US20100136082A1 - In situ system for intra-articular chondral and osseous tissue repair - Google Patents

In situ system for intra-articular chondral and osseous tissue repair Download PDF

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US20100136082A1
US20100136082A1 US12/520,850 US52085007A US2010136082A1 US 20100136082 A1 US20100136082 A1 US 20100136082A1 US 52085007 A US52085007 A US 52085007A US 2010136082 A1 US2010136082 A1 US 2010136082A1
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cartilage
repair patch
wound site
cartilage repair
stem cells
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Burkhard Mathies
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Laboratoire Medidom SA
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Laboratoire Medidom SA
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    • 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
    • A61F2/30756Cartilage endoprostheses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/22Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24Collagen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20Gaseous substances, e.g. vapours
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/20Polysaccharides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives 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
    • 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
    • A61F2/30756Cartilage endoprostheses
    • A61F2002/30766Scaffolds for cartilage ingrowth and regeneration
    • 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
    • A61F2/3094Designing or manufacturing processes
    • A61F2002/30971Laminates, i.e. layered products
    • 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

Definitions

  • the present invention is in the field of bioaffecting and body treating compositions having components associated as layers or impregnated matrix (believed to be classified in Class 424/400). Specifically, the present invention relates to compositions in a physical form to adapt for surgical implanting or inserting in the living body (believed to be classified in Class 424/400; 423). More specifically, the present invention relates to such compositions in which the surgical implant or material is errodable, resorbable, or dissolving (believed to be classified in Class 424/400; 423; 426).
  • the hyalinic articular cartilage is a specialized connective tissue in the body with weight bearing and shock absorbing properties and functions. Injury to or loss of this specialized connective tissue in a joint leads to pain and impaired joint function.
  • the orthopedic surgical arts field has been motivated to develop therapies which replace or promote regeneration of damaged joint cartilage. This is in response to the large number of joint injuries that occur yearly, and the increasing number of the elderly with joint problems.
  • these therapies are merely surgical methods which debride and mechanically repair the injury, with or without the addition to the injury site of an active composition to promote healing or to prevent inflammation/infection.
  • osteochondral injuries which are a combination lesion of bone and cartilage, represent therapeutic challenges, and fully satisfactory therapeutic compositions and treatment methods are still lacking in many cases.
  • certain surgical procedures for osteochondritis dissecans using autologous chondrocyte transplantation require extensive periods for the cell cultivation and growth aspect and multiple surgeries.
  • these therapies often result in the propagation of a fibrocartilaginous replacement tissue, which is a poor substitute for hyaline articular cartilage. See J. Kramer et al., Cell. Mol. Life Sci., 63, 616-626 (2006).
  • the present invention is an in situ healing/tissue growth promoting system and method, utilizing natural, non-human Hyaluronic Acid and 5 autologous mesenchymal stem cells to regenerate intra-articular cartilage lesions. More specifically, a system and method is provided that can stimulate growth of hyaline-like cartilage in situ to correct intra-articular cartilage defects.
  • the present system comprises a medical cartilage repair patch consisting of a natural composite 10 Hyaluronic Acid and collagen fiber matrix additionally embedded with growth hormones and/or growth factors, and Diacerein and/or Rhein compositions.
  • the system utilizes autologous mesenchymal stem-cells obtained through micro-fracture of the subchondral bone during installation of the cartilage repair patch as a component of the system to accomplish chondral and osseous tissue engineering in intra-articular defects.
  • the implantable laminate cartilage repair patch of the present invention is a surgical device that is bio-compatible and physiologically absorbable for in situ cartilage repair in intra-articular lesions.
  • the cartilage repair patch is a laminate or multi-layered device.
  • the device has a basement or bottom layer which is adapted to be disposed adjacent the bone site to be treated. This layer is “cell-porous” in that it allows the migration of cells from the wound site to pass through the layer.
  • On top of and closely associated with the basement layer is a cartilagenic matrix layer.
  • the cartilagenic matrix is a collagenous layer and is a sink for the diffusion of autologous stem cells and other blood components at the wound site.
  • the matrix layer includes chemical components which promote the generation of hyaline-like cartilage in the presence of the autologous stem cells.
  • the top layer may be occlusive to one degree or another, for example, not allow cells to pass through, but allowing other small things, like water, gas and small molecules to pass through. All of these elements and features in combination provide the flexible, bio-compatible materials which are physiologically absorbable laminate cartilage repair patch of the present invention.
  • FIG. 1 is a cross-sectional view of subchondral bone showing a chondral/osteo-chondral lesion where a section of cartilage covering the osseous portion of the bone is missing.
  • FIG. 2A is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, detailing the composition of the matrix of the patch wherein the collagen and the Hyaluronic Acid are disposed as fibers.
  • FIG. 2B is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, detailing the composition of the inner matrix of the patch, wherein the collagen is disposed as fibers and the Hyaluronic Acid is disposed as a cream suspension or as a viscoelastic solution.
  • FIG. 2C is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, showing a lower and an upper layer both having a mechanical stabilizing feature in each layer.
  • FIG. 2D is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, showing an embodiment having only a lower layer and with a mechanical stabilizing feature.
  • FIG. 2E is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, showing an embodiment wherein the lower layer has complex mechanical stabilizing features in it.
  • FIG. 3 is a generalized flow chart illustrating the main stages of the method of the present inventive system.
  • FIGS. 4A and 4B are cross-sectional views of a representative wound site and illustrate a first stage of preparation of the wound site to receive the present flexible laminate cartilage repair patch: (A) causing micro-fractures or perforations into the surface of the subchondral bone, and (B) forming a blood clot from local bleeding initiated by the causing of the micro-fractures.
  • FIG. 5 is a cross-sectional view of a representative wound site and illustrates a step of the second stage of the present system: applying the autologous serum enhanced “fibrin glue” at the wound site.
  • FIG. 6A is a cross-sectional view of a representative wound site and illustrates the placement of the flexible laminate cartilage repair patch to the wound site over a fibrin glue/blood clot.
  • FIG. 6B is a cross-sectional view of a representative wound site and illustrates the migration of Mesenchymal Stem Cells and other injury responsive blood components from the blood clot into the fibrin glue to form a blood clot/fibrin glue composite.
  • FIG. 6C is a cross-sectional view of a representative wound site and illustrates the migration of Mesenchymal Stem Cells and other injury responsive blood components from the blood clot/fibrin glue composite further still into the matrix of the cartilage repair patch.
  • FIG. 7 is a cross-sectional view of a representative wound site and illustrates the resultant repaired site after the cartilage repair patch has been reabsorbed and the site transformed into bone and/or a hyaline-like cartilage.
  • one of the problems faced in this field is how to promote regeneration of a cartilaginous tissue at the defect or wound site (cartilage lesion) 6 that is as close as possible to the natural cartilage 8 proximate the site, or as otherwise would have covered the subchondral bone 4 at the site 6 .
  • This is particularly challenging at wound sites where the lesion involve both cartilage and bone.
  • the present invention is an implantable cartilage repair patch 10 that is bio-compatible and physiologically absorbable, and that functions in situ to promote the regeneration of cartilage in intra-articular chondral or osteo-chondral lesions 6 (see FIG. 1 ).
  • the present cartilage repair patch 10 is a sterilizeable, flexible laminate 12 that can be implanted at a wound site 6 and act to promote the generation of hyaline-like cartilage.
  • the objective of the cartilage repair patch 10 is to stimulate growth of hyaline-like cartilage in-situ following arthroscopic or open surgical application of the cartilage repair patch 10 in patients with chondral or osteo-chondral damage.
  • An additional object is that the cartilage repair patch 10 is biodegradable through the interaction of its constituents with collagenase and other proteases and will be reabsorbed and disappear over time.
  • the laminate 12 of the cartilage repair patch 10 is constructed completely of materials that are both bio-compatible and physiologically absorbable, so that the cartilage repair patch can be implanted indwelling in a patient and disappear from the implantation site over time.
