OSTEOIMPLANT AND METHOD OF MAKING
SAME
CROSS REFERENCE TO RELATED
APPLICATIONS
[0001] This application is a continuation-in-part of International Application No. PCT/US01/22853, filed Jul. 19, 2001, and claims the 35 U.S.C. §119 (e) benefit of provisional applications No. 60/219,198, filed Jul. 19, 2000 and No. 60/288,212 filed May 2, 2001. The entire contents of aforesaid applications PCT/US01/22853, Nos. 60/219,198 and 60/288,212 are incorporated by reference herein.
BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention
[0003] This invention relates to an osteoimplant of predetermined dimensions and shape made up of a coherent aggregate of elongate bone particles and to a method for making the osteoimplant. Among its other applications, the osteoimplant can be fashioned as a plug for insertion in a space or cavity within an implant used in an orthopedic procedure, e.g., an intervertebral spacer employed in spinal fusion, or for insertion in a cavity associated with a relatively well-defined bone defect, e.g., an extraction socket, a bore hole, etc.
[0004] 2. Description of the Related Art
[0005] Shaped or cut bone elements have been used extensively to treat various medical problems in human and animal orthopedic surgical practice. The use of such bone has also extended to the fields of, e.g., cosmetic and reconstructive surgery, dental reconstructive surgery, podiatry, orthopaedics, neurosurgery and other medical fields involving hard tissue. The use of autograft bone (where the patient provides the source), allograft bone (where another individual of the same species provides the source) or xenograft bone (where another individual of a different species provides the source) is well known in both human and veterinary medicine. In particular, transplanted bone is known to provide support, promote healing, fill bony cavities, separate bony elements (such as vertebral bodies), promote fusion (where bones are induced to grow together into a single, solid unit) or stabilize the sites of fractures. More recently, processed bone has been developed into shapes for use in new surgical applications or as new materials for implants that were historically based on non-biologically derived materials.
[0006] A particularly advantageous application of shaped or cut bone elements, particularly those derived from allograft bone, is that involving the fusion of adjacent vertebral bodies where there has been damage or injury to the intervertebral disc.
[0007] Intervertebral discs, located between the end plates of adjacent vertebrae, stabilize the spine, distribute forces between vertebrae and cushion vertebral bodies. A normal intervertebral disc includes a semi-gelatinous component, the nucleus pulpous, which is surrounded and confined by an outer fibrous ring, the annulus fibrous. In a healthy, spine, the annulus fibrous prevents the nucleus pulpous from protruding outside the disc space.
[0008] Spinal discs may be displaced or damaged due to trauma, disease, or aging. Disruption of the annulus fibrosis
allows the nucleus pulposus to protrude into the vertebral canal, a condition commonly referred to as a herniated or ruptured disc. The extruded nucleus pulposus may press upon a spinal nerve, resulting in nerve damage, pain, numbness, muscle weakness and/or paralysis. Intervertebral discs may also deteriorate due to the normal aging process or disease. As a disc dehydrates and hardens, the disc space height will be reduced leading to instability of the spine, decreased mobility and pain.
[0009] Sometimes the only relief from the symptoms of these conditions is a discectomy or surgical removal of a portion or all of an intervertebral disc followed by fusion of the adjacent vertebrae. The removal of the damaged or unhealthy disc will allow the disc space to collapse. Collapse of the disc space can cause instability of the spine, abnormal joint mechanics, premature development of arthritis or nerve damage in addition to severe pain. Pain relief via discectomy and arthrodesis requires preservation of the disc space and eventual fusion of the affected motion segments.
[0010] Bone grafts have been used to fill the intervertebral space to prevent disc space collapse and promote fusion of adjacent vertebrae across the disc space. In early techniques, bone material was simply implanted between adjacent vertebrae, typically at the posterior aspect of the vertebra, and the spinal column was stabilized by way of a plate or rod spanning the affected vertebrae. Once fusion occurred, the hardware used to maintain the stability of the vertebrae became superfluous and became a permanent non-functional foreign body. Moreover, the surgical procedures employed to implant a rod or plate to stabilize the spine while fusion was taking place were frequently lengthy and involved.
