KR20010108176A - Bone-derived implant for load-supporting applications - Google Patents

Abstract

One or more layers 22, 23 of fully mineralized or partially demineralized cortical bone, and, optionally, one or more layers of other material 22, 23. The bone guide implant 20 is provided. The layers 22, 23 constituting the implant 20 are assembled into a single structure to make the implant 20 exhibiting good overall load-bearing properties.

Description

Bone-derived implant for load-supporting applications

The use of autograft bone, alograft bone or xenograft bone is well known in human medicine and veterinary medicine. Stevenson et al., "Clinical Orthopedic and Related Research, 323, pp. 66-74, 1996". In particular, transplanted bones support, promote repair, fill bony cavities, separate bony elements, such as vertebral bodies, and promote fusion And stabilize the fracture site. More recently, processed bone has been developed in a form for use in new surgical applications, or as a new material for implants that has historically been made of non-biologically derived materials.

US Pat. No. 4,678,470 describes a non-layered bone grafting material made from bone by a process involving tanning with glutaraldehyde. The bone may be ground, used in large blocks, or processed into precise shapes. Tanning stabilizes the material and also makes it non-antigenic. The bone material may also be softened.

Although the use of a continuous sheet of softened or partially softened bone is disclosed in US Pat. No. 5,556,430, the sheet must be elastic enough to conform to the skeletal area used, so weakening of strength is inevitable. Do.

Surgically implantable sheets, described in US Pat. No. 5,507,813, are softened selectively and have a length that includes biocompatible ingredients, adhesives, fillers, plasticizers, and the like. It is shaped into elongate bone particles.

US Pat. No. 4,932,973 discloses an artificial organic bone matrix having holes or perforations extending into the organic bone matrix. These holes are marked as being the center of cartilage and bone induction following the implantation of the bone matrix.

US Pat. No. 4,394,370 discloses a one-piece sponge-like bone graft material, made from fully softened bone powder or micro particulate bone, and renewed collagen. The sponge-like graft is optionally cross-linked with glutaraldehyde.

Another one-piece porous implant is disclosed in US Pat. No. 5,683,459. The implant consists of a biodegradable polymeric macrostructure consisting of interconnecting open cell meshwork, and a chemically arranged ground substance such as hyaluronic acid. Consisting of a biodegradable polymeric microstructure.

The present invention is at least partly made of strength-imparting cortical bone and used for repair, replacement and / or augmentation of various parts of an animal or human skeletal system. A bone-derived implant for. More particularly, the present invention relates to an osteoinductive implant consisting of two or more layers, at least one of which is fully mineralized or partially softened cortical bone. Optionally, one or more layers are made of different materials. The individual layers that make up the implant are assembled into a single structure that can support the load.

Various embodiments will be described below with reference to the drawings.

1 is a cross-sectional view of a bone as seen from the interosseous region segmented longitudinally into several cortical bone layers,

2 is an enlarged perspective view of an osteoinductive implant of the present invention having a layer of fully mineralized cortical bone alternately coupled with layers of partially and / or fully softened cortical bone,

3 is a partial view of the human spine showing the dowel-shaped osteoinductive implant of the present invention, installed between the vertebrae and the vertebrae,

4 is a diagram showing a human skull showing an osteoinductive implant of the present invention made as a substitute for cheekbones,

5 is an enlarged perspective view of a lattice-like section of an osteoinductive implant,

FIG. 6 is a partial view of the human vertebra showing the installation of the bone guide implant of FIG. 5 at the vertebral region.

The present invention provides an osteoinductive implant capable of supporting a load and, in a preferred embodiment, incorporates a medically / surgically useful material to promote and / or accelerate the growth of new bone at the surgical site ( Incorporate the bone repair activity and ability of the bone guide implant to provide a long felt need in the field of the present invention.

It is therefore an object of the present invention to provide an osteoinductive implant composed of a plurality of superimposed layers, fixed to each other in a monolithic structure, and having properties similar to the compressive strength properties of natural bone.