  • the cartilage repair patch laminate 12 has a first top (optionally occlusive) layer 16 , and a second bottom or basement porous layer 22 . See FIGS. 2A to 2C .
  • the cartilage repair patch laminate 12 is only two layers: a basement layer 22 and a matrix layer 30 . See FIGS. 2D and 2E .
  • the basement layer is intended to be interfaced with the surface of the bone at the wound site 6 .
  • Both of the basement layer 16 and the top layer 22 are made of sheet collagen (see Angele et al., U.S. Pat. No. 6,737,072. The content of which is incorporated herein by reference).
  • An example of a satisfactory commercially available source of sheet collagen is: XENODERMTM, Biometica AG, Switzerland.
  • Disposed on the porous basement layer 22 is a cartilagenic matrix layer 30 .
  • the cartilagenic matrix layer 30 provides a collagenous substrate in which to entrap mesenchymal stem-cells, and a cell growth support medium on which they will grow and differentiate into chondrocytes in presence of the other natural components of the matrix layer 30 .
  • the matrix layer 30 is a sterile or sterilizeable, porous collagenous composite pad, interspersed with non-human collagen fibers 36 and natural Hyaluronic Acid fibers 40 .
  • the natural collagen is derived from a non-human source, such as porcine, bovine or vegetal collagen.
  • the natural Hyaluronic Acid (HA) is derived from a natural non-mammalian source, such as via bacterial fermentation and via extraction from rooster combs. Other names for HA include: hyaluronic acid sodium salt, sodium hyaluronate, and hyaluronan.
  • the natural HA can be provided in the matrix 30 in form of natural HA fibers 40 as shown in FIG. 2A , or as HA powder 40 a in a gel or cream suspension 42 dispersed into the vacant spaces of the collagen fibers 36 as in FIG. 2B .
  • the composite cartilagenic matrix 30 also includes one or more tissue growth hormones (e.g., Somatotropine) and/or stimulators of growth factors 46 .
  • Growth factor stimulators are chemicals that enhance the expression of a growth factor at a given site.
  • the growth factor stimulators are Diacerein 46 a and Rhein 46 b.
  • the suspension 42 also contains Rhein 46 b and/or Diacerein 46 a.
  • the weight range ratio of collagen to HA should be from about 0.1:99.9 to about 50:50 when the natural HA has a molecular weight of between 0.5 to 6 million Dalton.
  • Diacerein or Rhein concentrations should be in the range of about 10 to 50 micromolar added to the matrix in a powder form or as HA gel or cream containing the Diacerein or Rhein.
  • Other compositions that are anticipated for inclusion in the matrix layer 30 include Chitosan compositions and Poly-Lactic Acid compositions.
  • the matrix fibers 40 & 40 a provide a support medium for the stem cells to grow and differentiate into chondrocytes.
  • the exogenous growth factors 46 such as Diacerein down regulate inflammatory parameters (e.g., cytokines: IL-1, TNF-alpha, alpha, and free radicals) which contribute to inflammation and cartilage breakdown.
  • Diacerein stimulates the production of certain growth factors, like TGF- ⁇ that additionally will stimulate production of cartilage components such as HA, collagen type-II, and proteoglycans (including aggrecans). Growth hormone will stimulate the production of cartilage and bone tissue. Further, endogenous growth factors 50 from an autologous serum fraction are added to the fibrin glue composition 54 stimulates differentiation of stem cells 60 in the blood clot/patch interface. The cumulative effect of these interactions leads to growth of hyaline-like cartilage.
  • FIG. 3 is a generalized flow chart illustrating the main stages of the method of the present inventive system.
  • the present system comprises three stages: preparation of the wound site 100 ; preparation and installation of the fibrin glue 120 ; and application of the cartilage repair patch 140 .
  • a blood sample is taken from the patient and an autologous serum fraction is obtained.
  • the autologous serum fraction is used as a source of wound healing components, such as TGF- ⁇ 1, and will be added at implantation within the fibrin-glue to the wound site 6 . These endogenous components will enhance mesenchymal stem cell differentiation.
  • micro-fractures/perforations are made at the subchondral bone surface 14 to cause local bleeding 58 which perfuses the wound site 6 with fresh blood. See FIG. 4A .
  • Causing local bleeding 58 at the subchondral bone surface 14 can be accomplished in a number of ways.
  • the preparation of the existing chondral or osteochondral lesions is accomplished by causing micro-fractures or perforations 56 in the surface 14 of the subchondral bone 4 —often associated with abrasion of sclerotic bone.
  • the micro-fractures/perforations/abrasions 56 in the subchondral bone 4 causes bleeding 58 into the wound site 6 .
  • the blood 58 entering the wound site 6 contains autologous mesenchymal stem cells 60 and other healing components released by the subchondral bone 4 in response to the causing of the micro-fractures, perforations or abrasions 56 .
  • the blood 58 that perfuses the wound site 6 results in a blood clot 59 that forms at the site.
  • the present system uses the micro-fracture technique to cause bleeding and stimulate release of autologous mesenchymal stem cells (MSCs) and growth factors into the clot 59 .
  • MSCs autologous mesenchymal stem cells
  • These pluripotential MSCs in the presence of the present cartilage repair patch 10 will differentiate into chondrocytes and produce extracellular hyaline-like cartilage matrix to repair/replace the existing chondral/osteo-chondral lesion 6 .
  • the second stage 120 of the method of the present system is accomplished.
  • This stage 120 is the preparation and application of the fibrin glue 54 to the blood clot 59 at the wound site 6 .
  • the fibrin glue 54 mingles with the fresh blood clot to form a blood clot/fibrin glue composite clot 54 - 59 .
  • other means of installing the fibrin glue 54 in place are known to and selectable by one of ordinary skill in the art for practice in the present system.
  • the cartilage repair patch 10 can be sutured in place (not shown).
  • the third stage 140 of the present method is then to be accomplished.
  • This third stage 140 is the placement of the flexible laminate repair patch 10 to the wound site over the fibrin glue/blood clot composite 59 / 54 at the wound site 6 .
  • the flexible laminate cartilage repair patch 10 is applied to the wound site 6 .
  • the fibrin glue 54 also may be freely applied after the repair patch 10 is in place to further accomplish adhering the repair patch 10 to the wound site 6 .
  • the surgical stages of the present system are completed and the cartilage repair patch 10 continues healing purpose in situ.
  • FIG. 6B Mesenchymal Stem Cells and other injury responsive blood components from the blood clot 59 migrate into the fibrin glue 54 .
  • FIG. 6C illustrates the further migration of the Mesenchymal Stem Cells and other injury responsive blood components from the fibrin glue/blood clot composite 54 / 59 continues through the porous outer layer 22 and into the matrix layer 30 of the cartilage repair patch 10 .
  • the mesenchymal stem cells and autologous growth factors interact with the constituents of the cartilage repair patch 10 .
  • the presence of these components results from their diffusion from the clot 59 into the cartilagenic matrix 30 of the cartilage repair patch 10 .
  • the occlusive layer 16 of the cartilage repair patch 10 prevents for a time the further diffusion of these different compositions into the joint space. Conversely, the mobile constituents of the matrix layer 30 can migrate out of the cartilage repair patch and into the mass of the fibrin clot 54 , and further, into the blood clot 59 at the surface 14 of the subchrondral bone 4 .
  • the Diacerein 46 a and the Rhein 46 b inhibit the production and activity of inflammatory cytokines such as IL-1 ⁇ , nitric oxide (NO), free radicals and matrix metalloproteinases all of which are involved in inflammation and cartilage destruction, particular in osteoarthritic joints.
  • the Diacerein 46 a and the Rhein 46 b also stimulate the production of growth factors such as TGF- ⁇ which in turn stimulates expression of cartilage components such as hyaluronic acid, proteoglycans, aggrecans and collagenase II, all of which are important components of cartilage matrix.
  • the growth hormone will also stimulate the growth of cartilage and bone tissue. Over time, as illustrated in FIG. 7 , the cartilage repair patch 10 is reabsorbed and the defect site 6 is relatively rapidly transformed into a more physiologically hyaline-like cartilage 90 .
  • a collagen sheet 22 (Xenoderm—porcine type 1 and 2 collagen) was used for the lower layer 22 .
  • the Lower layer had mechanical properties to resist shear and pull stress and was resorbable in about 6 weeks.
  • the collagen sheet 22 was put into a form, and then loaded with a collagen-HA suspension to which was added either a solution of Diacerein or Diacerein powder to obtain a concentration of 5-50 micromol. in dry-weight in patch after freeze-drying and sterilization.
  • the result is a double layer collagen-pad with the lower layer to be disposed adjacent the bone surface. After manufacturing and before sterilization, the pads are put into a mechanical press to obtain a thickness of 0.5-2 mm.
  • HA-concentration in the dry-frozen end product was in the range of about 0.1% to 2%.
  • the HA is natural HA, that is, non-chemically modified HA, of fermentation origin.
  • a device and therapy is provided which better promotes regeneration of damaged joint cartilage.
  • a treatment and device for osteochondral injuries is provided that does not require cell culture.
  • a treatment and device for such injuries that does not result in propagation of a fibrocartilaginous replacement tissue at the injury site.
  • a treatment and device which better insures that the resultant replacement tissue is appreciably representative of natural hyaline-like articular cartilage.

