Bone graft composites and spacers

BONE GRAFT COMPOSITES AND SPACERS

FIELD OF THE INVENTION

The present invention relates to bone graft substitute materials and spacers composed of the materials for arthro- 5 desis. In specific applications of the invention the materials are provided in synergistic combination with osteogenic compositions.

BACKGROUND OF THE INVENTION 10

Spinal fusion is indicated to provide stabilization of the spinal column for painful spinal motion and disorders such as structural deformity, traumatic instability, degenerative instability, and post-resection iatrogenic instability. Fusion, or arthrodesis, is achieved by the formation of an osseous 15 bridge between adjacent motion segments. This can be accomplished within the disc space, anteriorly between contiguous vertebral bodies or posteriorly between consecutive transverse processes, laminae or other posterior aspects of the vertebrae. 20

An osseous bridge, or fusion mass, is biologically produced by the body upon skeletal injury. This normal bone healing response is used by surgeons to induce fusion across abnormal spinal segments by recreating spinal injury conditions along the fusion site and then allowing the bone to heal. A successful fusion requires the presence of osteogenic or osteopotential cells, adequate blood supply, sufficient inflammatory response, and appropriate preparation of local bone. This biological environment is typically provided in a ^ surgical setting by decortication, or removal of the outer, cortical bone to expose the vascular, cancellous bone, and the deposition of an adequate quantity of high quality graft material.

A fusion or arthrodesis procedure is often performed to 35 treat an anomoly involving an intervertebral disc. Intervertebral discs, located between the endplates of adjacent vertebrae, stabilize the spine, distribute forces between vertebrae and cushion vertebral bodies. A normal intervertebral disc includes a semi-gelatinous component, the 4Q nucleus pulposus, which is surrounded and confined by an outer, fibrous ring called the annulus fibrosis. In a healthy, undamaged spine, the annulus fibrosis prevents the nucleus pulposus from protruding outside the disc space.

Spinal discs may be displaced or damaged due to trauma, 45 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 on the spinal nerve, which may result in nerve damage, pain, numbness, 50 muscle weakness and 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. 55

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 60 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. 65

Bone grafts are often used to fill the intervertebral space to prevent disc space collapse and promote fusion of the

adjacent vertebrae across the disc space. In early techniques, bone material was simply disposed between the adjacent vertebrae, typically at the posterior aspect of the vertebrae, 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 segment became superfluous and was a permanent foreign body. Moreover, the surgical procedures necessary to implant a rod or plate to stabilize the level during fusion were frequently lengthy and involved.

It was therefore determined that a more optimal 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 plating. There have been an extensive number of attempts to develop an acceptable intra-discal implant that could be used to replace a damaged disc and maintain the stability of the disc interspace between the adjacent vertebrae, at least until complete arthrodesis is achieved. To be successful 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 cyclic compressive spinal loads for the life of the patient.

Many attempts to restore the intervertebral disc space after removal of the disc have relied on metal devices. U.S. Pat. Nos. 4,878,915 to Brantigan teaches a solid metal plug. U.S. Pat. Nos. 5,044,104; 5,026,373 and 4,961,740 to Ray; 5,015,247 to Michelson and U.S. Pat. No. 4,820,305 to Harms et al., U.S. Pat. No. 5,147,402 to Bohler et al. and 5,192,327 to Brantigan teach hollow metal cage structures. Unfortunately, due to the stiffness of the material, some metal implants may stress shield the bone graft, increasing the time required for fusion or causing the bone graft to resorb inside the cage. Subsidence, or sinking of the device into bone, may also occur when metal implants are implanted between vertebrae if fusion is delayed. Metal devices are also foreign bodies which can never be fully incorporated into the fusion mass.

Various bone grafts and bone graft substitutes have also been used to promote osteogenesis and to avoid the disadvantages of metal implants. Autograft is often preferred because it is osteoinductive. Both allograft and autograft are biological materials which are replaced over time with the patient's own bone, via the process of creeping substitution. Over time a bone graft virtually disappears unlike a metal implant which persists long after its useful life. Stress shielding is avoided because bone grafts have a similar modulus of elasticity as the surrounding bone. Commonly used implant materials have stiffness values far in excess of both cortical and cancellous' bone. Titanium alloy has a stiffness value of 114 Gpa and 316L stainless steel has a stiffness of 193 Gpa. Cortical bone, on the other hand, has a stiffness value of about 17 Gpa. Moreover, bone as an implant also allows excellent postoperative imaging because it does not cause scattering like metallic implants on CT or MRI imaging.