It is another object of the present invention to provide for the penetration and penetration of pores, apertures, perforations, channels or spaces by allowing and promoting penetration by endogenous and exogenous bone therapeutic materials and blood supply. It is to provide a bone implant having a network, and at the same time to provide a means for incorporating one or more bone repair materials.

Another object of the present invention is bone that can be made in a variety of shapes and sizes that are not limited by the constraints imposed by the general anatomical size and / or shape of the donor bone used in the construction of the implant. To provide an induction implant.

In accordance with the above and other objects of the present invention, it is composed of a plurality of overlapping layers assembled in a unitary structure, at least one of which is a compressive-strength transfer layer made of unsoftened or partially softened cortices. In addition, an osteoinductive implant is provided.

The bone guide implant of the present invention is similar to the mechanical strength characteristics of natural bones, and allows for the phased transfer of load-bearing support to newly formed bone tissue over time. In terms of the ability to enable it, there is a significant advantage over the technology of conventional bone and bone guide implants.

Another important advantage over prior art implants of osteoinductive implants here is the carrier of one or more medically / surgically useful substances that promote the growth and / or repair of new bone. It is in the ability to act as and effectively incorporate it.

As used herein, the term "osteogenic" should be understood to describe the ability of a substance to induce the production of new bone through the involvement of living cells from within the substance.

As used herein, the term "osteoconductive" should be understood to describe the ability of a material or material to provide biologically inert surfaces to accommodate the growth of new host bones.

As used herein, the term "osteoinductive" should be understood to describe the ability of a substance to replenish a cell from a host that has the potential for repair of bone tissue.

The osteoinductive implant of the present invention consists of at least two overlapping layers, at least one of which is a compression strength-imparting layer derived from an unsoftened or partially softened cortical bone. The partially softened cortical bone layer, when present as a compressive strength-transfer layer, has a significantly higher percentage than the compressive strength of the comparative layer of softened cortical bone, eg, preferably at least about 40, more preferably at least about 50 And even more preferably at least about 60 percent compressive strength. Layers of partially softened corrugated bone that exhibit significantly lower values than about 40 percent of the compressive strength of the layer to be compared to the fully mineralized cortical bone can be selectively used in osteoinductive implants for other capacities other than load-bearing. . Depending on the thickness of the layer, there may be between two and about 200 layers throughout the bone guide implant. The osteoinductive implant can include layers of varying thickness, for example, the compressive strength-transfer layer (s) can be significantly thicker or thinner than any layer (s) which may be present. Thicknesses ranging from about 0.5 to about 20, and preferably from about 1.5 to about 15, can advantageously be used. In general, the number and thickness of the compressive-strength delivery layers in a given bone guide implant are sufficient to provide the compressive strength of the overall implant, which is about 25 to about 250, preferably about 100 to 200 MPa. It should be.

Sources of the cortical bone used in the osteoinductive implants of the present invention are preferably allogenic, but also include xenogenic materials such as bovine and swine bone. When partially or fully softened cortical bone is used, such bone is known in the art of known softening techniques, for example, in Proc. Nat. Acad. Sci. 69, pp. Obtained using techniques using strong acids, such as hydrochloric acid, described in 1601-5 (1972). The degree of softening is a function of the concentration of the acid solution, the shape of the bone and the duration of the softening treatment. Reference may be made to Lewandrowski. Et al., J. Biomed Materials Res, 31, pp365-372 (1996), which is also part of this specification. The use of partially or fully softened bone may be beneficial in that such materials exhibit better initial osteogenic and / or osteoinductive activity than fully mineralized bone.

The compressive strength-transfer layer (s) of an osteoinductive implant may be made of a monolithic section of bone, or two or more subsections, for example in an edge-to-edge manner similar to planing. (in edge-to-edge fashion) can be provided as multi-sectional layers bonded to one another. In this way, a relatively large compressive strength-transfer layer is incorporated into smaller bone sections to provide an implant that is not limited by the size and / or shape of the cortical bone, the overall size of which is available for its construction. Can be configured.