Abstract

Disclosed is a device and method which provide a surgical therapy for in situ treatment and repair of intra-articular cartilage lesions and/or defects. The device is an implantable laminate cartilage repair patch which is bio-compatible and physiologically absorbable. The cartilage repair patch has a first outer cell occlusive layer; a second outer, cell porous layer adapted to be disposed proximate a subchondral bone wound site; and a cartilagenic matrix disposed between the first and second layers. The cartilagenic matrix is a sink for diffusion of autologous stem cells and includes chemical components promoting generation of hyaline-like cartilage in the presence of the autologous stem cells. The method of the present invention provides the autologous compositions, which when used in combination with the repair patch provides a therapeutic system to regenerate replacement hyaline-like intraarticular cartilage.

Description

  • The present application claims the benefit of prior filed U.S. provisional patent application Ser. No. 60/871,554 filed 22 Dec. 2006, the content of which is incorporated herein by reference.
  • FIELD OF THE INVENTION
  • The present invention is in the field of bioaffecting and body treating compositions having components associated as layers or impregnated matrix (believed to be classified in Class 424/400). Specifically, the present invention relates to compositions in a physical form to adapt for surgical implanting or inserting in the living body (believed to be classified in Class 424/400; 423). More specifically, the present invention relates to such compositions in which the surgical implant or material is errodable, resorbable, or dissolving (believed to be classified in Class 424/400; 423; 426).
  • BACKGROUND OF THE INVENTION
  • One of the goals of medicine, including the surgical arts, is the recovery of health that has been lost, whether the loss occurred as a result of injury or disease. In the surgical arts, ever more effective treatment strategies for addressing cartilage defects are being sought. Such defects in joints (intra-articular) can result from a number of different causes, including trauma and diseases such as osteoarthritis. The hyalinic articular cartilage is a specialized connective tissue in the body with weight bearing and shock absorbing properties and functions. Injury to or loss of this specialized connective tissue in a joint leads to pain and impaired joint function.
  • Although the hyalinic articular cartilage does have some self-repairing capabilities, these are very limited. Therefore, the orthopedic surgical arts field has been motivated to develop therapies which replace or promote regeneration of damaged joint cartilage. This is in response to the large number of joint injuries that occur yearly, and the increasing number of the elderly with joint problems. Typically, these therapies are merely surgical methods which debride and mechanically repair the injury, with or without the addition to the injury site of an active composition to promote healing or to prevent inflammation/infection.
  • More recently, the field has tried bio-engineering influenced therapies which added a structural composition to the injury, such as autologous tissue grafts, in order to promote appropriate healing. However, osteochondral injuries, which are a combination lesion of bone and cartilage, represent therapeutic challenges, and fully satisfactory therapeutic compositions and treatment methods are still lacking in many cases. For example, certain surgical procedures for osteochondritis dissecans using autologous chondrocyte transplantation require extensive periods for the cell cultivation and growth aspect and multiple surgeries. Additionally, these therapies often result in the propagation of a fibrocartilaginous replacement tissue, which is a poor substitute for hyaline articular cartilage. See J. Kramer et al., Cell. Mol. Life Sci., 63, 616-626 (2006).
  • Therefore, it would be beneficial in the field to have alternative treatment for osteochondral injuries that do not require cell culture, and do not result in propagation of a fibrocartilaginous replacement tissue at the injury site. It would be even more advantageous if the resultant replacement tissue was appreciably representative of natural hyalinelike articular cartilage.
  • SUMMARY OF THE INVENTION
  • The present invention is an in situ healing/tissue growth promoting system and method, utilizing natural, non-human Hyaluronic Acid and 5 autologous mesenchymal stem cells to regenerate intra-articular cartilage lesions. More specifically, a system and method is provided that can stimulate growth of hyaline-like cartilage in situ to correct intra-articular cartilage defects. To this end, the present system comprises a medical cartilage repair patch consisting of a natural composite 10 Hyaluronic Acid and collagen fiber matrix additionally embedded with growth hormones and/or growth factors, and Diacerein and/or Rhein compositions. The system utilizes autologous mesenchymal stem-cells obtained through micro-fracture of the subchondral bone during installation of the cartilage repair patch as a component of the system to accomplish chondral and osseous tissue engineering in intra-articular defects.
  • The implantable laminate cartilage repair patch of the present invention is a surgical device that is bio-compatible and physiologically absorbable for in situ cartilage repair in intra-articular lesions. The cartilage repair patch is a laminate or multi-layered device. The device has a basement or bottom layer which is adapted to be disposed adjacent the bone site to be treated. This layer is “cell-porous” in that it allows the migration of cells from the wound site to pass through the layer. On top of and closely associated with the basement layer is a cartilagenic matrix layer. The cartilagenic matrix is a collagenous layer and is a sink for the diffusion of autologous stem cells and other blood components at the wound site. The matrix layer includes chemical components which promote the generation of hyaline-like cartilage in the presence of the autologous stem cells. Also optionally, the top layer may be occlusive to one degree or another, for example, not allow cells to pass through, but allowing other small things, like water, gas and small molecules to pass through. All of these elements and features in combination provide the flexible, bio-compatible materials which are physiologically absorbable laminate cartilage repair patch of the present invention.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a cross-sectional view of subchondral bone showing a chondral/osteo-chondral lesion where a section of cartilage covering the osseous portion of the bone is missing.
  • FIG. 2A is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, detailing the composition of the matrix of the patch wherein the collagen and the Hyaluronic Acid are disposed as fibers.
  • FIG. 2B is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, detailing the composition of the inner matrix of the patch, wherein the collagen is disposed as fibers and the Hyaluronic Acid is disposed as a cream suspension or as a viscoelastic solution.
  • FIG. 2C is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, showing a lower and an upper layer both having a mechanical stabilizing feature in each layer.
  • FIG. 2D is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, showing an embodiment having only a lower layer and with a mechanical stabilizing feature.
  • FIG. 2E is a cross-sectional side view of the sterilizeable, flexible laminate wound cartilage repair patch of the present invention, showing an embodiment wherein the lower layer has complex mechanical stabilizing features in it.
  • FIG. 3 is a generalized flow chart illustrating the main stages of the method of the present inventive system.
  • FIGS. 4A and 4B are cross-sectional views of a representative wound site and illustrate a first stage of preparation of the wound site to receive the present flexible laminate cartilage repair patch: (A) causing micro-fractures or perforations into the surface of the subchondral bone, and (B) forming a blood clot from local bleeding initiated by the causing of the micro-fractures.
  • FIG. 5 is a cross-sectional view of a representative wound site and illustrates a step of the second stage of the present system: applying the autologous serum enhanced “fibrin glue” at the wound site.
  • FIG. 6A is a cross-sectional view of a representative wound site and illustrates the placement of the flexible laminate cartilage repair patch to the wound site over a fibrin glue/blood clot.
  • FIG. 6B is a cross-sectional view of a representative wound site and illustrates the migration of Mesenchymal Stem Cells and other injury responsive blood components from the blood clot into the fibrin glue to form a blood clot/fibrin glue composite.
  • FIG. 6C is a cross-sectional view of a representative wound site and illustrates the migration of Mesenchymal Stem Cells and other injury responsive blood components from the blood clot/fibrin glue composite further still into the matrix of the cartilage repair patch.
  • FIG. 7 is a cross-sectional view of a representative wound site and illustrates the resultant repaired site after the cartilage repair patch has been reabsorbed and the site transformed into bone and/or a hyaline-like cartilage.
  • DETAILED DESCRIPTION OF THE INVENTION
  • Referring now to the drawings, the details of preferred embodiments of the present invention are graphically and schematically illustrated. Like elements in the drawings are represented by like numbers, and any similar elements are represented by like numbers with a different lower case letter suffix.
  • As shown in FIG. 1, one of the problems faced in this field is how to promote regeneration of a cartilaginous tissue at the defect or wound site (cartilage lesion) 6 that is as close as possible to the natural cartilage 8 proximate the site, or as otherwise would have covered the subchondral bone 4 at the site 6. This is particularly challenging at wound sites where the lesion involve both cartilage and bone.
  • As shown in FIGS. 2A to 2E, the present invention is an implantable cartilage repair patch 10 that is bio-compatible and physiologically absorbable, and that functions in situ to promote the regeneration of cartilage in intra-articular chondral or osteo-chondral lesions 6 (see FIG. 1). The present cartilage repair patch 10 is a sterilizeable, flexible laminate 12 that can be implanted at a wound site 6 and act to promote the generation of hyaline-like cartilage. The objective of the cartilage repair patch 10 is to stimulate growth of hyaline-like cartilage in-situ following arthroscopic or open surgical application of the cartilage repair patch 10 in patients with chondral or osteo-chondral damage. An additional object is that the cartilage repair patch 10 is biodegradable through the interaction of its constituents with collagenase and other proteases and will be reabsorbed and disappear over time.
