated elastomeric matrix of this example (not shown here) demonstrated, e.g., the communication and interconnectivity of pores therein.
[00175] The density of the reticulated foam was determined as described above in Example 3. A post-reticulation density value of 2.83 lbs/ft3 (0.0453 g/cc) was obtained.
[00176] Tensile tests were conducted on reticulated foam samples as described above in Example 3. The average post-reticulation tensile strength peφendicular to the direction of foam rise was determined as about 26.4 psi (18,560 kg/m2). The post reticulation elongation to break peφendicular to the direction of foam rise was determined to be about 250%.. The average post-reticulation tensile strength parallel to the direction of foam rise was determined as about 43.3 psi (30,470 kg/m ). The post-reticulation elongation to break parallel to the direction of foam rise was determined to be about 270%.
[00177] Compressive tests were conducted using specimens measuring 50 mm x
50 mm x 25 mm. The tests were conducted using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 10 mm/min (0.4 inches /minute). The post-reticulation compressive strengths at 50% compression, parallel to and peφendicular to the direction of foam rise, were determined to be 1.53 psi (1,080 9 9 kg/m ) and 0.95 psi (669 kg/m ), respectively. The post-reticulation compressive strengths at 75% compression, parallel to and peφendicular to the direction of foam 7 rise, were determined to be 3.53 psi (2,485 kg/m ) and 2.02 psi (1,420 kg/m ), respectively. The post-reticulation compression set, determined after subjecting the reticulated sample to 50% compression for 22 hours at 25°C then releasing the compressive stress, parallel to the direction of foam rise, was determined to be about
4.5%.
[00178] The resilient recovery of the reticulated foam was measured by subjecting 1 inch (25.4 mm) diameter and 0.75 inch (19 mm) long foam cylinders to 75% uniaxial compression in their length direction for 10 or 30 minutes and measuring the time required for recovery to 90% ("t-90%") and 95% ("t-95%") of their initial length. The percentage recovery of the initial length after 10 minutes ("r- 10") was also determined. Separate samples were cut and tested with their length direction parallel to and peφendicular to the foam rise direction. The results obtained from an average of two tests are shown in the following table: Table 4
Figure imgf000064_0001
[00179] In contrast, a comparable foam with little to no reticulation typically has t-90 values of greater than about 60-90 seconds after 10 minutes of compression.
[00180] The measurement of the liquid flow through the material was measured in the following way using a Liquid permeability apparatus or Liquid Permeaeter (Porous Materials, Inc., Ithaca, NY). The foam samples were between 7.0 and 7.7 mm in thickness and covered a hole 8.2 mm in diameter in the center of a metal plate that was placed at the bottom of the Liquid Permeaeter filled with water. The water was allowed to extrude through the sample under gravity and the permeability of water through the foam was determined to be 180 L/min/psi/cm2 in the direction of foam nse and 160 L/min/psi/cm in the peφendicular to foam rise.
[00181] Example 5 - Fabrication of a Crosslinked Reticulated Polyurethane
Matrix
[00182] A crosslinked Polyurethane Matrix was made using similar starting materials and following procedures similar to the one described in Example 3. Glycerol was used as an additional starting material. The proportions of the components that were used are set forth in the following table: Table 5
Ingredient Parts by Weight PolyCD™CD220(g) 100 Propylene carbonate (g) 5.80 Tegostab BF-2370 (g) 1.50 Ortegol 501 (g) 1.00 Rubinate 9258 (g) 49.29 Distiled water) (g) 1.80 Dabco 33 LV (g) 0.50 Glycerine (g) 2.46
[00183] The reaction profile is as follows:
Figure imgf000065_0001
[00184] The average pore diameter of the foam, as determined from optical microscopy observations, was greater than about 225 μm.
[00185] The following foam testing was carried out according to ASTM D3574:
Bulk density was measured using specimens of dimensions 50 mm x 50 mm x 25 mm. The density was calculated by dividing the weight of the sample by the volume of the specimen. A density value of 3.65 lbs/ft3 (0.060 g/cc) was obtained.
[00186] Tensile tests were conducted on samples that were cut peφendicular to the direction of foam rise. The dog-bone shaped tensile specimens were cut from blocks of foam. Each test specimen measured about 12.5 mm thick, about 25.4 mm wide, and about 140 mm long; the gage length of each specimen was 35 mm and the gage width of each specimen was 6.5 mm. Tensile properties (tensile strength and elongation at break) were measured using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 500 mm/min (19.6 inches/minute). The average tensile strength peφendicular to the direction of foam rise was determined as 37.8 psi (26,500 kg/m2). The elongation to break peφendicular to the direction of foam rise was determined to be 141%.
[00187] Reticulation of the foam described above was carried out by the following procedure: A block of foam measuring approximately 15.25 cm x 15.25 cm x 7.6 cm (6 in. x 6 in. x 3 in.) was placed into a pressure chamber, the doors of the chamber were closed, and an airtight seal to the surrounding atmosphere was maintained. The pressure within the chamber was reduced to below about 100 millitorr by evacuation for at least about two minutes to remove substantially all of the air in the foam. A mixture of hydrogen and oxygen gas, present at a ratio sufficient to support combustion, was charged into the chamber over a period of at least about three minutes. The gas in the chamber was then ignited by a spark plug. The ignition exploded the gas mixture within the foam. The explosion was believed to have at least partially removed many of the cell walls between adjoining pores, thereby forming a reticulated elastomeric matrix structure.
[00188] A scanning electron micrograph image of the reticulated elastomeric matrix of this example (not shown here) demonstrated, e.g., the communication and interconnectivity of pores therein.
[00189] The density of the reticulated foam was determined as described above and a value of 4.00 lbs/ft (0.0656 g/cc) was obtained.
[00190] Tensile tests were conducted on reticulated foam samples as described above and the average post-reticulation tensile strength peφendicular to the direction of foam rise was determined as about 35.3 psi (24,680 kg/m2). The post-reticulation elongation to break peφendicular to the direction of foam rise was determined to be about 125%.
[00191] Compressive tests were conducted using specimens measuring 50 mm x
50 mm x 25 mm. The tests were conducted using an INSTRON Universal Testing Instrument Model 1122 with a cross-head speed of 10 mm min (0.4 inches /minute). The post-reticulation compressive strengths peφendicular to the direction of foam rise at 50% and 75 % compression strains were determined to be 3.83 psi (2,680 kg/m ) and 9.33 psi (6,530 kg/m2), respectively.
[00192] Example 6 - Testing in a Rabbit Model
[00193] An example of a device according to the invention, a cylindrical scaffold of reticulated polycarbonate prepared consistent with Examples 3 to 5, referred to as the "ARDX implant", was used for annular repair in the rabbit model of degenerative disc disease. This model is considered a standard model to evaluate the vertebral disc. See, for example, H.S. An et al., "Biological Repair of Intervertebral Disc," Spine, 2003 Aug. 1; 28 (15 Suppl.); D.G. Anderson et al., "Comparative Gene Expression Profiling of Normal and degenerative Discs: Analysis of a Rabbit Annular Laceration Mode," Spine. 2002 Jun 15; 27(12): 1291-96; and M.W. Kroeber et al., "New in Vivo Animal Model to Create Intervertebral Disc Degeneration and to Investigate the Effects of Therapeutic Strategy to Stimulate Disc Regeneration," Spine, 2002 Dec. 1 ; 27(23): 2684-90. Four adult female New Zealand rabbits were utilized for the experiment. Under a general anesthetic via a posterior-lateral approach, the lumbar spine was exposed. The annulus of disc spaces from LI to L5 were then incised in with a #15 scalpel laterally to induce the traumatic injury. Three of the annular defects were repaired with the ARDX implant, which was positioned into the spinal annular defect and secured with a non-resorbable suture. The fourth disc space was left unrepaired as a control. The animals were sacrificed at four weeks, and the spinal segments were processed for histology with H&E and SO stains. The findings at harvest showed excellent tolerance of the implants and grossly maintained disc space. The histology showed the preservation of the disc space and intact nucleus.
[00194] The ARDX implant was well integrated with good tissue in-growth, as is shown in the micrograph (No2L45 SO stain lOOx) of Fig. 19 and the closeup view in Fig. 20, where the implant 130 abuts nucleus 132 adjacent to annulus 134. Annulus 134 is in turn adjacent to vertebral end plate 136. In the detail shown in Fig. 20 new tissue growth 138 can be seen. A strut or projection 140 from implant 130 can be seen. The early regeneration of matrix secretion and organized collagen fibers preserved the disc space and prevented degeneration when compared to control samples.
[00195] Overall the ARDX implant device promoted repair and regeneration of spinal annulus and disc in the rabbit model.
[00196] While illustrative embodiments of the invention have been described above, it is, of course, understood that many and various modifications will be apparent to those in the relevant art, or may become apparent as the art develops. Such modifications are contemplated as being within the spirit and scope of the invention or inventions disclosed in this specification.