Various implants have been constructed from bone or graft substitute materials to fill the intervertebral space after the removal of the disc. For example, the Cloward dowel is a circular graft made by drilling an allogeneic or autogeneic plug from the illium. Cloward dowels are bicortical, having porous cancellous bone between two cortical surfaces. Such dowels have relatively poor biomechanical properties, in particular a low compressive strength. Therefore, the Cloward dowel is not suitable as an intervertebral spacer without internal fixation due to the risk of collapsing prior to fusion under the intense cyclic loads of the spine.

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Bone dowels having greater biomechanical properties have been produced and marketed by the University of Florida Tissue Bank, Inc., 1 Progress Boulevard, P.O. Box 31, S. Wing, Alachua, Fla. 32615. Unicortical dowels from allogeneic femoral or tibial condyles are available. The 5 University of Florida has also developed a diaphysial cortical dowel having superior mechanical properties. This dowel also provides the further advantage of having a naturally preformed cavity formed by the existing meduallary canal of the donor long bone. The cavity can be packed 10 with osteogenic materials such as bone or bioceramic.

Unfortunately, the use of bone grafts presents several disadvantages. Autograft is available in only limited quantities. The additional surgery also increases the risk of infection and blood loss and may reduce structural integrity :5 at the donor site. Furthermore, some patients complain that the graft harvesting surgery causes more short-term and long-term pain than the fusion surgery.

Allograft material, which is obtained from donors of the

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same species, is more readily obtained. However, allogeneic bone does not have the osteoinductive potential of autogenous bone and therefore may provide only temporary support. The slow rate of fusion using allografted bone can lead to collapse of the disc space before fusion is accomplished. 25

Both allograft and autograft present additional difficulties. Graft alone may not provide the stability required to withstand spinal loads. Internal fixation can address this problem but presents its own disadvantages such as the need for more 3Q complex surgery as well as the disadvantages of metal fixation devices. Also, the surgeon is often required to repeatedly trim the graft material to obtain the correct size to fill and stabilize the disc space. This trial and error approach increases the length of time required for surgery. 3J Furthermore, the graft material usually has a smooth surface which does not provide a good friction fit between the adjacent vertebrae. Slippage of the graft may cause neural and vascular injury, as well as collapse of the disc space. Even where slippage does not occur, micromotion at the 4Q graft/fusion-site interface may disrupt the healing process that is required for fusion.

Several attempts have been made to develop a bone graft substitute which avoids the disadvantages of metal implants and bone grafts while capturing advantages of both. For 45 example Unilab, Inc. markets various spinal implants composed of hydroxyapatite and bovine collagen. In each case developing an implant having the biomechanical properties of metal and the biological properties of bone without the disadvantages of either has been extremely difficult or 50 impossible.

These disadvantages have led to the investigation of bioactive substances that regulate the complex cascade of cellular events of bone repair. Such substances include bone morphogenetic proteins, for use as alternative or adjunctive 55 graft materials. Bone morphogenetic proteins (BMPs), a class of osteoinductive factors from bone matrix, are capable of inducing bone formation when implanted in a fracture or surgical bone site. Recombinantly produced human bone morphogenetic protein-2 (rhBMP-2) has been demonstrated go in several animal models to be effective in regenerating bone in skeletal defects. The use of such proteins has led to a need for appropriate carriers and fusion spacer designs.

Due to the need for safer bone graft materials, bone graft substitutes, such as bioceramics, have recently received 65 considerable attention. The challenge has been to develop a bone graft substitute which avoids the disadvantages of

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metal implants and bone grafts while capturing the advantages of both. Calcium phosphate ceramics are biocompatible and do not present the infectious or immunological concerns of allograft materials. Ceramics may be prepared in any quantity which is a great advantage over autograft bone graft material. Furthermore, bioceramics are osteoconductive, stimulating osteogenesis in boney sites. Bioceramics provide a porous matrix which further encourages new bone growth. Unfortunately, ceramic implants typically lack the strength to support high spinal loads and therefore require separate fixation before the fusion.