  • The laminate 12 of the cartilage repair patch 10 is constructed completely of materials that are both bio-compatible and physiologically absorbable, so that the cartilage repair patch can be implanted indwelling in a patient and disappear from the implantation site over time. In one embodiment, the cartilage repair patch laminate 12 has a first top (optionally occlusive) layer 16, and a second bottom or basement porous layer 22. See FIGS. 2A to 2C. In another preferred embodiment, the cartilage repair patch laminate 12 is only two layers: a basement layer 22 and a matrix layer 30. See FIGS. 2D and 2E. The basement layer is intended to be interfaced with the surface of the bone at the wound site 6. Both of the basement layer 16 and the top layer 22 are made of sheet collagen (see Angele et al., U.S. Pat. No. 6,737,072. The content of which is incorporated herein by reference). An example of a satisfactory commercially available source of sheet collagen is: XENODERM™, Biometica AG, Switzerland. Disposed on the porous basement layer 22 is a cartilagenic matrix layer 30. The cartilagenic matrix layer 30 provides a collagenous substrate in which to entrap mesenchymal stem-cells, and a cell growth support medium on which they will grow and differentiate into chondrocytes in presence of the other natural components of the matrix layer 30.
  • In a preferred embodiment, the matrix layer 30 is a sterile or sterilizeable, porous collagenous composite pad, interspersed with non-human collagen fibers 36 and natural Hyaluronic Acid fibers 40. The natural collagen is derived from a non-human source, such as porcine, bovine or vegetal collagen. The natural Hyaluronic Acid (HA) is derived from a natural non-mammalian source, such as via bacterial fermentation and via extraction from rooster combs. Other names for HA include: hyaluronic acid sodium salt, sodium hyaluronate, and hyaluronan. The natural HA can be provided in the matrix 30 in form of natural HA fibers 40 as shown in FIG. 2A, or as HA powder 40 a in a gel or cream suspension 42 dispersed into the vacant spaces of the collagen fibers 36 as in FIG. 2B.
  • In the preferred embodiment, the composite cartilagenic matrix 30 also includes one or more tissue growth hormones (e.g., Somatotropine) and/or stimulators of growth factors 46. Growth factor stimulators are chemicals that enhance the expression of a growth factor at a given site. In the embodiment illustrated, the growth factor stimulators are Diacerein 46 a and Rhein 46 b. In the embodiment illustrated in FIG. 2B, the suspension 42 also contains Rhein 46 b and/or Diacerein 46 a. The weight range ratio of collagen to HA should be from about 0.1:99.9 to about 50:50 when the natural HA has a molecular weight of between 0.5 to 6 million Dalton. The Diacerein or Rhein concentrations should be in the range of about 10 to 50 micromolar added to the matrix in a powder form or as HA gel or cream containing the Diacerein or Rhein. Other compositions that are anticipated for inclusion in the matrix layer 30 include Chitosan compositions and Poly-Lactic Acid compositions.
  • Autologous mesenchymal stem cells 60 derived from a source external to the cartilage repair patch 10 diffuse into the patch 10 through the porous basement layer 22 and into the matrix layer 30 where they are supported by the fibrous components (collagen fibers 36 and /or HA fibers 40 a) of the matrix 30. The matrix fibers 40 & 40 a provide a support medium for the stem cells to grow and differentiate into chondrocytes. The exogenous growth factors 46, such as Diacerein down regulate inflammatory parameters (e.g., cytokines: IL-1, TNF-alpha, alpha, and free radicals) which contribute to inflammation and cartilage breakdown. Diacerein stimulates the production of certain growth factors, like TGF-β that additionally will stimulate production of cartilage components such as HA, collagen type-II, and proteoglycans (including aggrecans). Growth hormone will stimulate the production of cartilage and bone tissue. Further, endogenous growth factors 50 from an autologous serum fraction are added to the fibrin glue composition 54 stimulates differentiation of stem cells 60 in the blood clot/patch interface. The cumulative effect of these interactions leads to growth of hyaline-like cartilage.
  • FIG. 3 is a generalized flow chart illustrating the main stages of the method of the present inventive system. In a preferred method of use, the present system comprises three stages: preparation of the wound site 100; preparation and installation of the fibrin glue 120; and application of the cartilage repair patch 140. In the first stage 100, as part of the set up, a blood sample is taken from the patient and an autologous serum fraction is obtained. The autologous serum fraction is used as a source of wound healing components, such as TGF-β1, and will be added at implantation within the fibrin-glue to the wound site 6. These endogenous components will enhance mesenchymal stem cell differentiation.
  • Also in this stage, micro-fractures/perforations are made at the subchondral bone surface 14 to cause local bleeding 58 which perfuses the wound site 6 with fresh blood. See FIG. 4A. Causing local bleeding 58 at the subchondral bone surface 14 can be accomplished in a number of ways. In the preferred embodiment illustrated in FIG. 4B, the preparation of the existing chondral or osteochondral lesions is accomplished by causing micro-fractures or perforations 56 in the surface 14 of the subchondral bone 4—often associated with abrasion of sclerotic bone. As shown in the figure, the micro-fractures/perforations/abrasions 56 in the subchondral bone 4 causes bleeding 58 into the wound site 6. The blood 58 entering the wound site 6 contains autologous mesenchymal stem cells 60 and other healing components released by the subchondral bone 4 in response to the causing of the micro-fractures, perforations or abrasions 56.
  • As shown in FIG. 4B, the blood 58 that perfuses the wound site 6 results in a blood clot 59 that forms at the site. The present system uses the micro-fracture technique to cause bleeding and stimulate release of autologous mesenchymal stem cells (MSCs) and growth factors into the clot 59. These pluripotential MSCs in the presence of the present cartilage repair patch 10 will differentiate into chondrocytes and produce extracellular hyaline-like cartilage matrix to repair/replace the existing chondral/osteo-chondral lesion 6.
  • After the wound site 6 is prepared, the second stage 120 of the method of the present system is accomplished. This stage 120 is the preparation and application of the fibrin glue 54 to the blood clot 59 at the wound site 6. As shown in FIG. 5, the fibrin glue 54 mingles with the fresh blood clot to form a blood clot/fibrin glue composite clot 54-59. However, other means of installing the fibrin glue 54 in place are known to and selectable by one of ordinary skill in the art for practice in the present system. For example, the cartilage repair patch 10 can be sutured in place (not shown).
  • After the fibrin glue 54 is applied in the wound site, the third stage 140 of the present method is then to be accomplished. This third stage 140 is the placement of the flexible laminate repair patch 10 to the wound site over the fibrin glue/blood clot composite 59/54 at the wound site 6. In FIG. 6A, the flexible laminate cartilage repair patch 10 is applied to the wound site 6. The fibrin glue 54 also may be freely applied after the repair patch 10 is in place to further accomplish adhering the repair patch 10 to the wound site 6. Once this step is accomplished, the surgical stages of the present system are completed and the cartilage repair patch 10 continues healing purpose in situ.
  • As shown in FIG. 6B, Mesenchymal Stem Cells and other injury responsive blood components from the blood clot 59 migrate into the fibrin glue 54. FIG. 6C illustrates the further migration of the Mesenchymal Stem Cells and other injury responsive blood components from the fibrin glue/blood clot composite 54/59 continues through the porous outer layer 22 and into the matrix layer 30 of the cartilage repair patch 10. In the matrix layer 30, the mesenchymal stem cells and autologous growth factors interact with the constituents of the cartilage repair patch 10. The presence of these components results from their diffusion from the clot 59 into the cartilagenic matrix 30 of the cartilage repair patch 10. The occlusive layer 16 of the cartilage repair patch 10 prevents for a time the further diffusion of these different compositions into the joint space. Conversely, the mobile constituents of the matrix layer 30 can migrate out of the cartilage repair patch and into the mass of the fibrin clot 54, and further, into the blood clot 59 at the surface 14 of the subchrondral bone 4.
  • The Diacerein 46 a and the Rhein 46 b inhibit the production and activity of inflammatory cytokines such as IL-1β, nitric oxide (NO), free radicals and matrix metalloproteinases all of which are involved in inflammation and cartilage destruction, particular in osteoarthritic joints. The Diacerein 46 a and the Rhein 46 b also stimulate the production of growth factors such as TGF-β which in turn stimulates expression of cartilage components such as hyaluronic acid, proteoglycans, aggrecans and collagenase II, all of which are important components of cartilage matrix. The growth hormone will also stimulate the growth of cartilage and bone tissue. Over time, as illustrated in FIG. 7, the cartilage repair patch 10 is reabsorbed and the defect site 6 is relatively rapidly transformed into a more physiologically hyaline-like cartilage 90.
  • The Collagen Cartilage Repair Patch Example
  • A collagen sheet 22 (Xenoderm—porcine type 1 and 2 collagen) was used for the lower layer 22. The Lower layer had mechanical properties to resist shear and pull stress and was resorbable in about 6 weeks. The collagen sheet 22 was put into a form, and then loaded with a collagen-HA suspension to which was added either a solution of Diacerein or Diacerein powder to obtain a concentration of 5-50 micromol. in dry-weight in patch after freeze-drying and sterilization. The result is a double layer collagen-pad with the lower layer to be disposed adjacent the bone surface. After manufacturing and before sterilization, the pads are put into a mechanical press to obtain a thickness of 0.5-2 mm. HA-concentration in the dry-frozen end product was in the range of about 0.1% to 2%. The HA is natural HA, that is, non-chemically modified HA, of fermentation origin.
  • In an advantage, a device and therapy is provided which better promotes regeneration of damaged joint cartilage.
  • In another advantage, a treatment and device for osteochondral injuries is provided that does not require cell culture.
  • In yet another advantage, a treatment and device for such injuries is provided that does not result in propagation of a fibrocartilaginous replacement tissue at the injury site.
  • In still another advantage, a treatment and device is provided which better insures that the resultant replacement tissue is appreciably representative of natural hyaline-like articular cartilage.
  • While the above description contains many specifics, these should not be construed as limitations on the scope of the invention, but rather as exemplifications of one or another preferred embodiment thereof. Many other variations are possible, which would be obvious to one skilled in the art. Accordingly, the scope of the invention should be determined by the scope of the appended claims and their equivalents, and not just by the embodiments.