Claims

We Claim:
1. An apparatus that comprises a scaffold comprised of a biodurable, resiliently compressible, elastomeric reticulated composition to repair and/or regenerate spinal/vertebral connective tissue defects.
2. An apparatus that comprises a scaffold comprised of a biodurable, resiliently compressible, elastomeric reticulated composition to repair and/or regenerate spinal-annular nuclear tissue defects.
3. An apparatus that comprises a tissue scaffold comprised of a biodurable, resiliently compressible, elastomeric reticulated composition for spinal annulo-nucleoplasty regeneration.
4. An apparatus for one of Claims 1 to 3 that comprises an at least partially cylindrical member.
5. The apparatus of Claim 4, wherein, when the elastomeric composition is compressed from a relaxed configuration to a first, compact configuration for delivery via a delivery-device, it expands to a second, working configuration, in vitro, at least about 80% of the size of the relaxed configuration in at least one dimension.
6. The apparatus of Claim 5, wherein the recovery properties of the elastomeric composition are such that a dimension of the second, working configuration is within about 20% of a relaxed dimension of the relaxed configuration after compression to from about 50 to about 10% of the relaxed dimension.5.
7. The apparatus of Claim 4, wherein the elastomeric composition is hydrophobic.
8. The apparatus of Claim 4, wherein the elastomeric composition comprises a thermoplastic elastomer selected from the group consisting of polycarbonate polyurethanes, polyester polyurethanes, polyether polyurethanes, polysiloxane polyurethanes, polyurethanes with mixed soft segments, polycarbonates, polyesters, polyethers, polysiloxanes, polyurethanes, and mixtures of two or more thereof.
9. The apparatus of Claim 8, wherein the elastomeric composition comprises polyurethane.
10. The apparatus of Claim 8, wherein the elastomeric composition comprises a polycarbonate polyurethane.
11. The apparatus of Claim 8, wherein the thermoplastic elastomer is prepared by reacting a polyol component with an isocynanate component.
12. The apparatus of Claim 11, wherein the polyol component comprises a polycarbonate polyol, hydrocarbon polyol, polysiloxane polyol, poly(carbonate-co-hydrocarbon) polyol, poly(carbonate-co-siloxane) polyol, poly(hydrocarbon-co-siloxane) polyol, or mixtures thereof.
13. The apparatus of Claim 11 , wherein the polyol component comprises a difunctional polycarbonate diol.
14. The apparatus of Claim 11, wherein the isocyanate component comprises tetramethylene diisocyanate, cyclohexane-l,2-diisocyanate, cyclohexane- 1 ,4-diisocyanate, hexamethylene diisocyanate, isophorone diisocyanate, methylene- bis-(p-cyclohexyl isocyanate), p-phenylene diisocyanate, 4,4'-diphenylmethane diisocyanate, 2,4'-diphenylmethane diisocyanate, 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, m-tetramethylxylene diisocyanate, or mixtures thereof.
15. The apparatus of Claim 11, wherein the isocyanate component comprises MDI, wherein the MDI is a mixture of at least about 5% by weight of 2,4'- MDI with the balance 4,4'-MDI.
16. The apparatus of Claim 4, wherein the elastomeric composition comprises a reticulated elastomeric matrix comprising a plurality of pores, the pores having an average diameter or other largest transverse dimension of at least about 20 μm.
17. The apparatus of Claim 16, wherein the pores have an average diameter or other largest transverse dimension of from about 20 μm to about 150 μm.
18. The apparatus of Claim 16, wherein the pores have an average diameter or other largest transverse dimension of from about 150 μm to about 250 μm.
19. The apparatus of Claim 16, wherein the pores have an average diameter or other largest transverse dimension of from about 250 μm to about 500 μm.
20. The apparatus of Claim 4, wherein the elastomeric matrix has a compressive strength at 50% compression of from about 1 to about 500 psi, a tensile strength of from about 1 to about 500 psi, and an ultimate tensile elongation of at least about 25%.
21. The apparatus of Claim 4, wherein the elastomeric composition has a compression set after 22 hours compression at about 25°C to 25% of its thickness in one dimension of not more than about 50%.
22. The apparatus of Claim 4, wherein the reticulated elastomeric matrix is configured to permit cellular ingrowth and proliferation into the elastomeric matrix.
23. The apparatus of Claim 4, endoporously coating a reticulated elastomeric matrix with a coating material selected to encourage cellular ingrowth and proliferation.
24. The apparatus of Claim 4, wherein the coating material comprises a foamed coating of a biodegradable material, the biodegradable material comprising collagen, fibronectin, elastin, hyaluronic acid or mixtures thereof.
25. The apparatus of Claim 4, wherein the implantable device comprises a plurality of elastomeric matrices.
26. The apparatus of Claim 4 which comprises a structural component adapted to maintain the scaffold in a desired location.
27. The apparatus of Claim 26, wherein the structural component comprises a compressible element at least partially within the scaffold that compresses during delivery and expands or releases upon delivery to engage tissue.
28. The apparatus of Claim 27, wherein the structural component comprises a longitudinal shaft member with umbrella- like spokes.
29. The apparatus of Claim 27, wherein the structural component comprises one or more arrangements of radial projections.
30. The apparatus of Claim 29 which can be rotated in one direction to engage tissue and in another direction to disengage tissue.
31. A system for treating a spinal annular defect which comprises an apparatus of Claim 4 and a delivery means.
32. The system of Claim 31 , wherein the delivery means is a cannula, trocar, catheter, laproscope, or endoscope.
33. A method of treating spinal annular defects which comprises:
(a) inserting an apparatus of Claim 4 into the lumen of a delivery means;
(b) advancing the distal tip of the delivery means into an opening in an annulus;
(c) advancing the apparatus through the lumen into the opening; and
(d) withdrawing the delivery means, whereby the apparatus expands into the opening.
34. The method of Claim 33, wherein the delivery vehicle is a trocar, cannula, or catheter, with visual assistance through an endoscopic instrument.
PCT/US2004/043455 2003-12-24 2004-12-23 Repair of spnal annular defects and annulo-nucleoplasty regeneration WO2005065280A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2004311838A AU2004311838A1 (en) 2003-12-24 2004-12-23 Repair of spnal annular defects and annulo-nucleoplasty regeneration
CA002551133A CA2551133A1 (en) 2003-12-24 2004-12-23 Repair of spinal annular defects and annulo-nucleoplasty regeneration
EP04815520A EP1697082A2 (en) 2003-12-24 2004-12-23 Repair of spnal annular defects and annulo-nucleoplasty regeneration
JP2006547415A JP2007531557A (en) 2003-12-24 2004-12-23 Spinal ring defects and ring nucleation regeneration
US11/475,444 US20070162131A1 (en) 2004-12-23 2006-06-26 Repair of spinal annular defects

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/746,563 US7763077B2 (en) 2003-12-24 2003-12-24 Repair of spinal annular defects and annulo-nucleoplasty regeneration
US10/746,563 2003-12-24

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/475,444 Continuation-In-Part US20070162131A1 (en) 2004-12-23 2006-06-26 Repair of spinal annular defects

Publications (2)

Publication Number Publication Date
WO2005065280A2 true WO2005065280A2 (en) 2005-07-21
WO2005065280A3 WO2005065280A3 (en) 2007-04-19

Family

ID=34710707

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2004/043455 WO2005065280A2 (en) 2003-12-24 2004-12-23 Repair of spnal annular defects and annulo-nucleoplasty regeneration

Country Status (6)

Country Link
US (1) US7763077B2 (en)
EP (1) EP1697082A2 (en)
JP (1) JP2007531557A (en)
AU (1) AU2004311838A1 (en)
CA (1) CA2551133A1 (en)
WO (1) WO2005065280A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110153022A1 (en) * 2008-05-30 2011-06-23 Synthes Usa, Llc Balloon-assisted annulus repair
US11141427B2 (en) 2015-11-06 2021-10-12 University Health Network Compositions and methods for degenerative disc regeneration

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7998213B2 (en) 1999-08-18 2011-08-16 Intrinsic Therapeutics, Inc. Intervertebral disc herniation repair
WO2009033100A1 (en) 2007-09-07 2009-03-12 Intrinsic Therapeutics, Inc. Bone anchoring systems
US8323341B2 (en) 2007-09-07 2012-12-04 Intrinsic Therapeutics, Inc. Impaction grafting for vertebral fusion
US7717961B2 (en) 1999-08-18 2010-05-18 Intrinsic Therapeutics, Inc. Apparatus delivery in an intervertebral disc
EP1624832A4 (en) 1999-08-18 2008-12-24 Intrinsic Therapeutics Inc Devices and method for augmenting a vertebral disc nucleus
US7220281B2 (en) 1999-08-18 2007-05-22 Intrinsic Therapeutics, Inc. Implant for reinforcing and annulus fibrosis
MXPA03003600A (en) 1999-08-18 2004-12-02 Intrinsic Orthopedics Inc Devices and method for nucleus pulposus augmentation and retention.
US7972337B2 (en) 2005-12-28 2011-07-05 Intrinsic Therapeutics, Inc. Devices and methods for bone anchoring
US20040054414A1 (en) 2002-09-18 2004-03-18 Trieu Hai H. Collagen-based materials and methods for augmenting intervertebral discs
US7744651B2 (en) 2002-09-18 2010-06-29 Warsaw Orthopedic, Inc Compositions and methods for treating intervertebral discs with collagen-based materials
CN100394989C (en) 2002-11-15 2008-06-18 华沙整形外科股份有限公司 Collagen-based materials and methods for augmenting intervertebral discs
CA2525792C (en) 2003-05-15 2015-10-13 Biomerix Corporation Reticulated elastomeric matrices, their manufacture and use in implantable devices
US7763077B2 (en) 2003-12-24 2010-07-27 Biomerix Corporation Repair of spinal annular defects and annulo-nucleoplasty regeneration
US8771294B2 (en) 2004-11-26 2014-07-08 Biomerix Corporation Aneurysm treatment devices and methods
EP1954215A4 (en) * 2005-11-21 2012-12-19 Nicast Ltd Spinal nucleus prosthesis device
US7723422B2 (en) * 2005-12-23 2010-05-25 Boston Scientific Scimed, Inc. Functionalized block copolymers
US20070208426A1 (en) * 2006-03-03 2007-09-06 Sdgi Holdings, Inc. Spinal implant with improved surface properties for delivery
GB0605960D0 (en) * 2006-03-24 2006-05-03 Galley Geoffrey H Expandable spinal prosthesis
US20080004703A1 (en) * 2006-06-30 2008-01-03 Warsaw Orthopedic, Inc. Method of treating a patient using a collagen material
US20080004431A1 (en) * 2006-06-30 2008-01-03 Warsaw Orthopedic Inc Method of manufacturing an injectable collagen material
US8399619B2 (en) 2006-06-30 2013-03-19 Warsaw Orthopedic, Inc. Injectable collagen material
US8118779B2 (en) 2006-06-30 2012-02-21 Warsaw Orthopedic, Inc. Collagen delivery device
US20080082170A1 (en) * 2006-09-29 2008-04-03 Peterman Marc M Apparatus and methods for surgical repair
US20080107711A1 (en) * 2006-11-08 2008-05-08 Alexis Paul Shelokov Bioabsorbable Implantable Material Fortified with Antibiotics for Localized Delivery of Drugs
US8377016B2 (en) * 2007-01-10 2013-02-19 Wake Forest University Health Sciences Apparatus and method for wound treatment employing periodic sub-atmospheric pressure
US20080300684A1 (en) * 2007-05-31 2008-12-04 Shelokov Alexis P System and method for controlled delivery of bone morphogenic protein and other bone graft substitutes for bone formation, repair and healing
US8709054B2 (en) 2007-08-07 2014-04-29 Transcorp, Inc. Implantable vertebral frame systems and related methods for spinal repair
WO2009021144A2 (en) * 2007-08-07 2009-02-12 Transcorp, Inc. Device for variably adjusting intervertebral distraction and lordosis
US7867263B2 (en) * 2007-08-07 2011-01-11 Transcorp, Inc. Implantable bone plate system and related method for spinal repair
US8430882B2 (en) 2007-09-13 2013-04-30 Transcorp, Inc. Transcorporeal spinal decompression and repair systems and related methods
US8323320B2 (en) * 2007-09-13 2012-12-04 Transcorp, Inc. Transcorporeal spinal decompression and repair system and related method
WO2009036360A1 (en) * 2007-09-13 2009-03-19 Transcorp, Inc. Device and method for tissue retraction in spinal surgery
WO2009045912A2 (en) * 2007-09-28 2009-04-09 Transcorp, Inc. Vertebrally-mounted tissue retractor and method for use in spinal surgery
US20090112332A1 (en) * 2007-10-31 2009-04-30 Alexis Paul Shelokov Bone graft and bone graft substitutes with antibiotics for sustained, localized release of antibiotics for reducing postoperative surgical wound infection in spinal and other bone surgery
WO2009070607A1 (en) 2007-11-27 2009-06-04 Transcorp, Inc. Methods and systems for repairing an intervertebral disc using a transcorporal approach
KR20110070976A (en) 2008-07-18 2011-06-27 웨이크 포리스트 유니버시티 헬스 사이언시즈 Apparatus and method for cardiac tissue modulation by topical application of vacuum to minimize cell death and damage
US8801801B2 (en) * 2009-04-03 2014-08-12 Biomerix Corporation At least partially resorbable reticulated elastomeric matrix elements and methods of making same
WO2011003133A1 (en) * 2009-07-06 2011-01-13 Tony Goldschlager Surgical method and tool
US8273110B2 (en) * 2009-09-22 2012-09-25 Globus Medical, Inc. System and method for installing an annular repair rivet through a vertebral body port
US8425569B2 (en) 2010-05-19 2013-04-23 Transcorp, Inc. Implantable vertebral frame systems and related methods for spinal repair
WO2012097381A1 (en) * 2011-01-14 2012-07-19 Biomerix Corporation At least partially resorbable reticulated elastomeric matrix elements and methods of making same
US9114190B2 (en) 2013-02-08 2015-08-25 Laser Spine Institute, Llc Regeneration of spinal discs
US10561503B2 (en) * 2015-07-21 2020-02-18 Aleeva Medical Inc. Method for relieving pain and regenerating intervertebral disc
DE102016124049B4 (en) * 2016-12-12 2018-09-27 Christoph Karl Joint implant for tissue regeneration at the joint