Assembly of the overlapping layer into a robust monolithic structure can be accomplished by various means / treatment methods, for example cyanoacrylates; Epoxy-based compounds, dental resin sealants, dental resin cements, glass ionomer cements, polymethyl methacrylate, gelatin -Gelatin-resorcinol-formaldehyde glues, collagen-based glues; Inorganic bonding agents such as zinc phosphate, magnesium phosphate or other phosphate-based cements, zinc carboxylate and the like; And application of known conventional biologically compatible adhesives, such as protein-based binders such as fibrin glues and muscle-derived adhesive proteins; Mechanical fasteners such as pins, screws, dowels, etc., which can be made of natural or synthetic and nonbioabsorbable materials as well as bioabsorbable materials; Laser tissue welding; And by the use of ultrasonic bonding.

If desired, the layers of the bone guide implant may be, for example, in a tongue-and-groove form, in mechanically interlocked form, to facilitate assembly into the final product and / or to secure the layers together in a safer manner. ) Or in a mortise-and-tenon fashion. The osteoinductive implant of the present invention may optionally have one or more layers, consisting of one or more other materials, in addition to a fully or partially mineralized compressive strength-transmitting cortical bone layer. For example, these optional layers may be highly or fully softened bone, graphite or pyrolytic carbon, hydroxyapatite, tricalcium phosphate, bioglass. Minerals or other bioceramic or natural or synthetic polymers, such as, for example, starches, polyglycolide, polylactide, glycolide-lactide copolymers, etc. copolymers, bioabsorbable materials such as polymethyl methacrylate, polytetrafluoroethylene, polyurethane, polyethylene and nylon, and the like. It may be based on or include nonbioabsorbable polymers.

If desired, the compression strength axis of the one or more compressive strength-transfer layers is relative to the compressive strength axis of one or more other compressive strength-transfer layers in a plywood-like arrangement. May be offset. For example, the compressive strength axes of the alternating compressive strength-transfer layers are offset by 90 degrees from the compressive strength axes of the other compressive strength-transfer layers of the implant to distribute the full load-bearing capacity of the implant in the transverse direction. (off set)

Bone-induced implants of the desired size and / or shape can be made by machining or other mechanical shaping operations, such as, for example, press-molding. Computerized molding of certain implants, followed by computerized control of implant shaping, can be used to create complex shaped osteogenic implants that are highly precisely tailored to the intended application site.

Bone-guided implants, if desired, have an average diameter from a few microns to several millimeters and can communicate with the surface of the implant through small pores, apertures, perforations or channels. It may have more or more cavities. The cavities and small pores, apertures, perforations and channels associated with them are new, for example, with osteogenic, osteoconductive and / or osteoinductive effects. It may be partially or completely filled with one or more medically / surgically useful materials that promote or accelerate bone growth or bone treatment. Useful materials of this kind that can be incorporated into the osteoinductive implants of the invention include, for example, collagen, insoluble collagen derivatives, and the like, and soluble solids and / or therein. Liquids dissolved therein, for example antiviral agents effective against antiviral agents, in particular HIV and hepatitis; Antimicrobials and / or erythromycin, bacitracin, neomycin, penicillin, polymyxin B, tetratracyclines, biomycin ), Chloromycetin and streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin Same antibiotics; Biocidal / biostatic sugars such as dextroal, glucose and the like; Amino acids, peptides, vitamins, inorganic elements, co-factors for protein synthesis; Hormones; Endocrine tissue or tissue fragments; Synthesizers; Enzymes such as collagenase, peptidases, oxidases, and the like; Polymer cell scaffolds with parenchymal cells; Angiogenic drugs and polymeric carriers containing such drugs; Collagen lattices; Antigenic agents; Cytoskeletal agents; Cartilage fragments, living cells such as chondrocytes, bone marrow cells, mesenchymal stem cells, natural extracts, tissue implants (tissue transplants), bone, softened bone powder (or the aforementioned "demineralized bone matrix"), blood, serum, soft tissue , Autogenous tissues such as bone marrow, etc .; bioadhesives, bone morphogenic proteins (BMPs), transforming growth factors (TGF-beta), insulin- Insulin-like growth factor (IGF-1); growth hormones such as somatotropin; bone digesters; antitumor agents; immuno-suppressants Permeation enhancers, for example laurate (l) fatty acid esters such as aureate, myristate and stearate monoesters of polyethylene glycol, enamine derivatives, alpha-keto aldehydes, and the like And, similarly, these and similar medically / surgically useful materials may be incorporated into any of the osteoinductive implants of the present invention or its constituent layers during the implant assembly step. Can be incorporated. Suitable coalescing methods include coating, immersion, saturation, packing and the like. The amount of medically / surgically useful material used in this way can vary widely by the optimal level that is readily determined by routine experimentation in certain circumstances.