Claims (12)

1. An implantable laminate cartilage repair patch, the cartilage repair patch comprising:
a first outer cell occlusive layer;
a second outer, cell porous layer adapted to be disposed proximate a subchondral bone wound site; and
a cartilagenic matrix disposed between the first and second outer layers, the cartilagenic matrix being a sink for diffusion of autologous stem cells and including chemical components promoting generation of hyaline-like cartilage in the presence of autologous stem cells.
2. The implantable laminate cartilage repair patch of claim 1, wherein the cartilagenic matrix is a biologically compatible and physiologically absorbable composite including natural hyaluronic acid and collagen.
3. The implantable laminate cartilage repair patch of claim 1, wherein the cartilagenic matrix is a biologically compatible and physiologically absorbable composite including natural hyaluronic acid and collagen, wherein the collagen consists essentially of collagen from a non-human source.
4. The implantable laminate cartilage repair patch of claim 1, wherein the cartilagenic matrix is a biologically compatible and physiologically absorbable composite natural hyaluronic acid and collagen, wherein the natural hyaluronic acid of the cartilagenic matrix consists essentially of a natural, non-human hyaluronic acid.
5. The implantable laminate cartilage repair patch of claim 1, wherein the cartilagenic matrix is a biologically compatible and physiologically absorbable composite including natural hyaluronic acid and collagen, wherein the natural hyaluronic acid of the cartilagenic matrix consists essentially of a natural, non-human hyaluronic acid from a bacterial fermentation source.
6. The implantable laminate cartilage repair patch of claim 1, wherein the cartilagenic matrix is embedded with a chemical composition promoting cartilage regeneration.
7. The implantable laminate cartilage repair patch of claim 1, wherein the cartilagenic matrix is embedded with at least one chemical composition promoting cartilage regeneration selected from the group of compositions consisting of: a growth factor composition, a diacerein composition, a rhein composition, a poly-lactic acid composition, and a natural, non-mammalian hyaluronic acid composition.
8. A method of in situ intra-articular cartilage repair at an intra-articular wound site in a patient, comprising:
providing an implantable laminate cartilage repair patch comprising:
a first outer cell occlusive layer;
a second outer, cell porous layer adapted to be disposed proximate a subchondral bone wound site; and
a cartilagenic matrix disposed between the first and second outer layers, the cartilagenic matrix being a sink for diffusion of autologous stem cells and including chemical components promoting generation of hyaline-like cartilage in the presence of autologous stem cells;
preparing the wound site;
causing a fibrin glue and blood clot layer to be disposed at the wound site; and
applying the cartilage repair patch in proper orientation over the fibrin glue and blood clot layer at the wound site, closing the wound site and allowing the cartilage repair patch to initiate growth of hyaline-like cartilage at the wound site, and the cartilage repair patch over time to be absorbed.
9. The method of claim 8, wherein preparing the wound site comprises:
taking a blood sample from the patient and obtaining an autologous serum fraction having endogenous wound healing components including components that cause differentiation of mesenchymal stem cells; and
micro-fracturing a subchondral bone surface at the wound site to cause local bleeding to perfuse the wound site with fresh blood containing autologous mesenchymal stem cells released by the subchondral bone in response to the micro-fracturing.
10. The method of claim 8, wherein preparing the wound site comprises:
taking a blood sample from the patient and obtaining an autologous serum fraction having endogenous wound healing components including components that cause differentiation of mesenchymal stem cells; and
micro-fracturing a subchondral bone surface at the wound site to cause local bleeding to perfuse the wound site with fresh blood containing autologous mesenchymal stem cells released by the subchondral bone in response to the micro-fracturing, wherein the autologous mesenchymal stem cells released by the subchondral bone are pluripotent mesenchymal stem cells, which in the presence of the cartilage repair patch will differentiate into chondrocytes and produce an extracellular hyaline-like cartilage at the wound site.
11. The method of claim 8, wherein the causing the fibrin glue and blood clot layer to be disposed at the wound site further comprises suturing the cartilage repair patch in place.
12. The method of further comprises replacing the thrombin fraction of the fibrin glue in a 50/50 proportion with autologous centrifugated serum, mixing it with blood obtained from the microfracture/abrasion site of the wound site, and placing the this fibrin glue/blood clot into the wound bed under the cartilage repair patch to seal and obtain a mechanically stable construct.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3150184A1 (en) 2015-09-29 2017-04-05 Fundacja Rozwoju Kardiochirurgii Im. Prof. Zbigniewa Religi Medical instrument