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074582A1 (en) * 2000-03-31 2001-10-11 Hydrophilix Llc Foam composite
US20030074075A1 (en) * 2001-08-27 2003-04-17 Thomas James C. Expandable implant for partial disc replacement and reinforcement of a disc partially removed in a discectomy and for reduction and maintenance of alignment of cancellous bone fractures and methods and apparatuses for same

Family Cites Families (449)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US14118A (en) * 1856-01-15 stare
US198599A (en) * 1877-12-25 Improvement in tents
US1896071A (en) 1931-04-24 1933-02-07 George A Clark Pessary
US2546754A (en) 1947-11-19 1951-03-27 Jones John Leslie Vaginal applicator
US2616422A (en) 1948-10-18 1952-11-04 Jones John Leslie Vaginal applicator
US3279996A (en) 1962-08-28 1966-10-18 Jr David M Long Polysiloxane carrier for controlled release of drugs and other agents
US3175025A (en) 1963-04-05 1965-03-23 Chemotronics International Inc Process for bonding and/or reticulation
US3334629A (en) 1964-11-09 1967-08-08 Bertram D Cohn Occlusive device for inferior vena cava
US3896819A (en) 1969-04-01 1975-07-29 Alejandro Zaffaroni IUD having a replenishing drug reservoir
US3789841A (en) 1971-09-15 1974-02-05 Becton Dickinson Co Disposable guide wire
US6436135B1 (en) 1974-10-24 2002-08-20 David Goldfarb Prosthetic vascular graft
US3946106A (en) 1974-10-24 1976-03-23 G. D. Searle & Co. Microsealed pharmaceutical delivery device
US4374669A (en) 1975-05-09 1983-02-22 Mac Gregor David C Cardiovascular prosthetic devices and implants with porous systems
US4282199A (en) 1980-02-25 1981-08-04 J. M. Huber Corporation Carbon black process
US4315844A (en) 1980-07-08 1982-02-16 J. M. Huber Corporation Organic elastomers containing kaolin clay modified with isocyanate coupling agents and mercaptoethanol
US4545390A (en) 1982-09-22 1985-10-08 C. R. Bard, Inc. Steerable guide wire for balloon dilatation procedure
US4643184A (en) 1982-09-29 1987-02-17 Mobin Uddin Kazi Embolus trap
US4512338A (en) 1983-01-25 1985-04-23 Balko Alexander B Process for restoring patency to body vessels
US4503569A (en) 1983-03-03 1985-03-12 Dotter Charles T Transluminally placed expandable graft prosthesis
US4531916A (en) 1983-07-08 1985-07-30 W. L. Gore & Associates, Inc. Dental implant with expanded PTFE gingival interface
GB8428109D0 (en) 1984-11-07 1984-12-12 Biocompatibles Ltd Biocompatible surfaces
US5104392A (en) 1985-03-22 1992-04-14 Massachusetts Institute Of Technology Laser spectro-optic imaging for diagnosis and treatment of diseased tissue
US4619274A (en) 1985-04-18 1986-10-28 Advanced Cardiovascular Systems, Inc. Torsional guide wire with attenuated diameter
US4923464A (en) 1985-09-03 1990-05-08 Becton, Dickinson And Company Percutaneously deliverable intravascular reconstruction prosthesis
US4733665C2 (en) 1985-11-07 2002-01-29 Expandable Grafts Partnership Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft
US5133755A (en) 1986-01-28 1992-07-28 Thm Biomedical, Inc. Method and apparatus for diodegradable, osteogenic, bone graft substitute device
US4739768B2 (en) 1986-06-02 1995-10-24 Target Therapeutics Inc Catheter for guide-wire tracking
US4737152A (en) 1986-07-02 1988-04-12 Becton, Dickinson And Company Catheter assembly
FR2606641B1 (en) 1986-11-17 1991-07-12 Promed FILTERING DEVICE FOR BLOOD CLOTS
CA1340581C (en) 1986-11-20 1999-06-08 Joseph P. Vacanti Chimeric neomorphogenesis of organs by controlled cellular implantation using artificial matrices
DE3750480T2 (en) 1986-11-29 1995-03-02 Terumo Corp BALLOONED CATHETER.
DE3644588C1 (en) 1986-12-27 1988-03-10 Ethicon Gmbh Implant and process for its manufacture
US4890612A (en) 1987-02-17 1990-01-02 Kensey Nash Corporation Device for sealing percutaneous puncture in a vessel
JPS63238872A (en) 1987-03-25 1988-10-04 テルモ株式会社 Instrument for securing inner diameter of cavity of tubular organ and catheter equipped therewith
US4871542A (en) 1987-04-30 1989-10-03 Ferring Service Center, N.V. Method and apparatus useful for delivering medicinal compositions into the bladder and urinary tract
US5108438A (en) * 1989-03-02 1992-04-28 Regen Corporation Prosthetic intervertebral disc
US4813934A (en) 1987-08-07 1989-03-21 Target Therapeutics Valved catheter device and method
DK163713C (en) 1987-09-02 1992-09-07 Ole Gyring Nieben DEVICE FOR THE POSITION OF A PARTICULAR CATHETTE IN A BODY
US5035891A (en) 1987-10-05 1991-07-30 Syntex (U.S.A.) Inc. Controlled release subcutaneous implant
WO1989005319A1 (en) 1987-12-02 1989-06-15 Tyndale Plains-Hunter, Ltd. Hydrophilic polyurethanes of improved strength
US4832047A (en) 1987-12-15 1989-05-23 Target Therapeutics Guide wire device
FR2632864B2 (en) 1987-12-31 1990-10-19 Biomat Sarl ANTI-EMBOLIC ELASTIC FILTERING SYSTEM FOR CELLAR VEIN AND ASSEMBLY OF MEANS FOR ITS PLACEMENT
US4884579A (en) 1988-04-18 1989-12-05 Target Therapeutics Catheter guide wire
US4832055A (en) 1988-07-08 1989-05-23 Palestrant Aubrey M Mechanically locking blood clot filter
US5374261A (en) 1990-07-24 1994-12-20 Yoon; Inbae Multifunctional devices for use in endoscopic surgical procedures and methods-therefor
US5019090A (en) 1988-09-01 1991-05-28 Corvita Corporation Radially expandable endoprosthesis and the like
US5092877A (en) 1988-09-01 1992-03-03 Corvita Corporation Radially expandable endoprosthesis
US4913141A (en) 1988-10-25 1990-04-03 Cordis Corporation Apparatus and method for placement of a stent within a subject vessel
US4994069A (en) 1988-11-02 1991-02-19 Target Therapeutics Vaso-occlusion coil and method
GB2226245A (en) 1988-11-18 1990-06-27 Alan Crockard Endoscope, remote actuator and aneurysm clip applicator.
NZ228382A (en) 1989-03-17 1992-08-26 Carter Holt Harvey Plastic Pro Drug administering coil-like device for insertion in body cavity of animal
US4985467A (en) 1989-04-12 1991-01-15 Scotfoam Corporation Highly absorbent polyurethane foam
US5312356A (en) 1989-05-22 1994-05-17 Target Therapeutics Catheter with low-friction distal segment
US4955862A (en) 1989-05-22 1990-09-11 Target Therapeutics, Inc. Catheter and catheter/guide wire device
US5061914A (en) 1989-06-27 1991-10-29 Tini Alloy Company Shape-memory alloy micro-actuator
US5622188A (en) 1989-08-18 1997-04-22 Endovascular Instruments, Inc. Method of restoring reduced or absent blood flow capacity in an artery
DE69015926T2 (en) 1989-08-25 1995-05-18 Scimed Life Systems Inc Device for changing a catheter while holding the guide wire.
DE3929883A1 (en) 1989-09-08 1991-03-14 Akzo Gmbh METHOD FOR THE PRODUCTION OF DESOXYCELLULOSE CONVERSIONS
US5525348A (en) 1989-11-02 1996-06-11 Sts Biopolymers, Inc. Coating compositions comprising pharmaceutical agents
US5061274A (en) 1989-12-04 1991-10-29 Kensey Nash Corporation Plug device for sealing openings and method of use
US5122136A (en) 1990-03-13 1992-06-16 The Regents Of The University Of California Endovascular electrolytically detachable guidewire tip for the electroformation of thrombus in arteries, veins, aneurysms, vascular malformations and arteriovenous fistulas
US6083220A (en) 1990-03-13 2000-07-04 The Regents Of The University Of California Endovascular electrolytically detachable wire and tip for the formation of thrombus in arteries, veins, aneurysms, vascular malformations and arteriovenous fistulas
US6425893B1 (en) 1990-03-13 2002-07-30 The Regents Of The University Of California Method and apparatus for fast electrolytic detachment of an implant
US5354295A (en) 1990-03-13 1994-10-11 Target Therapeutics, Inc. In an endovascular electrolytically detachable wire and tip for the formation of thrombus in arteries, veins, aneurysms, vascular malformations and arteriovenous fistulas
US5851206A (en) 1990-03-13 1998-12-22 The Regents Of The University Of California Method and apparatus for endovascular thermal thrombosis and thermal cancer treatment
US5013316A (en) 1990-03-26 1991-05-07 Marlowe Goble E Soft tissue anchor system
US5064434A (en) 1990-04-04 1991-11-12 Haber Terry M Genitourinary implant
US5108407A (en) 1990-06-08 1992-04-28 Rush-Presbyterian St. Luke's Medical Center Method and apparatus for placement of an embolic coil
US5229431A (en) 1990-06-15 1993-07-20 Corvita Corporation Crack-resistant polycarbonate urethane polymer prostheses and the like
CA2038605C (en) 1990-06-15 2000-06-27 Leonard Pinchuk Crack-resistant polycarbonate urethane polymer prostheses and the like
US5098440A (en) 1990-08-14 1992-03-24 Cordis Corporation Object retrieval method and apparatus
US5167624A (en) 1990-11-09 1992-12-01 Catheter Research, Inc. Embolus delivery system and method
US5133731A (en) 1990-11-09 1992-07-28 Catheter Research, Inc. Embolus supply system and method
US5109867A (en) 1991-04-19 1992-05-05 Target Therapeutics Extendable guidewire assembly
US5228453A (en) 1991-05-07 1993-07-20 Target Therapeutics, Inc. Catheter guide wire
US5296518A (en) 1991-05-24 1994-03-22 Hampshire Chemical Corp. Hydrophilic polyurethaneurea foams containing no toxic leachable additives and method to produce such foams
US5217484A (en) 1991-06-07 1993-06-08 Marks Michael P Retractable-wire catheter device and method
US5308342A (en) 1991-08-07 1994-05-03 Target Therapeutics, Inc. Variable stiffness catheter
US5188621A (en) 1991-08-26 1993-02-23 Target Therapeutics Inc. Extendable guidewire assembly
US5226911A (en) 1991-10-02 1993-07-13 Target Therapeutics Vasoocclusion coil with attached fibrous element(s)
US5304194A (en) 1991-10-02 1994-04-19 Target Therapeutics Vasoocclusion coil with attached fibrous element(s)
US5256146A (en) 1991-10-11 1993-10-26 W. D. Ensminger Vascular catheterization system with catheter anchoring feature
EP0539237A1 (en) 1991-10-25 1993-04-28 Cook Incorporated Expandable transluminal graft prosthesis for repair of aneurysm and method for implanting
US5258000A (en) 1991-11-25 1993-11-02 Cook Incorporated Tissue aperture repair device
DK0791333T3 (en) 1991-12-12 2000-05-01 Target Therapeutics Inc Several extruder-carocclusion coil construction with interlocking coupling
US5234437A (en) 1991-12-12 1993-08-10 Target Therapeutics, Inc. Detachable pusher-vasoocclusion coil assembly with threaded coupling
US5261916A (en) 1991-12-12 1993-11-16 Target Therapeutics Detachable pusher-vasoocclusive coil assembly with interlocking ball and keyway coupling
EP0625891B1 (en) 1992-02-14 1997-01-08 Board Of Regents The University Of Texas System Multi-phase bioerodible implant/carrier and method of manufacturing and using same
US5263964A (en) 1992-05-06 1993-11-23 Coil Partners Ltd. Coaxial traction detachment apparatus and method