The osteoinductive implants of the present invention are for application to, for example, bone injury sites resulting from injury, injury generated during surgical operations, infections, malignant tumors or developmental malformations. Bone guided implants of appropriate size and shape as needed, such as the repair of simple and compound fractures and non-unions, external and internal fixations; Open arthrodesis, general arthroplasty, hip arthroplasty of the hip, femoral and humeral head replacement, femoral head surface replacement Joint reconstructions and total joint replacement; Repairs of the vertebral column, tumors surgery, including spinal fusion and internal fixation, for example deficit filling, disc resection discectomy, laminectomy, excision of spinal cord tumors, anterior cervical and thoracic operations, repair of spinal injuries, scoliosis, spinal jeonmanjeung (lordosis) and kyphosis (kyphosis) treated (treatments), transmembrane fixation of the fracture (intermaxillary fixation of fractures), jaw surgery (mentoplasty), temporomandibular joint replacement surgery (temporomandibular joint replacement), alveolar projection augmentation and repair alcohol ( Plastic surgery, neurosurgery and mouth and mouth, including alveolar ridge augmentation and reconstruction, inlay bone grafts, implant placement and revision, sinus lifts, etc. And face can be used as a surgical graft (graft) or substitute (replacement) in a wide range of fields (orthopaedic, neurosurgical and oral and maxillofacial surgical procedures). Specific bones that can be repaired or replaced with the bone guide implants of the present invention include, ethmoid, frontal, nasal, occipital, parietal, temporal and mandible. ), Maxilla, zygomatic, cervical vertebra of the cervix, thoracic vertebra of the thorax, lumbar vertebra, lumbar sacrum, ribs, sternum , Clavicle, scapula, humerus, radial, ulna, carpal bones, metacarpal bones, phalanges, ileum, sciatic (ischium), pubis, femur, tibia, fibula, patella, heels (calcaneus), tarsal and metatarsal bones.

In the accompanying drawings, as shown in FIG. 1, the outer skin portion of the bone 10 removed from the diaphyseal region is sectioned in the longitudinal direction of the bone and cut into the outer cortical bone layers 11 of various widths. . If desired, the cortical bone layers 11 may be further cut into a uniform size and shape, as in the bone layer 22 of the implant 20 shown in FIG. 2.

2 shows one osteoinductive implant 20 in which the fully mineralized cortical bone layer 22 and the partially softened cortical bone layer 23 are alternately layered. Alternatively, one or more layers 23 may be made of a material other than partially demineralized bone, such as minerals such as fully demineralized bone or hydroxyapatite. have. The total thickness of the bone implant will usually be at least about 5 mm, and preferably at least about 10 mm. The bone guide implant 20 may be cut, machined, and / or otherwise shaped into other desired shapes or sizes for implantation into the body. For example, a generally cylindrical bone implant may be made to be used as a substitute for long bone segments such as the femur. To form into a cylindrical shape, a generally square or rectangular osteoinductive implant can be molded to the diameter required in the lathe. The cavity may be formed by removing material with a drill or the like, or alternatively, the cavity may be formed by appropriately assembling the molded layers.