Of the calcium phosphate (TCP) ceramics, hydroxyapatite (HA) and tricalcium phosphate ceramics have been most commonly used for bone grafting. Hydroxyapatite is chemically similar to inorganic bone substance and biocompatible with bone. However, it is slowly degraded. (3-tricalcium phosphate is rapidly degraded in vivo and is too weak to provide support under the cyclic loads of the spine until fusion occurs. Developing an implant having the biomechanical properties of metal and the biological properties of bone without the disadvantages of either has been extremely difficult or impossible.

It recently became apparent that natural bone mineral is not actually as close to the chemistry and structure of hydroxyapatite as was previously believed. (Spector, 21 Clinics in Plastic Surgery 437^-44, 1994, the complete text of which is herein incorporated by reference.) Natural bone mineral contains carbonate ions, magnesium, sodium, hydrogenophosphate ions and trace elements. Bone mineral also has a different crystalline structure than HA. Other details of bone chemistry are disclosed in U.S. Pat. No. 4,882,149 to Spector. Mimicing the chemistry and microstructure of bone is important to obtain a beneficial modulus of elasticity and resorbtion rate.

Several attempts have been made to make materials which are closer to the microstructure of bone. Some disclose removing organic material from bone to yield bone mineral. Some of the materials are used as drug carriers as disclosed in, for example, U.S. Pat. No. 5,417,975. U.S. Pat. No. 4,882,149 to Spector describes a bone mineral material which is free from fat and bone proteins. The result is a powdery, brittle radiopaque material which can be used to deliver bone growth proteins. The Spector mineral is thought to be closer to natural bone mineral than synthetic calcium phosphate ceramics but it does not have characteristics which allow it to be shaped into formed objects. U.S. Pat. Nos. 4,314,380 to Miyata et al. and 5,573,771 disclose adding collagen or gelatin to bone mineral. However, it is unclear how close these materials are to the natural structure of bone because the crystalline structure is disrupted when all of the proteins are removed from the treated bone. Urist et al. (110 Arch Surg 416,1975) discloses a chemosterilized antigen-extracted autodigested alloimplant which is thought to preserve the morphogenetic potential of the material. None of these materials are thought to yield a noncollagenous-protein-free bone mineral which is identical to natural bone.

A need has remained for fusion spacers which stimulate bone ingrowth and avoid the disadvantages of metal implants yet provide sufficient strength to support the vertebral column until the adjacent vertebrae are fused.

A need has also remained for bone graft substitutes which provide the osteogenic potential and low risk of infectious or immunogenic complications of autograft without the disadvantages of autograft.

SUMMARY OF THE INVENTION

In accordance with one aspect of the invention, bone graft compositions and vertebral spacers composed of bone graft 5

compositions are provided. In one aspect, the invention provides deactivated bone graft compositions in synergistic combination with a bone growth factor.

One object of the invention is to provide a bone graft substitute having the natural mineral structure, 5 nonimmunogenicity, safety and osteoinductive potential of autograft. Another object of the invention is to provide spacers for engagement between vertebrae which restore the intervertebral disc space and supports the vertebral column while encouraging bone ingrowth and avoiding stress shield- 1° ing.

One benefit of the present invention is that it solves many of the problems associated with the use of bone graft. The deactivation process removes immunogenic and disease causing agents while retaining the natural micro-structure of 15 bone. This feature allows the use of xenograft, which is available in virtually unlimited supply. Fortifying the graft with a bone growth factor makes the graft osteoinductive which makes the pain and risk of harvesting autograft unnecessary. An additional benefit is that the invention 20 provides a stable scaffold for bone ingrowth before fusion occurs. Still another benefit of this invention is that it allows the use of bone grafts without the need for metal cages or internal fixation, due to the increased speed of fusion. Other objects and further benefits of the present invention will 25 become apparent to persons of ordinary skill in the art from the following written description and accompanying Figures.