US5629008A (en) 1992-06-02 1997-05-13 C.R. Bard, Inc. Method and device for long-term delivery of drugs
ES2150427T3 (en) 1992-06-02 2000-12-01 Bard Inc C R PROCEDURE AND DEVICE OF IMPLANT FOR THE SUPPLY OF LONG-TERM DRUGS.
US5290295A (en) 1992-07-15 1994-03-01 Querals & Fine, Inc. Insertion tool for an intraluminal graft procedure
USRE37117E1 (en) 1992-09-22 2001-03-27 Target Therapeutics, Inc. Detachable embolic coil assembly using interlocking clasps and method of use
US5350397A (en) 1992-11-13 1994-09-27 Target Therapeutics, Inc. Axially detachable embolic coil assembly
IL106946A0 (en) 1992-09-22 1993-12-28 Target Therapeutics Inc Detachable embolic coil assembly
US5250071A (en) 1992-09-22 1993-10-05 Target Therapeutics, Inc. Detachable embolic coil assembly using interlocking clasps and method of use
US5312415A (en) 1992-09-22 1994-05-17 Target Therapeutics, Inc. Assembly for placement of embolic coils using frictional placement
US5356388A (en) 1992-09-22 1994-10-18 Target Therapeutics, Inc. Perfusion catheter system
US5382259A (en) 1992-10-26 1995-01-17 Target Therapeutics, Inc. Vasoocclusion coil with attached tubular woven or braided fibrous covering
IL103737A (en) 1992-11-13 1997-02-18 Technion Res & Dev Foundation Stapler device particularly useful in medical suturing
US5690666A (en) 1992-11-18 1997-11-25 Target Therapeutics, Inc. Ultrasoft embolism coils and process for using them
US5318527A (en) 1992-12-22 1994-06-07 Advanced Cardiovascular Systems, Inc. Fixed wire catheter exchange device
US5423849A (en) 1993-01-15 1995-06-13 Target Therapeutics, Inc. Vasoocclusion device containing radiopaque fibers
US5514378A (en) 1993-02-01 1996-05-07 Massachusetts Institute Of Technology Biocompatible polymer membranes and methods of preparation of three dimensional membrane structures
US5380334A (en) 1993-02-17 1995-01-10 Smith & Nephew Dyonics, Inc. Soft tissue anchors and systems for implantation
US5334210A (en) 1993-04-09 1994-08-02 Cook Incorporated Vascular occlusion assembly
US5800453A (en) 1993-04-19 1998-09-01 Target Therapeutics, Inc. Detachable embolic coil assembly using interlocking hooks and slots
US5925059A (en) 1993-04-19 1999-07-20 Target Therapeutics, Inc. Detachable embolic coil assembly
US5464650A (en) 1993-04-26 1995-11-07 Medtronic, Inc. Intravascular stent and method
US5409015A (en) 1993-05-11 1995-04-25 Target Therapeutics, Inc. Deformable tip super elastic guidewire
US5531715A (en) 1993-05-12 1996-07-02 Target Therapeutics, Inc. Lubricious catheters
AU7115294A (en) 1993-06-24 1995-01-24 Conceptus, Inc. Guidewire-type device axially moveable by torque or axial force and methods for use thereof
US5522895A (en) 1993-07-23 1996-06-04 Rice University Biodegradable bone templates
US5405322A (en) 1993-08-12 1995-04-11 Boston Scientific Corporation Method for treating aneurysms with a thermal source
EP0713364A4 (en) 1993-08-13 1996-12-27 Shalaby W Shalaby Microporous polymeric foams and microtextured surfaces
WO1995008354A1 (en) 1993-09-24 1995-03-30 Takiron Co., Ltd. Implantation material
US5723004A (en) 1993-10-21 1998-03-03 Corvita Corporation Expandable supportive endoluminal grafts
US5624449A (en) 1993-11-03 1997-04-29 Target Therapeutics Electrolytically severable joint for endovascular embolic devices
US5423829A (en) 1993-11-03 1995-06-13 Target Therapeutics, Inc. Electrolytically severable joint for endovascular embolic devices
US5615232A (en) 1993-11-24 1997-03-25 Novatel Communications Ltd. Method of estimating a line of sight signal propagation time using a reduced-multipath correlation function
US5487385A (en) 1993-12-03 1996-01-30 Avitall; Boaz Atrial mapping and ablation catheter system
US5730127A (en) 1993-12-03 1998-03-24 Avitall; Boaz Mapping and ablation catheter system
US5618314A (en) 1993-12-13 1997-04-08 Harwin; Steven F. Suture anchor device
US5935060A (en) 1996-07-12 1999-08-10 First Opinion Corporation Computerized medical diagnostic and treatment advice system including list based processing
US5486507A (en) 1994-01-14 1996-01-23 Fuisz Technologies Ltd. Porous particle aggregate and method therefor
US5429605A (en) 1994-01-26 1995-07-04 Target Therapeutics, Inc. Microballoon catheter
US5417708A (en) 1994-03-09 1995-05-23 Cook Incorporated Intravascular treatment system and percutaneous release mechanism therefor
US5686091A (en) 1994-03-28 1997-11-11 The Johns Hopkins University School Of Medicine Biodegradable foams for cell transplantation
JP2880070B2 (en) 1994-03-31 1999-04-05 株式会社カネカメディックス Medical wire having an indwelling member
US6475232B1 (en) 1996-12-10 2002-11-05 Purdue Research Foundation Stent with reduced thrombogenicity
EP0703798A1 (en) 1994-04-29 1996-04-03 Target Therapeutics, Inc. Method for producing lubricious catheters
US5556429A (en) * 1994-05-06 1996-09-17 Advanced Bio Surfaces, Inc. Joint resurfacing system
US6139510A (en) 1994-05-11 2000-10-31 Target Therapeutics Inc. Super elastic alloy guidewire
US5522819A (en) 1994-05-12 1996-06-04 Target Therapeutics, Inc. Dual coil medical retrieval device
US5725546A (en) 1994-06-24 1998-03-10 Target Therapeutics, Inc. Detachable microcoil delivery catheter
US5454795A (en) 1994-06-27 1995-10-03 Target Therapeutics, Inc. Kink-free spiral-wound catheter
EP0689805B1 (en) 1994-06-27 2003-05-28 Corvita Corporation Bistable luminal graft endoprostheses
US5522836A (en) 1994-06-27 1996-06-04 Target Therapeutics, Inc. Electrolytically severable coil assembly with movable detachment point
US5769899A (en) 1994-08-12 1998-06-23 Matrix Biotechnologies, Inc. Cartilage repair unit
US20020055786A1 (en) 1994-08-16 2002-05-09 Anthony Atala Reconstruction of urological structures with polymeric matrices
KR100341192B1 (en) 1994-08-17 2002-08-22 보스톤 사이언티픽 코포레이션 Implant, and method and device for inserting the implant
US5885278A (en) 1994-10-07 1999-03-23 E.P. Technologies, Inc. Structures for deploying movable electrode elements
CA2162620A1 (en) 1994-11-11 1996-05-12 Gene Samson Microcatheter-less coil delivery device
US6372228B1 (en) 1994-11-15 2002-04-16 Kenton W. Gregory Method of producing elastin, elastin-based biomaterials and tropoelastin materials
US5709934A (en) 1994-11-22 1998-01-20 Tissue Engineering, Inc. Bipolymer foams having extracellular matrix particulates
US5891558A (en) 1994-11-22 1999-04-06 Tissue Engineering, Inc. Biopolymer foams for use in tissue repair and reconstruction
US5690671A (en) 1994-12-13 1997-11-25 Micro Interventional Systems, Inc. Embolic elements and methods and apparatus for their delivery
US5814062A (en) 1994-12-22 1998-09-29 Target Therapeutics, Inc. Implant delivery assembly with expandable coupling/decoupling mechanism
US5578074A (en) 1994-12-22 1996-11-26 Target Therapeutics, Inc. Implant delivery method and assembly
IL116561A0 (en) 1994-12-30 1996-03-31 Target Therapeutics Inc Severable joint for detachable devices placed within the body
DK175166B1 (en) 1995-01-03 2004-06-21 Cook William Europ Method of manufacturing an assembly for placing an embolization coil in the vascular system and such assembly as well as an apparatus for advancing the assembly
US5750585A (en) 1995-04-04 1998-05-12 Purdue Research Foundation Super absorbent hydrogel foams
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
US5911731A (en) 1995-04-20 1999-06-15 Target Therapeutics, Inc. Anatomically shaped vasoocclusive devices
US5634926A (en) 1995-04-25 1997-06-03 Jobe; Richard P. Surgical bone fixation apparatus
US6143007A (en) 1995-04-28 2000-11-07 Target Therapeutics, Inc. Method for making an occlusive device
US5722989A (en) 1995-05-22 1998-03-03 The Regents Of The University Of California Microminiaturized minimally invasive intravascular micro-mechanical systems powered and controlled via fiber-optic cable
US5624461A (en) 1995-06-06 1997-04-29 Target Therapeutics, Inc. Three dimensional in-filling vaso-occlusive coils
US5766160A (en) 1995-06-06 1998-06-16 Target Therapeutics, Inc. Variable stiffness coils
NO962336L (en) 1995-06-06 1996-12-09 Target Therapeutics Inc Vaso-occlusive spiral
US5667513A (en) 1995-06-07 1997-09-16 Smith & Nephew Dyonics Inc. Soft tissue anchor delivery apparatus
US5820917A (en) 1995-06-07 1998-10-13 Medtronic, Inc. Blood-contacting medical device and method
US5989242A (en) 1995-06-26 1999-11-23 Trimedyne, Inc. Therapeutic appliance releasing device
US5725568A (en) 1995-06-27 1998-03-10 Scimed Life Systems, Inc. Method and device for recanalizing and grafting arteries
US5582619A (en) 1995-06-30 1996-12-10 Target Therapeutics, Inc. Stretch resistant vaso-occlusive coils
ATE197388T1 (en) 1995-06-30 2000-11-11 Target Therapeutics Inc EXPANSION-RESISTANT VASO-OCCLUSIVE SPIRAL
US5853418A (en) 1995-06-30 1998-12-29 Target Therapeutics, Inc. Stretch resistant vaso-occlusive coils (II)
US6019757A (en) 1995-07-07 2000-02-01 Target Therapeutics, Inc. Endoluminal electro-occlusion detection apparatus and method
US5782865A (en) 1995-08-25 1998-07-21 Grotz; Robert Thomas Stabilizer for human joints
US5601600A (en) 1995-09-08 1997-02-11 Conceptus, Inc. Endoluminal coil delivery system having a mechanical release mechanism
CA2186768C (en) 1995-09-29 2000-12-12 Pete Phong Pham Anatomically shaped vasoocclusive devices
US6440097B1 (en) 1995-10-06 2002-08-27 Target Therapeutics, Inc. Balloon catheter with delivery side holes
US5716413A (en) 1995-10-11 1998-02-10 Osteobiologics, Inc. Moldable, hand-shapable biodegradable implant material
AU690862B2 (en) 1995-12-04 1998-04-30 Target Therapeutics, Inc. Fibered micro vaso-occlusive devices
US5658308A (en) 1995-12-04 1997-08-19 Target Therapeutics, Inc. Bioactive occlusion coil
US5882334A (en) 1995-12-04 1999-03-16 Target Therapeutics, Inc. Balloon/delivery catheter assembly with adjustable balloon positioning
US6017388A (en) 1996-01-16 2000-01-25 Opta Food Ingredients, Inc. Starch-emulsifier composition and methods of making
US5749894A (en) 1996-01-18 1998-05-12 Target Therapeutics, Inc. Aneurysm closure method
US6168622B1 (en) 1996-01-24 2001-01-02 Microvena Corporation Method and apparatus for occluding aneurysms
US5702361A (en) 1996-01-31 1997-12-30 Micro Therapeutics, Inc. Method for embolizing blood vessels
US6638293B1 (en) 1996-02-02 2003-10-28 Transvascular, Inc. Methods and apparatus for blocking flow through blood vessels
US5776154A (en) 1996-02-20 1998-07-07 Cardiothoracic Systems, Inc. Surgical instruments for making precise incisions in a cardiac vessel