[0011] It was therefore determined that a better solution to the stabilization of an excised disc space is to fuse the vertebrae between their respective end plates, preferably without the need for anterior or posterior rod or plate. There have been numerous attempts to develop an acceptable intradiscal implant that could be used to replace a damaged disc and maintain the stability of the disc inter space between the adjacent vertebrae, at least until complete arthrodesis is achieved. The implant must provide temporary support and allow bone ingrowth. Success of the discectomy and fusion procedure requires the development of a contiguous growth of bone to create a solid mass because the implant may not withstand the compressive loads on the spine for the life of the patient.
[0012] Fusion cages provide a space for inserting a bone graft between adjacent portions of bone. In time, the bone and bone graft grow together through or around the fusion cage to fuse the graft and the bone solidly together. One current use of fusion cages is to treat a variety of spinal disorders, including degenerative disc diseases such as Grade I or II spondylolisthesis of the lumbar spine. Spinal fusion cages (included in the general term, "fusion cages") are inserted into the intervertebral disc space between two vertebrae for fusing them together. They distract (or expand) a collapsed disc space between two vertebrae to stabilize the vertebrae by preventing them from moving relative to each other.
[0013] The typical fusion cage is cylindrical, hollow and threaded. Alternatively, some known fusion cages are unthreaded or made in tapered, elliptical, or rectangular shapes. Known fusion cages are constructed from a variety
of materials including titanium alloys, porous tantalum, other metals, allograft bone, or ceramic material. For example, U.S. Pat. No. 5,015,247 to Michelson and U.S. Pat. No. 5,782,919 to Zdeblick disclose a threaded spinal cage the contents of which are incorporated herein by reference. The cages are hollow and can be filled with osteogenic material, such as autograft or allograft, prior to insertion into the intervertebral space. Apertures defined in the cage communicate with the hollow interior to provide a path for tissue growth between the vertebral end plates.
[0014] Fusion cages may be used to connect any adjacent portions of bone. Aprimary use is in the lumbar spine. Other sites include the cervical or thoracic segments of the spine. Fusion cages can be inserted in the lumbar spine using an anterior, posterior or lateral approach. Insertion is usually accomplished through a traditional open operation but a laparoscopic or percutaneous insertion technique can also be used.
[0015] Spinal fusion cages are typically designed to support vertebrae in the proper geometry during the fusion process and are not intended to provide a long term, permanent support. Actual bone fusion is the ultimate goal. In order to achieve fusion, bone conducting or inducing materials such as bone chips, ceramics, marrow, growth factors, etc., are packed into the cage in order to provide a favorable environment for bony ingrowth. The success of these methods depends to some extent on the surgeon's skill in packing the cages and retaining the materials in the cages during and after implantation. It is especially important that the filler material be in contact with the surfaces of the vertebral bodies on either side of the cage as well as any autograft material(s) employed at the surgical site. While many materials will function as adequate cage filler materials, the best results are obtained with materials that are osteoinductive and not just osteoconductive. Bone grafting materials for use in osteoimplants are described in U.S. Pat. No. 4,950,296, the contents of which are incorporated by reference herein.
[0016] Osteoconductive materials are ones that guide bone growth but do not stimulate it. Examples are bone chips and ceramics. Osteoinductive materials actually cause bone to form and result in faster and more certain healing. Examples of osteoinductive materials include cancellous bone, demineralized bone and various growth factors. The most common source of osteoinductive material is the patient's own bone. Typically, in spinal surgery, this is harvested from the iliac crest in the form of bone chips and marrow. While effective, it causes secondary damage (to the harvest site) and requires preparation before it can be used. Furthermore, it is somewhat difficult to maintain in place due to its semi-fluid nature.
[0017] Demineralized bone is an alternative to bone chips and marrow as an osteoinductive material. Demineralized bone comes in various forms including powder, gels, pastes, fibers and sheets. The more fluid forms such as powders, gels and pastes are relatively easy to implant at the repair site but difficult to maintain in place. The production of bone powder for filling osteoimplants is disclosed and incorporated herein by reference to U.S. Pat. No. 5,910,315 et al. The process of preparing shaped materials derived from elongate bone particles is incorporated herein by reference to U.S. Pat. No. 5,507,813.
[0018] In addition, there is the possibility of wasted material anytime a standard material has to be adapted to fill a
cage. Therefore, the need remains for an osteoinductive material that can be used to fill the relatively well-defined cavities of, for example, bone fusion devices, extraction sockets, bore holes, etc. and that doesn't require any special tailoring by the surgeon at the time of implantation yet remains where placed for periods of time sufficient to allow suitable bone fusion to take place. It would be advantageous if methods of producing such a material could be achieved efficiently and accurately by a simple process. The use of such an osteoinductive material at an appropriate surgical site would provide improved outcome for implant recipients.