BRIEF DESCRIPTION OF THE DRAWINGS 30

FIG. 1 is a top perspective view of a selectively deactivated bone BMP composite dowel according to this invention.

FIG. 2 shows bilateral dowel placement between L5 and 35 the sacrum.

FIG. 3 is a perspective view of a cortical dowel having a chamber.

FIG. 4 is a side perspective view of a dowel according to this invention.

FIG. 5 is a cross-section of another dowel of this invention.

FIG. 6 is a side elevational view of the dowel shown in FIG. 5. 45

FIG. 7 is a selectively deactivated cortical ring packed with an osteogenic material.

FIG. 8 is yet another selectively deactivated cortical ring embodiment provided by this invention.

FIG. 9 is another embodiment of a cortical ring provided by this invention.

DESCRIPTION OF THE PREFERRED
EMBODIMENT

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For the purposes of promoting an understanding of the principles of the invention, reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the go invention is thereby intended, such alterations and further modifications in the illustrated spacers, and such further applications of the principles of the invention as illustrated therein being contemplated as would normally occur to one skilled in the art to which the invention relates. 65

The present invention provides bone graft substitute compositions, spacers and surgical procedures. The bone

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graft compositions include selectively deactivated bone grafts in synergistic combination with an osteogenic material, such as a bone morphogenic protein (BMP). The bone grafts are selectively deactivated to remove all of the cellular material, fat and non-collagenous protein. In preferred embodiments, free collagen is also removed leaving structural or bound collagen which is associated with bone mineral to form the trabecular struts of bone. Although the graft is deproteinated and defatted, it still contains the natural crystalline structure of bone. Therefore, the deactivated bone of this invention has the natural micro-structure of bone without the risk of disease transmission or significant immunogenicity.

The natural crystalline structure of bone is maintained by the presence of structural collagen. This yields a selectively deactivated bone material with preferred physical characteristics. The presence of structural collagen and the natural mineral structure of bone results in an elasticity and radiopacity which is identical or nearly identical to bone. The material has sufficient resilience and elasticity to retain a formed body and yet remains rigid enough to maintain an open space between bone portions to result in a fusion mass. Other allograft materials such as demineralized bone matrix do not have the optimal physical properties to accomplish this without the assistance of a support.

When the selectively deactivated bone materials of this invention are combined with an osteogenic factor such as bone morphogenetic protein, the composite is an ideal bone graft substitute. The composite has the natural calcium phosphate structure of bone. This facilitates incorporation and substitution of the graft material giving the composites a desirable resorption rate of a few months. This compares favorably to the resorption rates of known materials which are typically either too fast, slow or unpredictable. For example, allograft typically is resorbed within 12-60 months but may, on the other hand, resorb too quickly before fusion can occur due to an immunogegenic response by the patient.

The combination of BMP and other osteogenic factors with a selectively deactivated bone graft according to this invention provides the osteoinductive potential of autograft without the need for a harvesting surgery. The osteoinductive composites of this invention enhance bone growth into and incorporation of the graft, resulting in fusion quicker than with graft alone. Allograft alone typically requires many months to incorporate and sometimes is never fully incorporated, but is merely encased within the patient's bone. The quicker fusion occuring within about five months provided by this invention compensates for the less desirable biomechanical properties of graft and makes the use of internal fixation and metal interbody fusion devices unnecessary. The spacers of this invention are not required to support the cyclic loads of the spine for very long because of the quick fusion rates which reduce the biomechanical demands on the spacer. However, when required the compositions of this invention may be used with internal fixation devices or may be reinforced as disclosed in copending U.S. Pat. application Ser. No. 08/872,689, filed on Jun. 11, 1997.

A further advantage provided by this invention is that because the bone is selectively deactivated, the graft may be autogeneic, allogeneic or xenogeneic. The components of bone which could cause disease or prompt the patient's body to reject the graft are removed by the deactivation process. Xenogenic bone, such as bovine bone, is available in virtually unlimited supply. Several osteogenic factors are also available in unlimited supply thanks to recombinant DNA technology. Therefore, the present invention solves all of the