US5730757A (en) 1996-02-20 1998-03-24 Cardiothoracic Systems, Inc. Access platform for internal mammary dissection
CA2198036C (en) 1996-02-20 2000-12-05 Charles S. Taylor Access platform for internal mammary dissection
US5894843A (en) 1996-02-20 1999-04-20 Cardiothoracic Systems, Inc. Surgical method for stabilizing the beating heart during coronary artery bypass graft surgery
US5976171A (en) 1996-02-20 1999-11-02 Cardiothoracic Systems, Inc. Access platform for internal mammary dissection
US5925054A (en) 1996-02-20 1999-07-20 Cardiothoracic Systems, Inc. Perfusion device for maintaining blood flow in a vessel while isolating an anastomosis
US5769870A (en) 1996-02-20 1998-06-23 Cardiothoracic Systems, Inc. Perfusion device for maintaining blood flow in a vessel while isolating an anastomosis
CA2197614C (en) 1996-02-20 2002-07-02 Charles S. Taylor Surgical instruments and procedures for stabilizing the beating heart during coronary artery bypass graft surgery
US5871496A (en) 1996-03-20 1999-02-16 Cardiothoracic Systems, Inc. Surgical instrument for facilitating the detachment of an artery and the like
US5713949A (en) 1996-08-06 1998-02-03 Jayaraman; Swaminathan Microporous covered stents and method of coating
US6171298B1 (en) 1996-05-03 2001-01-09 Situs Corporation Intravesical infuser
EP0900051A1 (en) 1996-05-08 1999-03-10 Salviac Limited An occluder device
US6190402B1 (en) 1996-06-21 2001-02-20 Musc Foundation For Research Development Insitu formable and self-forming intravascular flow modifier (IFM) and IFM assembly for deployment of same
US5980514A (en) 1996-07-26 1999-11-09 Target Therapeutics, Inc. Aneurysm closure device assembly
US5741331A (en) 1996-07-29 1998-04-21 Corvita Corporation Biostable elastomeric polymers having quaternary carbons
US5823198A (en) 1996-07-31 1998-10-20 Micro Therapeutics, Inc. Method and apparatus for intravasculer embolization
US6054142A (en) 1996-08-01 2000-04-25 Cyto Therapeutics, Inc. Biocompatible devices with foam scaffolds
US5962620A (en) 1996-08-26 1999-10-05 Tyndale Plains-Hunter, Ltd. Hydrophicic and hydrophobic polyether polyurethanes and uses therefor
US5824081A (en) 1996-09-13 1998-10-20 Lipomatrix Incorporated Hydraulic foam tissue implant
JP3754145B2 (en) 1996-09-20 2006-03-08 株式会社カネカメディックス Medical wire having in-vivo indwelling member
AUPO251096A0 (en) * 1996-09-23 1996-10-17 Cardiac Crc Nominees Pty Limited Polysiloxane-containing polyurethane elastomeric compositions
US5895391A (en) 1996-09-27 1999-04-20 Target Therapeutics, Inc. Ball lock joint and introducer for vaso-occlusive member
US6984240B1 (en) 1996-10-25 2006-01-10 Target Therapeutics, Inc. Detachable multidiameter vasoocclusive coil
US6019771A (en) 1996-12-02 2000-02-01 Cardiothoracic Systems, Inc. Devices and methods for minimally invasive harvesting of a vessel especially the saphenous vein for coronary bypass grafting
US6039967A (en) 1997-04-03 2000-03-21 Point Biomedical Corporation Intravesical drug delivery system
US6111052A (en) * 1997-04-30 2000-08-29 Medtronic, Inc. Polyurethane and polyurea biomaterials for use in medical devices
US5891159A (en) 1997-05-02 1999-04-06 Cardiothoratic Systems, Inc. Automatic purse string suture device
US6190311B1 (en) 1997-05-02 2001-02-20 Cardiothoracic Systems, Inc. Retractor and instrument platform for a less invasive cardiovascular surgical procedure
US5891192A (en) 1997-05-22 1999-04-06 The Regents Of The University Of California Ion-implanted protein-coated intralumenal implants
US6531154B1 (en) 1997-06-10 2003-03-11 Brown University Research Foundation Modulated release from biocompatible polymers
US5951539A (en) 1997-06-10 1999-09-14 Target Therpeutics, Inc. Optimized high performance multiple coil spiral-wound vascular catheter
US5830183A (en) 1997-06-30 1998-11-03 Schneider (Usa) Inc Clip device for vascular catheter
AU8102698A (en) 1997-07-02 1999-01-25 Novo Nordisk A/S Starch conversion process using thermostable isoamylases from (sulfolobus)
US5928260A (en) 1997-07-10 1999-07-27 Scimed Life Systems, Inc. Removable occlusion system for aneurysm neck
US5944733A (en) 1997-07-14 1999-08-31 Target Therapeutics, Inc. Controlled detachable vasoocclusive member using mechanical junction and friction-enhancing member
AUPO787897A0 (en) 1997-07-14 1997-08-07 Cardiac Crc Nominees Pty Limited Silicon-containing chain extenders
US6042592A (en) 1997-08-04 2000-03-28 Meadox Medicals, Inc. Thin soft tissue support mesh
AU8772198A (en) 1997-08-05 1999-03-08 Target Therapeutics, Inc. Detachable aneurysm neck bridge
US6063070A (en) 1997-08-05 2000-05-16 Target Therapeutics, Inc. Detachable aneurysm neck bridge (II)
US5916235A (en) 1997-08-13 1999-06-29 The Regents Of The University Of California Apparatus and method for the use of detachable coils in vascular aneurysms and body cavities
US5863627A (en) 1997-08-26 1999-01-26 Cardiotech International, Inc. Hydrolytically-and proteolytically-stable polycarbonate polyurethane silicone copolymers
US6589199B1 (en) 1997-08-28 2003-07-08 Boston Scientific Corporation System for implanting a cross-linked polysaccharide fiber and methods of forming and inserting the fiber
US5984929A (en) 1997-08-29 1999-11-16 Target Therapeutics, Inc. Fast detaching electronically isolated implant
US6322576B1 (en) 1997-08-29 2001-11-27 Target Therapeutics, Inc. Stable coil designs
CA2307763A1 (en) 1997-11-07 1999-05-20 Fergal Farrell Biostable polycarbonate urethane products
ATE382309T1 (en) 1997-11-07 2008-01-15 Salviac Ltd EMBOLIC PROTECTION DEVICE
AU739610B2 (en) 1997-11-07 2001-10-18 Salviac Limited Implantable occluder devices for medical use
US6135193A (en) 1997-11-17 2000-10-24 Lloyd; Virginia R. Auto shade with decorative reflective surface
US5911728A (en) 1997-11-18 1999-06-15 Cardiothoracic Systems, Inc. Cannula purse string suture clamping device
US6136015A (en) 1998-08-25 2000-10-24 Micrus Corporation Vasoocclusive coil
US6159165A (en) 1997-12-05 2000-12-12 Micrus Corporation Three dimensional spherical micro-coils manufactured from radiopaque nickel-titanium microstrand
US6036720A (en) 1997-12-15 2000-03-14 Target Therapeutics, Inc. Sheet metal aneurysm neck bridge
US6203547B1 (en) 1997-12-19 2001-03-20 Target Therapeutics, Inc. Vaso-occlusion apparatus having a manipulable mechanical detachment joint and a method for using the apparatus
SE511312C2 (en) 1997-12-22 1999-09-06 Sandvik Ab Ways to manufacture whisker reinforced ceramics
US6011995A (en) 1997-12-29 2000-01-04 The Regents Of The University Of California Endovascular device for hyperthermia and angioplasty and method for using the same
US6001111A (en) 1998-01-16 1999-12-14 Cardiothoracic Systems, Inc. Low profile vessel occluder with and without detachable applicator
JP2003522550A (en) 1998-02-10 2003-07-29 アーテミス・メディカル・インコーポレイテッド Occlusion, fixation, tensioning, and diverting devices and methods of use
US6015422A (en) 1998-02-18 2000-01-18 Montefiore Hospital And Medical Center Collapsible low-profile vascular graft implantation instrument and method for use thereof
US5941888A (en) 1998-02-18 1999-08-24 Target Therapeutics, Inc. Vaso-occlusive member assembly with multiple detaching points
US6077260A (en) 1998-02-19 2000-06-20 Target Therapeutics, Inc. Assembly containing an electrolytically severable joint for endovascular embolic devices
US6824550B1 (en) 2000-04-06 2004-11-30 Norbon Medical, Inc. Guidewire for crossing occlusions or stenosis
US6379374B1 (en) 1998-10-22 2002-04-30 Cordis Neurovascular, Inc. Small diameter embolic coil hydraulic deployment system
US6068644A (en) 1998-03-10 2000-05-30 Cordis Corporation Embolic coil hydraulic deployment system having improved catheter
US6063100A (en) 1998-03-10 2000-05-16 Cordis Corporation Embolic coil deployment system with improved embolic coil
US6183491B1 (en) 1998-03-10 2001-02-06 Cordis Corporation Embolic coil deployment system with improved embolic coil
US6117142A (en) 1998-03-10 2000-09-12 Cordis Corporation Embolic coil hydraulic deployment system with improved syringe injector
US6113622A (en) 1998-03-10 2000-09-05 Cordis Corporation Embolic coil hydraulic deployment system
US6183461B1 (en) 1998-03-11 2001-02-06 Situs Corporation Method for delivering a medication
US5925060A (en) 1998-03-13 1999-07-20 B. Braun Celsa Covered self-expanding vascular occlusion device
US6036706A (en) 1998-03-13 2000-03-14 Cardiothoracic Systems, Inc. Vascular clamp and method for using the same
US6042563A (en) 1998-03-27 2000-03-28 Cardiothoracic Systems, Inc. Methods and apparatus for occluding a blood vessel
AUPP268898A0 (en) 1998-03-31 1998-04-23 Cardiac Crc Nominees Pty Limited High modulus polyurethane compositions
IE980241A1 (en) 1998-04-02 1999-10-20 Salviac Ltd Delivery catheter with split sheath
US6190357B1 (en) 1998-04-21 2001-02-20 Cardiothoracic Systems, Inc. Expandable cannula for performing cardiopulmonary bypass and method for using same
US6679915B1 (en) 1998-04-23 2004-01-20 Sdgi Holdings, Inc. Articulating spinal implant
EP1555036B1 (en) 1998-04-27 2010-05-05 Surmodics Inc. Bioactive agent release coating
US6015424A (en) 1998-04-28 2000-01-18 Microvention, Inc. Apparatus and method for vascular embolization
US6113629A (en) 1998-05-01 2000-09-05 Micrus Corporation Hydrogel for the therapeutic treatment of aneurysms
US6168615B1 (en) 1998-05-04 2001-01-02 Micrus Corporation Method and apparatus for occlusion and reinforcement of aneurysms
US6224630B1 (en) * 1998-05-29 2001-05-01 Advanced Bio Surfaces, Inc. Implantable tissue repair device
ID28196A (en) 1998-06-05 2001-05-10 Polyganics Bv BIOMEDICAL POLYURETHANE MANUFACTURE AND USE OF IT
US6368316B1 (en) 1998-06-11 2002-04-09 Target Therapeutics, Inc. Catheter with composite stiffener
US6139564A (en) 1998-06-16 2000-10-31 Target Therapeutics Inc. Minimally occlusive flow disruptor stent for bridging aneurysm necks
US5935148A (en) 1998-06-24 1999-08-10 Target Therapeutics, Inc. Detachable, varying flexibility, aneurysm neck bridge
US6117441A (en) 1998-07-02 2000-09-12 The Population Council, Inc. Silicone core long term androgen delivery implant
US6165193A (en) 1998-07-06 2000-12-26 Microvention, Inc. Vascular embolization with an expansible implant
US6102917A (en) 1998-07-15 2000-08-15 The Regents Of The University Of California Shape memory polymer (SMP) gripper with a release sensing system
US6093199A (en) 1998-08-05 2000-07-25 Endovascular Technologies, Inc. Intra-luminal device for treatment of body cavities and lumens and method of use
US6152943A (en) 1998-08-14 2000-11-28 Incept Llc Methods and apparatus for intraluminal deposition of hydrogels