[0019] U.S. Pat. No. 5,507,813 describes a surgically implantable sheet formed from elongate bone particles, optionally those that have been demineralized. The sheet can further contain biocompatible ingredients, adhesives, fillers, plasticizers, etc. The osteoinductive sheet is rigid and relatively strong when dry and flexible and pliable when wetted or hydrated. These sheets are available under the tradename Grafton®Flex (Osteotech, Inc., Eatontown, N.J., USA). The sheets must be wetted/hydrated prior to use in order to render them useful for implantation.
[0020] U.S. Pat. No. 4,932,973 describes an artificial organic bone matrix with holes or perforations extending into the organic bone matrix. The holes or perforations are indicated to be centers of cartilage and bone induction following implantation of the bone matrix into living tissue.
[0021] U.S. Pat. No. 4,394,370 discloses a one-piece sponge-like bone graft material fabricated from fully demineralized bone powder or microparticulate bone, and reconstituted collagen. The sponge-like graft is optionally crosslinked with glutaraldehyde.
[0022] Another one-piece porous implant is described in U.S. Pat. No. 5,683,459. The implant is made up of a biodegradable polymeric macrostructure composed of chemotactic ground substances such as hyaluronic acid.
SUMMARY OF THE INVENTION
[0023] It is an object of the invention to provide an osteoimplant of predetermined dimensions and shape derived from elongate bone particles.
[0024] It is another object of the invention to provide an osteoimplant fabricated from a coherent aggregate of elongate bone particles wherein the osteoimplant possesses any one of a wide variety of sizes and shapes not limited by the original shape of the bone(s) from which the elongate bone particles are obtained.
[0025] It is a particular object of the invention to provide a low density osteoimplant which possesses an open pore structure allowing the osteoimplant to readily absorb fluids such as blood and yet still retain its original shape.
[0026] It is another object of the invention to provide an osteoimplant fabricated from elongate bone particles which is flexible when dry and which can be implanted while in the dry state.
[0027] It is yet another further object of the invention to provide an method of making an osteoimplant possessing the aforementioned characteristics.
[0028] It is still another object of the invention to provide a method of treating a bone defect which utilizes an osteoimplant possessing the aforementioned characteristics.
[0029] Another particular object of the invention is the provision of a plug for insertion in a cavity of an implant, e.g., an intervertebral implant, or bone defect site made up of a coherent aggregate of elongate bone particles sized and shaped to substantially fill the cavity of the implant or bone defect site.
[0030] These and other objects of the invention are met by the osteoimplant herein which comprises a coherent aggregate of elongate bone particles, the osteoimplant possessing predetermined dimensions and shape.
[0031] The term "osteoimplant" as utilized herein is intended to refer to any device or material for implantation that aids or augments bone formation or healing. Osteoimplants are often applied at a bone defect site, e.g., one resulting from injury, defect brought about during the course of surgery, infection, malignancy or developmental malformation. Therefore, such "osteoimplants" are envisioned as being suitably sized and shaped as required for use in a wide variety of orthopedic, neurosurgical, and oral and maxillofacial surgical procedures such as the repair of simple and compound fractures and non-unions, external and internal fixations, joint reconstructions such as arthrodesis, general arthroplasty, deficit filling, discectomy, laminectomy, anterior cervical and thoracic operations, spinal fusions, etc. Therefore, the osteoimplants utilized herein are intended for implantation at a bony site and are made of any biocompatible material(s), e.g., bone or bone particles, biocompatible synthetic materials, combinations thereof, etc, and may be designed for either animal or human use. Specifically, the osteoimplant suitable for use according to the disclosure herein will be any osteoimplant containing at least one defined cavity without limitation to the particular material(s) the osteoimplant is made of or the size or shape of the cavity. The term "biocompatible" and expressions of like import shall be understood to mean the absence of stimulation of an unacceptable biological response to an implant and is distinguished from a mild, transient inflammation and/or granulation response which can accompany implantation of most foreign objects into a living organism and is also associated with the normal healing response. Materials useful to the invention herein shall be biocompatible if, at the time of implantation, they are present in a sufficiently small concentration such that the above-defined condition is achieved.