As shown in FIG. 3, a cylindrical or dowel-shaped bone guide implant 30 is inserted into an intervertebral fibrocartilage site in front of the vertebrae 31.

In FIG. 4, a zygomatic bone-derived implant 40 is made of a size and shape that constitutes a portion of the zygomatic arch and a portion of the interior orbit of the skull 41.

The osteoinductive implant 50 is made of elongated sections 51 of a fully mineralized or partially softened compressive strength-carrying cortical bone having a uniform rectangular cross section, as shown in the cross-sectional view of FIG. For example, it is arranged in lattice-wise fashion using cyanoacrylate variety of adhesives. Due to the open structure of the implant 50 according to a pattern having longitudinal channels 52 and transverse channels 53, the implant of the above structure is either vascular penetration or Host bone ingrowth and / or diffusion of one or more medically / surgically useful materials. Vertical channels in the lattice array are, if desired, appropriately sized from fully mineralized or partially softened cortical bone, such as in cortical bone section 51, or from other substances closed in this specification. It may be partially or fully filled by sections 54 made in the shape of and. It is shown that a fully assembled bone implant 50 is installed in the intervertebral region 61 of FIG. 6.

The following examples further illustrate the osteoinductive implants of the present invention.

Example 1

The outer skin section of the bone of the diaphyseal region was cut into layers approximately 1.5 mm thick in the longitudinal direction using a diamond-bladed saw while continually soaked with water. The layers were then frozen to minus 70 ° C. and lyophilized for 48 hours. The layers were then assembled using a cyanoacrylate adhesive and clamped for two hours while the adhesive solidified. The resulting multilayered unitary structure is cut by a band saw, shaped into a polishing operation, and made by a hand-held motorized shaping tool to make a molded bone implant. Machined.

Example 2

As in Example 1, a section of the cortical bone of the diaphyseal region was cut into layers approximately 1.5 mm thick with a saw. Half of the slices were sufficiently softened by known methods using 0.6 N hydrochloric acid. Then, all of the layers were assembled to alternate layers with layers of fully mineralized bone, using a cyanoacrylate adhesive. This form of bone guide implant is shown in FIG. 2.

Example 3

In order to make elongate cortical bone sections with uniform rectangular cross sections, about 50 mm long diaphyseal bone segments were cut with a sawtooth, continuously moistened with water. The elongated bone sections are then assembled using a cyanoacrylate adhesive to create a lattice structure in which the layers of spaced-apart bone sections cross-align with each other. It became. One section of this type of bone guide implant is shown in FIG. 5.

Claims (36)