US6149664A (en) 1998-08-27 2000-11-21 Micrus Corporation Shape memory pusher introducer for vasoocclusive devices
US6296622B1 (en) 1998-12-21 2001-10-02 Micrus Corporation Endoluminal device delivery system using axially recovering shape memory material
US6478773B1 (en) 1998-12-21 2002-11-12 Micrus Corporation Apparatus for deployment of micro-coil using a catheter
US6500149B2 (en) 1998-08-31 2002-12-31 Deepak Gandhi Apparatus for deployment of micro-coil using a catheter
US6224610B1 (en) 1998-08-31 2001-05-01 Micrus Corporation Shape memory polymer intravascular delivery system with heat transfer medium
AU5905599A (en) 1998-09-04 2000-03-27 Boston Scientific Limited Detachable aneurysm neck closure patch
US7410482B2 (en) 1998-09-04 2008-08-12 Boston Scientific-Scimed, Inc. Detachable aneurysm neck bridge
US6342062B1 (en) 1998-09-24 2002-01-29 Scimed Life Systems, Inc. Retrieval devices for vena cava filter
US6355030B1 (en) 1998-09-25 2002-03-12 Cardiothoracic Systems, Inc. Instruments and methods employing thermal energy for the repair and replacement of cardiac valves
US6277125B1 (en) 1998-10-05 2001-08-21 Cordis Neurovascular, Inc. Embolic coil deployment system with retaining jaws
US6277126B1 (en) 1998-10-05 2001-08-21 Cordis Neurovascular Inc. Heated vascular occlusion coil development system
US6454811B1 (en) * 1998-10-12 2002-09-24 Massachusetts Institute Of Technology Composites for tissue regeneration and methods of manufacture thereof
US6187024B1 (en) 1998-11-10 2001-02-13 Target Therapeutics, Inc. Bioactive coating for vaso-occlusive devices
US6723112B2 (en) 1998-11-10 2004-04-20 Scimed Life Systems, Inc. Bioactive three loop coil
US6063395A (en) 1998-11-12 2000-05-16 Leiras Oy Drug delivery device especially for the delivery of progestins and estrogens
US6540780B1 (en) 1998-11-23 2003-04-01 Medtronic, Inc. Porous synthetic vascular grafts with oriented ingrowth channels
US6102932A (en) 1998-12-15 2000-08-15 Micrus Corporation Intravascular device push wire delivery system
US6383204B1 (en) 1998-12-15 2002-05-07 Micrus Corporation Variable stiffness coil for vasoocclusive devices
EP1010396B1 (en) 1998-12-16 2003-05-07 Arthesys Catheter system for release of embolization coils by hydraulic pressure
US6835185B2 (en) 1998-12-21 2004-12-28 Micrus Corporation Intravascular device deployment mechanism incorporating mechanical detachment
US6306159B1 (en) 1998-12-23 2001-10-23 Depuy Orthopaedics, Inc. Meniscal repair device
US6086591A (en) 1999-01-29 2000-07-11 Smith & Nephew, Inc. Soft tissue anchor
US6309384B1 (en) 1999-02-01 2001-10-30 Adiana, Inc. Method and apparatus for tubal occlusion
FR2789400B1 (en) 1999-02-04 2002-12-20 Bio Ethanol Nord Picardie PROCESS FOR PRODUCING ETHANOL WITH FREQUENT YEAST SUPPLY
US6183518B1 (en) * 1999-02-22 2001-02-06 Anthony C. Ross Method of replacing nucleus pulposus and repairing the intervertebral disk
US6368338B1 (en) 1999-03-05 2002-04-09 Board Of Regents, The University Of Texas Occlusion method and apparatus
US6221066B1 (en) 1999-03-09 2001-04-24 Micrus Corporation Shape memory segmented detachable coil
US6428558B1 (en) 1999-03-10 2002-08-06 Cordis Corporation Aneurysm embolization device
US6293923B1 (en) 1999-03-15 2001-09-25 Innoventions, Inc. Intravesicular balloon
US6602291B1 (en) * 1999-04-05 2003-08-05 Raymedica, Inc. Prosthetic spinal disc nucleus having a shape change characteristic
US6428576B1 (en) 1999-04-16 2002-08-06 Endospine, Ltd. System for repairing inter-vertebral discs
US20040162519A1 (en) 1999-04-27 2004-08-19 Helkowski Richard A. Aortic occlusion balloon cannula
WO2000067813A1 (en) 1999-05-07 2000-11-16 Salviac Limited Biostable polyurethane products
AU3844599A (en) 1999-05-07 2000-11-21 Salviac Limited Biostable polyether polyurethane product
US6096060A (en) 1999-05-20 2000-08-01 Linvatec Corporation Bioabsorbable threaded soft tissue anchor system
US6139535A (en) 1999-05-27 2000-10-31 Situs Corporation Method and apparatus for placement and activation of a medical device within a body cavity
US6610317B2 (en) 1999-05-27 2003-08-26 Acusphere, Inc. Porous paclitaxel matrices and methods of manufacture thereof
US6245107B1 (en) * 1999-05-28 2001-06-12 Bret A. Ferree Methods and apparatus for treating disc herniation
US20020169473A1 (en) 1999-06-02 2002-11-14 Concentric Medical, Inc. Devices and methods for treating vascular malformations
US6379329B1 (en) 1999-06-02 2002-04-30 Cordis Neurovascular, Inc. Detachable balloon embolization device and method
US6375668B1 (en) 1999-06-02 2002-04-23 Hanson S. Gifford Devices and methods for treating vascular malformations
EP1867300A3 (en) 1999-06-02 2008-02-27 Sethel Interventional, Inc. Intracorporeal occlusive device
US6280457B1 (en) 1999-06-04 2001-08-28 Scimed Life Systems, Inc. Polymer covered vaso-occlusive devices and methods of producing such devices
US6355699B1 (en) 1999-06-30 2002-03-12 Ethicon, Inc. Process for manufacturing biomedical foams
US6306424B1 (en) 1999-06-30 2001-10-23 Ethicon, Inc. Foam composite for the repair or regeneration of tissue
US6333029B1 (en) 1999-06-30 2001-12-25 Ethicon, Inc. Porous tissue scaffoldings for the repair of regeneration of tissue
US6702848B1 (en) 1999-07-20 2004-03-09 Peter Paul Zilla Foam-type vascular prosthesis with well-defined anclio-permissive open porosity
US6312421B1 (en) 1999-07-23 2001-11-06 Neurovasx, Inc. Aneurysm embolization material and device
US7892246B2 (en) 1999-07-28 2011-02-22 Bioconnect Systems, Inc. Devices and methods for interconnecting conduits and closing openings in tissue
US6425919B1 (en) * 1999-08-18 2002-07-30 Intrinsic Orthopedics, Inc. Devices and methods of vertebral disc augmentation
US7220281B2 (en) 1999-08-18 2007-05-22 Intrinsic Therapeutics, Inc. Implant for reinforcing and annulus fibrosis
US6390096B1 (en) 1999-09-17 2002-05-21 Pi Medical, Inc. Needle with pre-loaded implant for snoring treatment
WO2001023891A1 (en) 1999-09-29 2001-04-05 Japan Science And Technology Corporation High sensitive immunoassay
US6664389B1 (en) 1999-10-01 2003-12-16 National Starch And Chemical Investment Holding Coporation Highly resistant granular starch
US6602261B2 (en) 1999-10-04 2003-08-05 Microvention, Inc. Filamentous embolic device with expansile elements
US6238403B1 (en) 1999-10-04 2001-05-29 Microvention, Inc. Filamentous embolic device with expansible elements
EP1225935A4 (en) 1999-10-12 2009-07-29 Allan R Will Methods and devices for protecting a passageway in a body
US6383171B1 (en) 1999-10-12 2002-05-07 Allan Will Methods and devices for protecting a passageway in a body when advancing devices through the passageway
US6592625B2 (en) * 1999-10-20 2003-07-15 Anulex Technologies, Inc. Spinal disc annulus reconstruction method and spinal disc annulus stent
US20030153976A1 (en) * 1999-10-20 2003-08-14 Cauthen Joseph C. Spinal disc annulus reconstruction method and spinal disc annulus stent
DE10010840A1 (en) 1999-10-30 2001-09-20 Dendron Gmbh Device for implanting occlusion coils uses coils electrolytically corrodable at several points at intervals so variable sized lengths can be separated by electrolysis
US6458127B1 (en) 1999-11-22 2002-10-01 Csaba Truckai Polymer embolic elements with metallic coatings for occlusion of vascular malformations
AU774481B2 (en) * 1999-12-06 2004-07-01 Warsaw Orthopedic, Inc. Intervertebral disc treatment devices and methods
US6355063B1 (en) 2000-01-20 2002-03-12 Impra, Inc. Expanded PTFE drug delivery graft
US6273897B1 (en) 2000-02-29 2001-08-14 Ethicon, Inc. Surgical bettress and surgical stapling apparatus
US6544225B1 (en) 2000-02-29 2003-04-08 Cordis Neurovascular, Inc. Embolic coil hydraulic deployment system with purge mechanism
US6346117B1 (en) 2000-03-02 2002-02-12 Prodesco, Inc. Bag for use in the intravascular treatment of saccular aneurysms
US6554842B2 (en) 2000-03-10 2003-04-29 Radius Medical Technologies, Inc. Small diameter snare
US6402750B1 (en) * 2000-04-04 2002-06-11 Spinlabs, Llc Devices and methods for the treatment of spinal disorders
US6579291B1 (en) * 2000-10-10 2003-06-17 Spinalabs, Llc Devices and methods for the treatment of spinal disorders
US6689125B1 (en) * 2000-04-04 2004-02-10 Spinalabs, Llc Devices and methods for the treatment of spinal disorders
WO2001078626A1 (en) 2000-04-13 2001-10-25 Sts Biopolymers, Inc. Targeted therapeutic agent release devices and methods of making and using the same
WO2001087575A2 (en) 2000-05-12 2001-11-22 The Regents Of The University Of Michigan Reverse fabrication of porous materials
US6514264B1 (en) 2000-06-01 2003-02-04 Cordis Neurovascular, Inc. Embolic coil hydraulic deployment system with purge mechanism
US6530934B1 (en) 2000-06-06 2003-03-11 Sarcos Lc Embolic device composed of a linear sequence of miniature beads
US6398718B1 (en) 2000-06-15 2002-06-04 Innoventions, Inc. Intravesicular device
IL137090A (en) 2000-06-29 2010-04-15 Pentech Medical Devices Ltd Polymeric stent
US7727243B2 (en) 2000-06-29 2010-06-01 Concentric Medical., Inc. Systems, methods and devices for removing obstructions from a blood vessel
US7727242B2 (en) 2000-06-29 2010-06-01 Concentric Medical, Inc. Systems, methods and devices for removing obstructions from a blood vessel
US6730104B1 (en) 2000-06-29 2004-05-04 Concentric Medical, Inc. Methods and devices for removing an obstruction from a blood vessel
US8298257B2 (en) 2000-06-29 2012-10-30 Concentric Medical, Inc. Systems, methods and devices for removing obstructions from a blood vessel
US7285126B2 (en) 2000-06-29 2007-10-23 Concentric Medical, Inc. Systems, methods and devices for removing obstructions from a blood vessel
US7766921B2 (en) 2000-06-29 2010-08-03 Concentric Medical, Inc. Systems, methods and devices for removing obstructions from a blood vessel
US20040073243A1 (en) 2000-06-29 2004-04-15 Concentric Medical, Inc., A Delaware Corporation Systems, methods and devices for removing obstructions from a blood vessel
US6824545B2 (en) 2000-06-29 2004-11-30 Concentric Medical, Inc. Systems, methods and devices for removing obstructions from a blood vessel
US20050288686A1 (en) 2000-06-29 2005-12-29 Concentric Medical, Inc., A Delaware Corporation Systems, methods and devices for removing obstructions from a blood vessel
US6663650B2 (en) 2000-06-29 2003-12-16 Concentric Medical, Inc. Systems, methods and devices for removing obstructions from a blood vessel
US6638312B2 (en) 2000-08-04 2003-10-28 Depuy Orthopaedics, Inc. Reinforced small intestinal submucosa (SIS)