[0032] The term "particle" as utilized herein is intended to include bone pieces of all shapes, sizes, thickness and configuration such as fibers, threads, narrow strips, thin sheets, clips, shards, powders, etc., that posses regular, irregular or random geometries. It should be understood that some variation in dimension will occur in the production of the particles of this invention and particles demonstrating such variability in dimensions are within the scope in this invention. Particles useful herein can be homogenous, heterogeneous, and can include mixtures of human, xenogenic and/or transgenic material.
[0033] The term "human" as utilized herein in reference to suitable sources of implantable materials refers to autograft bone which is taken from at least one site in the graftee and implanted in another site of the graftee as well as allograft bone which is bone taken from a donor other than the graftee.
[0034] The term "autograft" as utilized herein refers to tissue that is extracted from the intended recipient of the implant.
[0035] The term "allograft" as utilized herein refers to tissue intended for implantation that is taken from a different member of the same species as the intended recipient.
[0036] The term "xenogenic" as utilized herein refers to material intended for implantation obtained from a donor source of a different species than the intended recipient. For example, when the implant is intended for use in an animal such as a horse (equine), xenogenic tissue of, e.g., bovine, porcine, caprine, etc., origin may be suitable.
[0037] The term "transgenic" as utilized herein refers to tissue intended for implantation that is obtained from an organism that has been genetically modified to contain within its genome certain genetic sequences obtained from the genome of a different species. The different species is usually the same species as the intended implant recipient but such limitation is merely included by way of example and is not intended to limit the disclosure here in anyway whatsoever.
[0038] The expressions "whole bone" and "substantially fully mineralized bone" refer to bone containing its full or substantially full, original mineral content.
[0039] The expression "demineralized bone" includes bone that has been partially, fully, segmentally or superficially (surface) demineralized.
[0040] The expression "substantially fully demineralized bone" as utilized herein refers to bone containing less than about 8% of its original mineral context.
[0041] The term "osteogenic" as applied to the bone plug and/or elongate bone particle composition thereof shall be understood as referring to the ability of an osteoimplant to facilitate or accelerate the growth of new bone tissue by one or more mechanisms such as osteogenesis, osteoconduction and/or osteoinduction.
[0042] The term "osteoinduction" shall be understood to refer to the mechanism by which a substance recruits cells from the host that have the potential for forming new bone and repairing bone tissue. Most osteoinductive materials can stimulate the formation of ectopic bone in soft tissue.
[0043] The term "osteoconduction" shall be understood to refer to the mechanism by which a non-osteoinductive substance serves as a suitable template or substrate along which bone may grow.
[0044] The term "osteogenesis" shall be understood to refer to cell-mediated bone formation. The term "device" as utilized herein is intended to refer to any osteoimplant that is manufactured predominately of non-bone materials. Such devices are typically made of those materials commonly used in the manufacture of biocompatible implants, e.g., biocompatible metals such as surgical Bioglass®, biocompatible polymeric materials, e.g., polylactic acid, polytetrafluoroethylene, etc., or any other suitable biocompatible non-bone material.
[0045] The term "plug" as utilized herein refers to a formed material of predetermined size and shape prepared according to the description herein from a coherent aggregate of elongate bone particles.
[0046] The term "cavity" as utilized herein should be understood in the broadest sense possible. Therefore, such term is intended herein to refer to any relatively well-defined
space or recess in some other osteoimplant (hereinafter referred to an "implant" to differentiate from the osteoimplant of the invention) or bone defect site. The term cavity is intended to encompass regions contained substantially within the implant, regions defined by an area or portion of the implant, as well as the regions defined by the placement of adjacent implants and regions defined by relatively welldefined bone defects such as extraction sockets, bore holes, etc. Therefore, the term "cavity" as utilized herein broadly includes any relatively well-defined defect at a surgical site.
[0047] The plug embodiment of the osteoimplant of the invention is configured to fit within the cavities of commercially available implants, e.g., spinal cages, and relatively well-defined cavities at a surgical site. The plugs are engineered to fit efficiently, are easy to insert and tend to remain where placed. An additional advantage of the plug is that in many of its configurations, it swells somewhat upon contact with body fluids thus ensuring good bone contact at the implant site even where the site is irregularly shaped. The plug, when made from demineralized bone, is generally osteoinductive and the fiber-like shape of the bone particles further provides a favorable scaffold for bone cell growth thus potentially combining osteoconductive and osteoinductive properties.