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE515245T1 (en) 2003-12-11 2011-07-15 Isto Technologies Inc PARTICLE CARTILAGE SYSTEM
US8512730B2 (en) 2004-07-12 2013-08-20 Isto Technologies, Inc. Methods of tissue repair and compositions therefor
WO2007025290A2 (en) 2005-08-26 2007-03-01 Isto Technologies, Inc. Implants and methods for repair, replacement and treatment of joint disease
US8163549B2 (en) 2006-12-20 2012-04-24 Zimmer Orthobiologics, Inc. Method of obtaining viable small tissue particles and use for tissue repair
WO2008128075A1 (en) 2007-04-12 2008-10-23 Isto Technologies, Inc. Compositions and methods for tissue repair
WO2009133430A1 (en) * 2008-04-30 2009-11-05 Wockhardt Research Centre Topical compositions of rhein or diacerein
JP5588862B2 (en) * 2008-05-12 2014-09-10 旭化成ケミカルズ株式会社 Polyphenylene ether resin composition having narrow molecular weight distribution
US8114156B2 (en) * 2008-05-30 2012-02-14 Edwin Burton Hatch Flexibly compliant ceramic prosthetic meniscus for the replacement of damaged cartilage in orthopedic surgical repair or reconstruction of hip, knee, ankle, shoulder, elbow, wrist and other anatomical joints
KR101114773B1 (en) * 2009-10-23 2012-03-05 세원셀론텍(주) A cartilage repair constituent manufacturing method thereof
RU2461621C1 (en) * 2011-08-25 2012-09-20 Учреждение Российской академии наук Государственный Научный Центр РФ Институт медико-биологических проблем РАН Method for stimulating formation of fibrocartilagenous regenerated clavus in mammals
RU2629809C2 (en) * 2012-03-22 2017-09-04 Трб Шемедика Интернасьональ С.А. Method for tendon or ligament reconstruction
KR101279812B1 (en) * 2012-05-16 2013-06-28 세원셀론텍(주) A manufacturing method of cartilage tissue repair composition
EP2903567B1 (en) 2012-10-02 2017-08-09 McCullen, Seth Implantable devices for musculoskeletal repair and regeneration
US10245306B2 (en) 2012-11-16 2019-04-02 Isto Technologies Ii, Llc Flexible tissue matrix and methods for joint repair
KR101401944B1 (en) * 2012-12-11 2014-05-30 세원셀론텍(주) Tissue sealant of collagen and fibrin mixed and method of manufacturing the same
US20140178343A1 (en) 2012-12-21 2014-06-26 Jian Q. Yao Supports and methods for promoting integration of cartilage tissue explants
US9168140B2 (en) * 2013-03-15 2015-10-27 Allosource Perforated osteochondral allograft compositions
EP3151848A4 (en) * 2014-06-06 2018-01-24 Vivoscript, Inc. Methods for repairing cartilage damage
WO2016054463A1 (en) 2014-10-02 2016-04-07 Mccullen Seth Anatomically designed meniscus implantable devices
US10179191B2 (en) 2014-10-09 2019-01-15 Isto Technologies Ii, Llc Flexible tissue matrix and methods for joint repair
RU2620884C1 (en) * 2016-08-10 2017-05-30 Анна Петровна Ведяева Method for directed bone tissue regeneration
WO2018204440A2 (en) 2017-05-02 2018-11-08 Mccullen Seth Composite joint implant

Citations (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350629A (en) * 1981-07-29 1982-09-21 Massachusetts Institute Of Technology Procedures for preparing composite materials from collagen and glycosaminoglycan
US4703108A (en) * 1984-03-27 1987-10-27 University Of Medicine & Dentistry Of New Jersey Biodegradable matrix and methods for producing same
US4837024A (en) * 1984-02-24 1989-06-06 The Regents Of The University Of California Compositions, articles and mehtod for improving wound healing
US4880429A (en) * 1987-07-20 1989-11-14 Stone Kevin R Prosthetic meniscus
US5067964A (en) * 1989-12-13 1991-11-26 Stryker Corporation Articular surface repair
US5397353A (en) * 1984-05-24 1995-03-14 Oliver; Roy F. Implant tissue
US5567806A (en) * 1991-08-02 1996-10-22 Abdul-Malak; Nabil Collagen crosslinked with a crosslinking agent for the manufacture of a suturable, biocompatible slowresorbing membrane, and such a membrane
US5681353A (en) * 1987-07-20 1997-10-28 Regen Biologics, Inc. Meniscal augmentation device
US6080194A (en) * 1995-02-10 2000-06-27 The Hospital For Joint Disease Orthopaedic Institute Multi-stage collagen-based template or implant for use in the repair of cartilage lesions
US20020025921A1 (en) * 1999-07-26 2002-02-28 Petito George D. Composition and method for growing, protecting, and healing tissues and cells
US6352558B1 (en) * 1996-02-22 2002-03-05 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method for promoting regeneration of surface cartilage in a damage joint
US20020028233A1 (en) * 2000-08-18 2002-03-07 Dimitrijevich Slobodan Dan Pericardial anti-adhesion patch
US20020045940A1 (en) * 1998-08-14 2002-04-18 Bruno Giannetti Methods, instruments and materials for chondrocyte cell transplantation
US20020103542A1 (en) * 2000-09-18 2002-08-01 Bilbo Patrick R. Methods for treating a patient using a bioengineered flat sheet graft prostheses
US20020111576A1 (en) * 2000-12-29 2002-08-15 Kimberly-Clark Worldwide, Inc. Bioabsorbable wound dressing
US20020122790A1 (en) * 2001-01-30 2002-09-05 Hunziker Ernst B. Compositions and methods for the treatment and repair of defects or lesions in articular cartilage using synovial-derived tissue or cells
US20020151986A1 (en) * 1996-08-30 2002-10-17 Asculai Samuel S. Method, Instruments,and kit for autologous tansplantation
US20020151985A1 (en) * 1990-05-29 2002-10-17 Stryker Corporation Synthetic bone matrix
US20020173806A1 (en) * 1996-08-30 2002-11-21 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
US20020183845A1 (en) * 2000-11-30 2002-12-05 Mansmann Kevin A. Multi-perforated non-planar device for anchoring cartilage implants and high-gradient interfaces
US20020183858A1 (en) * 2001-06-05 2002-12-05 Contiliano Joseph H. Attachment of absorbable tissue scaffolds to scaffold fixation devices
US20030004578A1 (en) * 2001-06-28 2003-01-02 Ethicon, Inc. Composite scaffold with post anchor for the repair and regeneration of tissue
US20030036801A1 (en) * 2001-07-16 2003-02-20 Schwartz Herbert E. Cartilage repair apparatus and method
US20030078617A1 (en) * 2001-07-16 2003-04-24 Schwartz Herbert E. Unitary surgical device and method
US20030114061A1 (en) * 2001-12-13 2003-06-19 Kazuhisa Matsuda Adhesion preventive membrane, method of producing a collagen single strand, collagen nonwoven fabric and method and apparatus for producing the same
US20030118560A1 (en) * 2001-12-20 2003-06-26 Kelly Sheila J. Composite biocompatible matrices
US6596304B1 (en) * 1998-09-18 2003-07-22 Imedex Biomateriaux Method for preparing two-layer bicomposite collagen material for preventing post-operative adhesions
US20030143207A1 (en) * 2001-10-18 2003-07-31 Livesey Stephen A. Remodeling of tissues and organ
US20030187515A1 (en) * 2002-03-26 2003-10-02 Hariri Robert J. Collagen biofabric and methods of preparing and using the collagen biofabric
US6629997B2 (en) * 2000-03-27 2003-10-07 Kevin A. Mansmann Meniscus-type implant with hydrogel surface reinforced by three-dimensional mesh
US20030219429A1 (en) * 1998-07-24 2003-11-27 Pharmacal Biotechnologies, Llc Composition and method for bone regeneration
US20030220700A1 (en) * 2002-05-22 2003-11-27 Hammer Joseph J. Attachment of absorbable tissue scaffolds ot fixation devices
US20030225355A1 (en) * 1998-10-01 2003-12-04 Butler Charles E. Composite material for wound repair
US6737072B1 (en) * 1998-12-03 2004-05-18 Michael Nerlich Matrix for tissue engineering formed of a hyaluronic acid ester and hydrolyzed collagen
US20040097612A1 (en) * 2002-11-15 2004-05-20 Etex Corporation Cohesive demineralized bone compositions
US20040141945A1 (en) * 2001-04-02 2004-07-22 Hirofumi Yura Glycosaminoglycan/collagen complexes and use thereof
US20040224022A1 (en) * 2000-08-30 2004-11-11 Depuy Acromed, Inc. Collagen/polysaccharide bilayer matrix
US20050043814A1 (en) * 2003-08-20 2005-02-24 Akihiko Kusanagi Acellular matrix implanted into an articular cartilage or osteochondral lesion protected with a biodegradable polymer modified to have extended polymerization time and methods for preparation and use thereof
US20050125077A1 (en) * 2003-12-05 2005-06-09 Harmon Alexander M. Viable tissue repair implants and methods of use
US20050186283A1 (en) * 1997-10-10 2005-08-25 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material, and method
US20050209705A1 (en) * 2004-03-09 2005-09-22 Niederauer Gabriele G Implant scaffold combined with autologous or allogenic tissue
US20050208114A1 (en) * 1998-03-24 2005-09-22 Petito George D Composition and method for healing tissues
US20050232967A1 (en) * 2004-04-20 2005-10-20 Kladakis Stephanie M Nonwoven tissue scaffold
US20050232979A1 (en) * 2002-06-03 2005-10-20 Yissum Research Development Company Of The Hebrew University Of Jerusalem Multi-layer collagenic article useful for wounds healing
US20050281856A1 (en) * 2004-05-10 2005-12-22 Mcglohorn Jonathan Implantable biostructure comprising an osteoconductive member and an osteoinductive material
US20060008905A1 (en) * 2001-10-19 2006-01-12 Ralph-Heiko Mattern Collagen/glycosaminoglycan compositions for use as terminally sterilizable matrices
US6989034B2 (en) * 2002-05-31 2006-01-24 Ethicon, Inc. Attachment of absorbable tissue scaffolds to fixation devices
US20060083730A1 (en) * 2003-08-20 2006-04-20 Akihiko Kusanagi Method for treatment of osteochondral and bone defects using an acellular matrix implant
US20060100138A1 (en) * 2004-11-10 2006-05-11 Olsen David R Implantable collagen compositions
US20060241756A1 (en) * 2003-10-13 2006-10-26 Aesculap Ag & Co., Kg Cartilage replacement implant and method for producing a cartilage replacement implant
US7141072B2 (en) * 1998-10-05 2006-11-28 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method for promoting regeneration of surface cartilage in a damaged joint using multi-layer covering
US20080119947A1 (en) * 2006-11-18 2008-05-22 Smith & Nephew, Inc. Annular Ring Implant
US20080125863A1 (en) * 2006-11-28 2008-05-29 Mckay William F Implant designs and methods of improving cartilage repair
US20080183300A1 (en) * 1999-12-03 2008-07-31 University Of Leeds Fixation technology
US7476250B1 (en) * 1999-04-06 2009-01-13 Mansmann Kevin A Semi-permeable membranes to assist in cartilage repair