US20050154463A1 (en) 2000-08-30 2005-07-14 Trieu Hal H. Spinal nucleus replacement implants and methods
US6723108B1 (en) 2000-09-18 2004-04-20 Cordis Neurovascular, Inc Foam matrix embolization device
US6605101B1 (en) 2000-09-26 2003-08-12 Microvention, Inc. Microcoil vaso-occlusive device with multi-axis secondary configuration
AU2001296800A1 (en) 2000-10-06 2002-04-15 Johns Hopkins University Systemic delivery of compounds through non-invasive bladder administration
US20030008015A1 (en) 2000-10-11 2003-01-09 Levisage Catherine S. Polymer controlled delivery of a therapeutic agent
US20040204701A1 (en) 2000-10-18 2004-10-14 Brian Cox Mechanism for the deployment of endovascular implants
US6689141B2 (en) 2000-10-18 2004-02-10 Microvention, Inc. Mechanism for the deployment of endovascular implants
US6607538B1 (en) 2000-10-18 2003-08-19 Microvention, Inc. Mechanism for the deployment of endovascular implants
US7445634B2 (en) * 2000-10-27 2008-11-04 Warsaw Orthopedic, Inc. Annulus repair systems and methods
US6589265B1 (en) 2000-10-31 2003-07-08 Endovascular Technologies, Inc. Intrasaccular embolic device
US6743251B1 (en) 2000-11-15 2004-06-01 Scimed Life Systems, Inc. Implantable devices with polymeric detachment junction
US20020072791A1 (en) 2000-12-07 2002-06-13 Eder Joseph C. Light-activated multi-point detachment mechanism
US6545097B2 (en) 2000-12-12 2003-04-08 Scimed Life Systems, Inc. Drug delivery compositions and medical devices containing block copolymer
US6623509B2 (en) 2000-12-14 2003-09-23 Core Medical, Inc. Apparatus and methods for sealing vascular punctures
US6852330B2 (en) 2000-12-21 2005-02-08 Depuy Mitek, Inc. Reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US6599323B2 (en) 2000-12-21 2003-07-29 Ethicon, Inc. Reinforced tissue implants and methods of manufacture and use
CA2365376C (en) 2000-12-21 2006-03-28 Ethicon, Inc. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US7192604B2 (en) 2000-12-22 2007-03-20 Ethicon, Inc. Implantable biodegradable devices for musculoskeletal repair or regeneration
US20020169497A1 (en) 2001-01-02 2002-11-14 Petra Wholey Endovascular stent system and method of providing aneurysm embolization
US7018394B2 (en) 2001-01-10 2006-03-28 Cordis Neurovascular, Inc. Embolic coil introducer system
US20030215564A1 (en) 2001-01-18 2003-11-20 Heller Phillip F. Method and apparatus for coating an endoprosthesis
US6702976B2 (en) 2001-01-29 2004-03-09 Witold Sokolowski Cold hibernated elastic memory self-deployable and rigidizable structure and method therefor
US6494884B2 (en) 2001-02-09 2002-12-17 Concentric Medical, Inc. Methods and devices for delivering occlusion elements
US6537569B2 (en) 2001-02-14 2003-03-25 Microvention, Inc. Radiation cross-linked hydrogels
US7169182B2 (en) 2001-07-16 2007-01-30 Spinecore, Inc. Implanting an artificial intervertebral disc
US20050177237A1 (en) 2001-04-12 2005-08-11 Ben Shappley Spinal cage insert, filler piece and method of manufacturing
US20020169066A1 (en) 2001-04-16 2002-11-14 Cerabio, L.L.C. Dense porous structures for use as bone substitutes
US6636758B2 (en) 2001-05-01 2003-10-21 Concentric Medical, Inc. Marker wire and process for using it
US20020177870A1 (en) 2001-05-25 2002-11-28 Ivan Sepetka Single lumen balloon catheter
US20020183858A1 (en) 2001-06-05 2002-12-05 Contiliano Joseph H. Attachment of absorbable tissue scaffolds to scaffold fixation devices
US6692510B2 (en) 2001-06-14 2004-02-17 Cordis Neurovascular, Inc. Aneurysm embolization device and deployment system
US6454780B1 (en) 2001-06-21 2002-09-24 Scimed Life Systems, Inc. Aneurysm neck obstruction device
US6702782B2 (en) 2001-06-26 2004-03-09 Concentric Medical, Inc. Large lumen balloon catheter
US6638245B2 (en) 2001-06-26 2003-10-28 Concentric Medical, Inc. Balloon catheter
US20030014075A1 (en) 2001-07-16 2003-01-16 Microvention, Inc. Methods, materials and apparatus for deterring or preventing endoleaks following endovascular graft implanation
ATE294535T1 (en) 2001-07-26 2005-05-15 Univ Oregon Health Sciences CLOSURE DEVICE FOR A VESSEL AND ATTACHMENT DEVICE
US6811560B2 (en) 2001-09-20 2004-11-02 Cordis Neurovascular, Inc. Stent aneurysm embolization method and device
WO2003037166A2 (en) 2001-11-01 2003-05-08 Boyd Lawrence M Devices and methods for the restoration of a spinal disc
US6811561B2 (en) 2001-11-15 2004-11-02 Cordis Neurovascular, Inc. Small diameter deployment system with improved headpiece
US6676624B2 (en) 2001-12-20 2004-01-13 Scimed Life Systems, Inc. Drainage devices and methods
US6953473B2 (en) 2001-12-20 2005-10-11 Boston Scientific Scimed, Inc. Detachable device with electrically responsive element
US20040068314A1 (en) 2002-01-16 2004-04-08 Jones Donald K. Detachable self -expanding aneurysm cover device
US6893464B2 (en) 2002-03-05 2005-05-17 The Regents Of The University Of California Method and apparatus for providing an expandable spinal fusion cage
US20030171773A1 (en) 2002-03-06 2003-09-11 Carrison Harold F. Methods for aneurysm repair
US6953465B2 (en) 2002-03-25 2005-10-11 Concentric Medical, Inc. Containers and methods for delivering vaso-occluding filaments and particles
US20030199887A1 (en) 2002-04-23 2003-10-23 David Ferrera Filamentous embolization device and method of use
US20030204246A1 (en) 2002-04-25 2003-10-30 Jack Chu Aneurysm treatment system and method
US7008979B2 (en) 2002-04-30 2006-03-07 Hydromer, Inc. Coating composition for multiple hydrophilic applications
US7044962B2 (en) * 2002-06-25 2006-05-16 Scimed Life Systems, Inc. Implantable prosthesis with displaceable skirt
US20050171572A1 (en) 2002-07-31 2005-08-04 Microvention, Inc. Multi-layer coaxial vaso-occlusive device
US20040044391A1 (en) 2002-08-29 2004-03-04 Stephen Porter Device for closure of a vascular defect and method of treating the same
US7025982B2 (en) 2002-09-19 2006-04-11 Medtronic, Inc. Medical assembly suitable for long-term implantation and method for fabricating the same
WO2004026371A2 (en) 2002-09-20 2004-04-01 Flowmedica, Inc. Method and apparatus for selective drug infusion via an intraaortic flow diverter delivery catheter
EP1585572A4 (en) 2002-09-20 2010-02-24 Flowmedica Inc Method and apparatus for intra aortic substance delivery to a branch vessel
AU2003276903A1 (en) 2002-09-20 2004-05-04 Flowmedica, Inc. Method and apparatus for selective material delivery via an intra-renal catheter
US7824701B2 (en) 2002-10-18 2010-11-02 Ethicon, Inc. Biocompatible scaffold for ligament or tendon repair
US6814746B2 (en) 2002-11-01 2004-11-09 Ev3 Peripheral, Inc. Implant delivery system with marker interlock
US20040115164A1 (en) 2002-12-17 2004-06-17 Pierce Ryan K. Soft filament occlusive device delivery system
US20050043585A1 (en) 2003-01-03 2005-02-24 Arindam Datta Reticulated elastomeric matrices, their manufacture and use in implantable devices
US20060015182A1 (en) * 2003-02-25 2006-01-19 Tsou Paul M Patch material for intervertebral disc annulus defect repair
US7368124B2 (en) 2003-03-07 2008-05-06 Depuy Mitek, Inc. Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof
US20040193246A1 (en) 2003-03-25 2004-09-30 Microvention, Inc. Methods and apparatus for treating aneurysms and other vascular defects
US20040265880A1 (en) 2003-05-09 2004-12-30 Sigma-Aldrich Co. Genomic and proteomic approaches for the development of cell culture medium
CA2525792C (en) 2003-05-15 2015-10-13 Biomerix Corporation Reticulated elastomeric matrices, their manufacture and use in implantable devices
WO2004103152A2 (en) 2003-05-16 2004-12-02 Spine Wave, Inc. Tissue distraction device
US20050060022A1 (en) 2003-05-21 2005-03-17 Felt Jeffrey C. Polymer stent
US20050021023A1 (en) 2003-07-23 2005-01-27 Scimed Life Systems, Inc. System and method for electrically determining position and detachment of an implantable device
US7723395B2 (en) 2004-04-29 2010-05-25 Kensey Nash Corporation Compressed porous materials suitable for implant
US20050149108A1 (en) 2003-12-17 2005-07-07 Microvention, Inc. Implant delivery and detachment system and method
US7763077B2 (en) 2003-12-24 2010-07-27 Biomerix Corporation Repair of spinal annular defects and annulo-nucleoplasty regeneration
US8012210B2 (en) 2004-01-16 2011-09-06 Warsaw Orthopedic, Inc. Implant frames for use with settable materials and related methods of use
US20050165480A1 (en) 2004-01-23 2005-07-28 Maybelle Jordan Endovascular treatment devices and methods
US7918872B2 (en) 2004-07-30 2011-04-05 Codman & Shurtleff, Inc. Embolic device delivery system with retractable partially coiled-fiber release
US20060025802A1 (en) 2004-07-30 2006-02-02 Sowers William W Embolic coil delivery system with U-shaped fiber release mechanism
US20060025801A1 (en) 2004-07-30 2006-02-02 Robert Lulo Embolic device deployment system with filament release
US7476249B2 (en) 2004-08-06 2009-01-13 Frank Robert E Implantable prosthesis for positioning and supporting a breast implant
WO2006024040A2 (en) 2004-08-25 2006-03-02 Microvention, Inc. Thermal detachment system for implantable devices
US20060052816A1 (en) 2004-08-31 2006-03-09 Cook Incorporated Device for treating an aneurysm
US7597703B2 (en) 2004-09-07 2009-10-06 Medtronic Vascular, Inc. Mechanically expandable occluder
US20060069323A1 (en) 2004-09-24 2006-03-30 Flowmedica, Inc. Systems and methods for bi-lateral guidewire cannulation of branched body lumens
US20060106420A1 (en) 2004-11-12 2006-05-18 Medtronic Vascular, Inc. Patch for treating a septal defect
US20060116714A1 (en) 2004-11-26 2006-06-01 Ivan Sepetka Coupling and release devices and methods for their assembly and use
US8771294B2 (en) 2004-11-26 2014-07-08 Biomerix Corporation Aneurysm treatment devices and methods
US20060116713A1 (en) 2004-11-26 2006-06-01 Ivan Sepetka Aneurysm treatment devices and methods
US20060116709A1 (en) 2004-11-26 2006-06-01 Ivan Sepetka Aneurysm treatment devices and methods
US7708754B2 (en) 2005-06-02 2010-05-04 Codman & Shurtleff, Pc Stretch resistant embolic coil delivery system with mechanical release mechanism
US7708755B2 (en) 2005-06-02 2010-05-04 Codman & Shurtleff Inc. Stretch resistant embolic coil delivery system with combined mechanical and pressure release mechanism
US7819892B2 (en) 2005-06-02 2010-10-26 Codman & Shurtleff, Inc. Embolic coil delivery system with spring wire release mechanism
US20060282112A1 (en) 2005-06-09 2006-12-14 Stephen Griffin Method and apparatus for enhanced electrolytic detachment
DE602007011251D1 (en) 2006-05-12 2011-01-27 Ev3 Inc IMPLANT AND RELEASE SYSTEM WITH SEVERAL MARKER LOCKS
JP5179089B2 (en) 2006-07-28 2013-04-10 テルモ株式会社 Medical long body