And a plurality of superimposed layers assembled into a unitary structure, at least one of which is a compression strength-imparting layer made of unsoftened or partially softened skin. , Bone guide implants. The bone guide implant of claim 1, wherein the partially demineralized bone layers exhibit a value that is not less than about 40 percent of the compressive strength of the layer to be compared of the fully mineralized bone. The bone guide implant according to claim 1, wherein the layer of partially softened bone exhibits a value no less than about 50 percent of the compressive strength of the layer to be compared of the fully mineralized bone. The bone guide implant according to claim 1, wherein the layer of partially softened bone exhibits a value no less than about 60 percent of the compressive strength of the layer to be compared of the fully mineralized bone. The bone guide implant according to claim 1 having at least two compressive strength-transfer layers. The bone guide implant according to claim 1 having a total thickness of at least about 5 mm. The bone guide implant according to claim 1 having a total thickness of at least about 10 mm. The bone guide implant according to claim 1, having a circle, oval or polygonal cross section or similar in at least part of its length, and optionally having a cavity in at least part of its length. The method of claim 8, wherein small pores, apertures, perforations or channels provide communication between the cavity and the surface of the bone. Osteotomy Implants. The bone guide implant according to claim 1 made in the shape of a graft. The bone guide implant according to claim 1 made in the shape of a replacement of a bone or a section thereof. The method of claim 11, wherein the intervertebral insert, the long bone, the cranial bone, the bone of the pelvis, or the bone of the hand or foot, or the aforementioned Osteotomy implants, made in the shape of some sections of bones. The bone guide implant according to claim 1, wherein at least one mechanical strength-imparting layer is provided in its monotone bone section. The method of claim 1, wherein at least one mechanical strength-imparting layer is provided in a multi-sectional bone section, wherein the subsections of the bones constituting the section are edge-to-edge with each other. Osteoinductive implants joined in an edge to edge manner. The bone guide implant according to claim 1, having an upper and lower exposed surface portion, wherein the surface portion is a surface portion of compression strength-imparting layers. The bone guide implant according to claim 1, wherein all or part of the at least one layer is made of at least one material that is not softened or partially softened cortical bone. The bone guide implant of claim 16 wherein the material promotes bone healing. 18. The osteoinductive implant of claim 17, wherein the material has osteogenic, osteoconductive and / or osteoinductive activity. 19. The method of claim 18, wherein the material comprises partially softened bone, nearly fully softened bone, growth factors, bone morphogenic protein, bone forming cells, progenitor cells. Osteoguided implant, selected from the group consisting of precursor cells, genetic material, inorganic compounds and polymers. The bone guide implant according to claim 1, wherein each strength-transfer layer has the same or different average thickness in the range of about 0.5 mm to about 20 mm. The bone guide implant according to claim 1, wherein each layer has the same or different average thickness in the range of about 1.5 mm to about 15 mm. The bone guide implant according to claim 1 wherein the compression strength axes of at least two consecutive compressive strength-transfer layers are offset from each other. The method of claim 1, wherein at least two consecutive compressive strength-transfer layers are offset from each other in a lattice-like arrangement that defines an array of channels in all three dimensions. Bone-guided implants, each made of spaced-apart sections spaced apart from each other in the compressive strength axis of the layers. 24. The bone guide implant according to claim 23, wherein one or more vertical channels in the array are partially or completely filled by the material of the section of one or more suitable shapes and sizes. The bone guide implant according to claim 24, wherein the section is fully mineralized bone, or partially or fully softened bone. 24. The osteoinductive implant of claim 23, wherein at least one channel contains an osteogenic, osteoconductive and / or osteoinductive material. 27. The method of claim 26, wherein the material is partially softened bone powder, nearly fully softened bone powder, growth factors, bone morphogenic protein, bone forming cells or precursor cells. An osteoinductive implant, selected from the group consisting of precursor cells, genetic materials, and inorganic compounds or polymers. 6. The osteoinductive method of claim 5, wherein one or more compressive-strength axes of the one or more compressive strength-transfer layers are offset relative to the compressive strength axes of the one or more other compressive strength-transfer layers. Implants. The bone guide implant according to claim 1 having a compressive strength from about 25 MPa to about 250 MPa. The bone guide implant according to claim 1 having a compressive strength from about 100 MPa to about 200 MPa. The bone guide implant according to claim 1 having from 2 to about 200 layers. The bone guide implant according to claim 16 having a means to promote diffusion of bone therapeutic material. 33. The osteoinductive implant of claim 32, wherein said means for promoting diffusion of bone therapeutic material constitutes channels that are partitioned within one or more layers. The bone guide implant according to claim 1, wherein all or a portion is made of allogenic and / or xenogenic cortical bone. The osteoinductive implant of claim 1, wherein the overlap layer is assembled with an adhesive. The bone guide implant according to claim 1, wherein the overlap layer is assembled with mechanical fasteners.