Family Cites Families (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1249315B (en) 1991-05-23 1995-02-22 Euroresearch Srl NON-POROUS COLLAGEN PLATE FOR THERAPEUTIC USE, METHOD AND EQUIPMENT TO OBTAIN IT
AU636544B1 (en) 1991-11-27 1993-04-29 Lignyte Co., Ltd. Water insoluble biocompatible hyaluronic acid polyion complex and method of making the same
CA2130295A1 (en) 1993-08-26 1995-02-27 Richard A. Berg Ionically crosslinked glycosaminoglycan gels for soft tissue augmentation and drug delivery
GB9400163D0 (en) 1994-01-06 1994-03-02 Geistlich Soehne Ag Membrane
CA2185447C (en) 1994-03-14 2009-05-05 Steven Goldstein Treated tissue for implantation and preparation methods
GB9503492D0 (en) 1995-02-22 1995-04-12 Ed Geistlich S Hne A G F R Che Chemical product
US20030039695A1 (en) 2001-08-10 2003-02-27 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Collagen carrier of therapeutic genetic material, and method
GB9721585D0 (en) 1997-10-10 1997-12-10 Geistlich Soehne Ag Chemical product
US5733337A (en) 1995-04-07 1998-03-31 Organogenesis, Inc. Tissue repair fabric
US5752974A (en) 1995-12-18 1998-05-19 Collagen Corporation Injectable or implantable biomaterials for filling or blocking lumens and voids of the body
JP3476631B2 (en) 1995-12-21 2003-12-10 株式会社アムニオテック Medical material composed of human-derived natural collagen membrane
US5824084A (en) 1996-07-03 1998-10-20 The Cleveland Clinic Foundation Method of preparing a composite bone graft
US5866165A (en) * 1997-01-15 1999-02-02 Orquest, Inc. Collagen-polysaccharide matrix for bone and cartilage repair
CA2304958C (en) 1997-09-26 2008-12-30 Noven Pharmaceuticals, Inc. Bioadhesive compositions and methods for topical administration of active agents
US20030180263A1 (en) 2002-02-21 2003-09-25 Peter Geistlich Resorbable extracellular matrix for reconstruction of bone
US6004333A (en) 1997-10-31 1999-12-21 Ethicon Endo-Surgery, Inc. Prosthetic with collagen for tissue repair
WO2000016822A1 (en) 1998-09-21 2000-03-30 The Brigham And Women's Hospital, Inc. Compositions and methods for tissue repair
EP1022031B1 (en) 1999-01-21 2005-03-23 Nipro Corporation Suturable adhesion-preventing membrane
CA2362600A1 (en) 1999-02-16 2000-08-24 Sulzer Biologics Inc. Device and method for regeneration and repair of cartilage lesions
US6623963B1 (en) 1999-12-20 2003-09-23 Verigen Ag Cellular matrix
DE60038315T2 (en) 2000-03-09 2009-05-14 Syntacoll Ag NEW MATERIAL ON Collagen BASE WITH IMPROVED PROPERTIES FOR USE IN HUMAN AND VETERINARY MEDICINE AND A MANUFACTURING PROCESS
GB0006439D0 (en) 2000-03-18 2000-05-10 Univ Nottingham Polymeric composite materials and their manufacture
KR20030061378A (en) 2000-12-07 2003-07-18 가부시키가이샤 재팬 티슈 엔지니어링 Substrate for tissue regeneration, material for transplantation, and processes for producing these
US6713085B2 (en) 2001-04-27 2004-03-30 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method and membrane for mucosa regeneration
JP2003160506A (en) * 2001-08-10 2003-06-03 Ed Geistlich Soehne Ag Fuer Chemische Industrie Collagen carrier of therapeutic genetic material and method
ATE390151T1 (en) 2001-10-26 2008-04-15 Cook Biotech Inc MEDICAL IMPLANT WITH MESH-LIKE STRUCTURE
CA2412012C (en) * 2001-11-20 2011-08-02 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Resorbable extracellular matrix containing collagen i and collagen ii for reconstruction of cartilage
EP1476202B1 (en) 2002-02-21 2009-01-14 Encelle, Inc. Cross-linked bioactive hydrogel matrices
JP2003245338A (en) * 2002-02-26 2003-09-02 Kyocera Corp Articular cartilage restorative material
US20040034418A1 (en) 2002-07-23 2004-02-19 Shu-Tung Li Membrane-reinforced implants
WO2004078120A2 (en) 2003-02-28 2004-09-16 Fibrogen, Inc. Collagen compositions and biomaterials
US8226715B2 (en) 2003-06-30 2012-07-24 Depuy Mitek, Inc. Scaffold for connective tissue repair
US10583220B2 (en) 2003-08-11 2020-03-10 DePuy Synthes Products, Inc. Method and apparatus for resurfacing an articular surface
ITMI20040347A1 (en) * 2004-02-26 2004-05-26 Pharma Medical Ltd NEW ASSOCIATION DRUG
JP2007532211A (en) 2004-04-15 2007-11-15 ニクリス アーゲー Bone morphogenetic matrix composite, process for its production and tissue engineering implant and skeleton with coating of bone morphogenetic composite matrix
GB0516846D0 (en) 2005-08-17 2005-09-21 Knight David P Meniscal repair device
US20090311221A1 (en) 2005-09-16 2009-12-17 St. Marianna University, School Of Medicine Biomaterials for regenerative medicine
JP5154427B2 (en) 2005-10-24 2013-02-27 エー・デー・ガイストリヒ・ゾーネ・アクチェンゲゼルシャフト・フュール・ヒェーミシェ・インダストリー Method and apparatus for collagen membrane or gel filled with synovial cells
US20070202084A1 (en) 2005-12-14 2007-08-30 Anika Therapeutics, Inc. Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defects
CN1986007B (en) 2005-12-20 2011-09-14 广东冠昊生物科技股份有限公司 Biological surgical patch
US20080020012A1 (en) 2006-06-22 2008-01-24 Ju Young M Collagen scaffolds, medical implants with same and methods of use
GB2440721A (en) 2006-08-11 2008-02-13 Univ Cambridge Tech Composite biomaterial formed by cooling a fluid composition on a porous solid and removing solidified crystals of the liquid carrier
CN101616698A (en) 2006-10-23 2009-12-30 库克生物科技公司 The ECM material of the enhanced processing of component characteristic
US8697044B2 (en) 2007-10-09 2014-04-15 Allergan, Inc. Crossed-linked hyaluronic acid and collagen and uses thereof
WO2009076391A2 (en) 2007-12-10 2009-06-18 Cook Biotech Incorporated Medical materials including modified extracellular matrix materials