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074582A1 (en) * 2000-03-31 2001-10-11 Hydrophilix Llc Foam composite
US20030074075A1 (en) * 2001-08-27 2003-04-17 Thomas James C. Expandable implant for partial disc replacement and reinforcement of a disc partially removed in a discectomy and for reduction and maintenance of alignment of cancellous bone fractures and methods and apparatuses for same

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110153022A1 (en) * 2008-05-30 2011-06-23 Synthes Usa, Llc Balloon-assisted annulus repair
US11141427B2 (en) 2015-11-06 2021-10-12 University Health Network Compositions and methods for degenerative disc regeneration
US11141426B2 (en) 2015-11-06 2021-10-12 University Health Network Compositions and methods comprising growth factors, chondroitin and glucosamine for degenerative disc regeneration
US11471480B2 (en) 2015-11-06 2022-10-18 University Health Network Compositions and methods comprising growth factors, chondroitin and glucosamine for degenerative disc regeneration
US11491180B2 (en) 2015-11-06 2022-11-08 University Health Network Compositions and methods for degenerative disc regeneration

Also Published As

Publication number Publication date
WO2005065280A3 (en) 2007-04-19
CA2551133A1 (en) 2005-07-21
US20050149046A1 (en) 2005-07-07
EP1697082A2 (en) 2006-09-06
AU2004311838A1 (en) 2005-07-21
US7763077B2 (en) 2010-07-27
JP2007531557A (en) 2007-11-08

Similar Documents

Publication Publication Date Title
US7763077B2 (en) Repair of spinal annular defects and annulo-nucleoplasty regeneration
US20070162131A1 (en) Repair of spinal annular defects
AU2004241111B2 (en) Manufacture and use of implantable reticulated elastomeric matrices
US20110184530A1 (en) High performance reticulated elastomeric matrix preparation, properties, reinforcement, and use in surgical devices, tissue augmentation and/or tissue repair
US9050176B2 (en) At least partially resorbable reticulated elastomeric matrix elements and methods of making same
US9308076B2 (en) Bi-phasic compressed porous reinforcement materials suitable for implant
US8801801B2 (en) At least partially resorbable reticulated elastomeric matrix elements and methods of making same
US8021426B2 (en) Mechanical apparatus and method for artificial disc replacement
US20100318108A1 (en) Composite mesh devices and methods for soft tissue repair
EP1589899A1 (en) Reticulated elastomeric matrices, their manufacture and use in implantable devices
KR20050107426A (en) In-situ formed intervertebral fusion device and method
AU2007345699A1 (en) Mechanical apparatus and method for artificial disc replacement
AU2006317686A1 (en) Mechanical apparatus and method for artificial disc replacement
CN101472564A (en) High performance reticulated elastomeric matrix

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2004311838

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2004311838

Country of ref document: AU

Date of ref document: 20041223

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004311838

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004815520

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2551133

Country of ref document: CA

Ref document number: 2006547415

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 11475444

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

WWP Wipo information: published in national office

Ref document number: 2004815520

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 11475444

Country of ref document: US