[0048] The plug can be formed in a range of shapes and sizes that fit commercially available osteoimplants, e.g., spinal cages, and relatively well-defined bone defects. Some designs of cages may require two or more shaped plugs. The present invention also provides efficient methods for manufacturing the preformed bone plug and methods of using the preformed bone plug for the surgical treatment and/or repair of a bone defect site.
[0049] The term "shaped" as applied to the aggregate of elongate bone particles herein refers to a determined or regular form or configuration in contrast to an indeterminate or vague form or configuration (as in the case of a lump or other solid matrix of no special form) and is characteristic of such materials as sheets, plates, disks, cones, pins, screws, tubes, teeth, bones, portion of bone, wedges, cylinders, threaded cylinders, and the like, as well as more complex geometric configurations.
[0050] The term "coherent" as applied to the aggregate of elongate bone particles refers to the ability of the bone particles to adhere to each other either, e.g., by entanglement, or by the use of a biocompatible binder or adhesive.
[0051] The expression "three-dimensional" refers to the ability of the coherent aggregate of elongate bone particles to assume any desired shape and size.
[0052] The expression "open pore structure" as it applies to the coherent aggregate of elongate bone particles constituting one embodiment of osteoimplant herein shall be understood as referring to the low density, absorbent, sponge-like nature of the osteoimplant in which there are a plurality of accessible pores or openings which are present throughout the entire volume of the aggregate.
[0053] The term "incorporation" utilized herein refers to the biological mechanism whereby host tissue gradually replaces the osteoimplant of the invention with native host bone tissue. This phenomenon is also known in the scientific literature as "bone remodeling" or "cellular based remodeling" and "wound healing response". Therefore, the term
"incorporation" utilized herein shall be understood as embracing what is conveyed to those skilled in the art by the foregoing expressions.
[0054] The expression "further treatment" as utilized herein refers to procedures such as, e.g., lyophilizing, crosslinking treatment, re-mineralization, sterilization, etc., performed either before, during or after the step of making the osteoimplant as well as post-processing procedures such as, e.g., machining, laser etching, welding, assembling of parts, cutting, milling, reactive etching, etc.
[0055] Another particularly useful embodiment of the invention herein is an osteoimplant provided as a coherent aggregate, or matrix, of elongate bone particles possessing an open pore structure and a bulk density of less than about 0.3 g/cm3. The open pore structure of the aggregate renders the osteoimplant highly absorbent of surrounding liquids. The osteoimplant formed from the aggregate is flexible when dry (i.e., when containing less than about 5 weight percent water) and does not require time consuming rehydration prior to implantation. It can assume any desired shape and/or configuration and can be cut to the desired dimensions, e.g., with surgical scissors, before and/or after the aggregate has absorbed fluid. Even in the wetted/hydrated state, the osteoimplant will maintain its original shape and coherency and can be readily handled by the medical practitioner.
[0056] Osteoinductivity can be conveniently quantified as the amount of bone formed in an ectopic site in an athymic nude rat. Scores are rated 0 to 4. The osteoimplants of the invention exhibit osteoinductivities of at least 2, typically greater than 3, when measured in an athymic rat assay as described in Edwards J T, Diegmann M H, Scarborough N L, Osteoinduction of Human Demineralized Bone: Characterization in an Animal Model, Clin. Orthop. Rel. Res. 357:219 228 (1998).
[0057] The osteoimplant of the invention can be combined with a wide variety of biocompatible substances which can be introduced into the porous matrix of the osteoimplant and/or into large cavities, depressions, and the like, produced in the osteoimplant. Thus, the implant herein functions as a highly effective carrier and/or delivery vehicle for bone-growth inducing and/or otherwise medically useful substances.
[0058] Further provided herein is a method of fabricating the osteoimplant herein which comprises providing a quantity of elongate demineralized bone particles, mixing the elongate demineralized bone particles with an aqueous wetting agent to provide a fluid composition preferably containing from about 5 to about 40 volume percent swollen, hydrated bone particles, placing the liquid composition in a mold, and removing a sufficient amount of aqueous wetting agent, e.g., by heating the fluid composition in the substantial absence of pressure at elevated temperature, to provide an osteoimplant comprising a shaped, coherent aggregate, or matrix, of elongate bone particles, preferably one of open pore structure and possessing a bulk density of less than about 0.3 g/cm3.
[0059] Further provided in accordance with the invention is a method of repairing and/or treating bone comprising implanting at a bone repair site an osteoimplant which comprises a shaped and dimensioned coherent aggregate of
|