Patent Citations (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4350629A (en) * 1981-07-29 1982-09-21 Massachusetts Institute Of Technology Procedures for preparing composite materials from collagen and glycosaminoglycan
US4837024A (en) * 1984-02-24 1989-06-06 The Regents Of The University Of California Compositions, articles and mehtod for improving wound healing
US4703108A (en) * 1984-03-27 1987-10-27 University Of Medicine & Dentistry Of New Jersey Biodegradable matrix and methods for producing same
US5397353A (en) * 1984-05-24 1995-03-14 Oliver; Roy F. Implant tissue
US4880429A (en) * 1987-07-20 1989-11-14 Stone Kevin R Prosthetic meniscus
US5681353A (en) * 1987-07-20 1997-10-28 Regen Biologics, Inc. Meniscal augmentation device
US6042610A (en) * 1987-07-20 2000-03-28 Regen Biologics, Inc. Meniscal augmentation device
US5067964A (en) * 1989-12-13 1991-11-26 Stryker Corporation Articular surface repair
US20020151985A1 (en) * 1990-05-29 2002-10-17 Stryker Corporation Synthetic bone matrix
US5567806A (en) * 1991-08-02 1996-10-22 Abdul-Malak; Nabil Collagen crosslinked with a crosslinking agent for the manufacture of a suturable, biocompatible slowresorbing membrane, and such a membrane
US6080194A (en) * 1995-02-10 2000-06-27 The Hospital For Joint Disease Orthopaedic Institute Multi-stage collagen-based template or implant for use in the repair of cartilage lesions
US6352558B1 (en) * 1996-02-22 2002-03-05 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method for promoting regeneration of surface cartilage in a damage joint
US20020151986A1 (en) * 1996-08-30 2002-10-17 Asculai Samuel S. Method, Instruments,and kit for autologous tansplantation
US20020173806A1 (en) * 1996-08-30 2002-11-21 Verigen Transplantation Service International (Vtsi) Ag Method for autologous transplantation
US20050186283A1 (en) * 1997-10-10 2005-08-25 Ed. Geistlich Soehne Ag Fuer Chemistrie Industrie Collagen carrier of therapeutic genetic material, and method
US20050208114A1 (en) * 1998-03-24 2005-09-22 Petito George D Composition and method for healing tissues
US20030219429A1 (en) * 1998-07-24 2003-11-27 Pharmacal Biotechnologies, Llc Composition and method for bone regeneration
US20020045940A1 (en) * 1998-08-14 2002-04-18 Bruno Giannetti Methods, instruments and materials for chondrocyte cell transplantation
US6596304B1 (en) * 1998-09-18 2003-07-22 Imedex Biomateriaux Method for preparing two-layer bicomposite collagen material for preventing post-operative adhesions
US20030225355A1 (en) * 1998-10-01 2003-12-04 Butler Charles E. Composite material for wound repair
US7141072B2 (en) * 1998-10-05 2006-11-28 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Method for promoting regeneration of surface cartilage in a damaged joint using multi-layer covering
US6737072B1 (en) * 1998-12-03 2004-05-18 Michael Nerlich Matrix for tissue engineering formed of a hyaluronic acid ester and hydrolyzed collagen
US7476250B1 (en) * 1999-04-06 2009-01-13 Mansmann Kevin A Semi-permeable membranes to assist in cartilage repair
US20020025921A1 (en) * 1999-07-26 2002-02-28 Petito George D. Composition and method for growing, protecting, and healing tissues and cells
US20080183300A1 (en) * 1999-12-03 2008-07-31 University Of Leeds Fixation technology
US6629997B2 (en) * 2000-03-27 2003-10-07 Kevin A. Mansmann Meniscus-type implant with hydrogel surface reinforced by three-dimensional mesh
US20020028233A1 (en) * 2000-08-18 2002-03-07 Dimitrijevich Slobodan Dan Pericardial anti-adhesion patch
US20040224022A1 (en) * 2000-08-30 2004-11-11 Depuy Acromed, Inc. Collagen/polysaccharide bilayer matrix
US20020103542A1 (en) * 2000-09-18 2002-08-01 Bilbo Patrick R. Methods for treating a patient using a bioengineered flat sheet graft prostheses
US20020183845A1 (en) * 2000-11-30 2002-12-05 Mansmann Kevin A. Multi-perforated non-planar device for anchoring cartilage implants and high-gradient interfaces
US20020111576A1 (en) * 2000-12-29 2002-08-15 Kimberly-Clark Worldwide, Inc. Bioabsorbable wound dressing
US20020122790A1 (en) * 2001-01-30 2002-09-05 Hunziker Ernst B. Compositions and methods for the treatment and repair of defects or lesions in articular cartilage using synovial-derived tissue or cells
US20040141945A1 (en) * 2001-04-02 2004-07-22 Hirofumi Yura Glycosaminoglycan/collagen complexes and use thereof
US20020183858A1 (en) * 2001-06-05 2002-12-05 Contiliano Joseph H. Attachment of absorbable tissue scaffolds to scaffold fixation devices
US20030004578A1 (en) * 2001-06-28 2003-01-02 Ethicon, Inc. Composite scaffold with post anchor for the repair and regeneration of tissue
US20030036801A1 (en) * 2001-07-16 2003-02-20 Schwartz Herbert E. Cartilage repair apparatus and method
US20080167716A1 (en) * 2001-07-16 2008-07-10 Schwartz Hebert E Cartilage repair apparatus and method
US20030078617A1 (en) * 2001-07-16 2003-04-24 Schwartz Herbert E. Unitary surgical device and method
US20030143207A1 (en) * 2001-10-18 2003-07-31 Livesey Stephen A. Remodeling of tissues and organ
US20060008905A1 (en) * 2001-10-19 2006-01-12 Ralph-Heiko Mattern Collagen/glycosaminoglycan compositions for use as terminally sterilizable matrices
US20030114061A1 (en) * 2001-12-13 2003-06-19 Kazuhisa Matsuda Adhesion preventive membrane, method of producing a collagen single strand, collagen nonwoven fabric and method and apparatus for producing the same
US20030118560A1 (en) * 2001-12-20 2003-06-26 Kelly Sheila J. Composite biocompatible matrices
US20030187515A1 (en) * 2002-03-26 2003-10-02 Hariri Robert J. Collagen biofabric and methods of preparing and using the collagen biofabric
US20030220700A1 (en) * 2002-05-22 2003-11-27 Hammer Joseph J. Attachment of absorbable tissue scaffolds ot fixation devices
US6989034B2 (en) * 2002-05-31 2006-01-24 Ethicon, Inc. Attachment of absorbable tissue scaffolds to fixation devices
US20050232979A1 (en) * 2002-06-03 2005-10-20 Yissum Research Development Company Of The Hebrew University Of Jerusalem Multi-layer collagenic article useful for wounds healing
US20040097612A1 (en) * 2002-11-15 2004-05-20 Etex Corporation Cohesive demineralized bone compositions
US20060083730A1 (en) * 2003-08-20 2006-04-20 Akihiko Kusanagi Method for treatment of osteochondral and bone defects using an acellular matrix implant
US20050043814A1 (en) * 2003-08-20 2005-02-24 Akihiko Kusanagi Acellular matrix implanted into an articular cartilage or osteochondral lesion protected with a biodegradable polymer modified to have extended polymerization time and methods for preparation and use thereof
US7217294B2 (en) * 2003-08-20 2007-05-15 Histogenics Corp. Acellular matrix implants for treatment of articular cartilage, bone or osteochondral defects and injuries and method for use thereof
US20060241756A1 (en) * 2003-10-13 2006-10-26 Aesculap Ag & Co., Kg Cartilage replacement implant and method for producing a cartilage replacement implant
US20050125077A1 (en) * 2003-12-05 2005-06-09 Harmon Alexander M. Viable tissue repair implants and methods of use
US20050209705A1 (en) * 2004-03-09 2005-09-22 Niederauer Gabriele G Implant scaffold combined with autologous or allogenic tissue
US20050232967A1 (en) * 2004-04-20 2005-10-20 Kladakis Stephanie M Nonwoven tissue scaffold
US20050281856A1 (en) * 2004-05-10 2005-12-22 Mcglohorn Jonathan Implantable biostructure comprising an osteoconductive member and an osteoinductive material
US20060100138A1 (en) * 2004-11-10 2006-05-11 Olsen David R Implantable collagen compositions
US20080119947A1 (en) * 2006-11-18 2008-05-22 Smith & Nephew, Inc. Annular Ring Implant
US20080125863A1 (en) * 2006-11-28 2008-05-29 Mckay William F Implant designs and methods of improving cartilage repair

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3150184A1 (en) 2015-09-29 2017-04-05 Fundacja Rozwoju Kardiochirurgii Im. Prof. Zbigniewa Religi Medical instrument

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