MXPA00007606A - Osteoimplant and method for its manufacture - Google Patents

Abstract

The invention relates to an osteoimplant fabricated from a solid aggregate of bone derived elements possessing chemical linkages between their adjacent surface-exposed collagen. Also described are various other components which can be incorporated into the bone implant material such as bone-growth inducing substances;and a method of manufacture.

Description

OSTEOIMPLA TE AND METHOD FOR ITS MANUFACTURE BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to an osteoimplant for use in the repair, replacement and / or enhancement of the different portions of animal or human skeletal systems and to a method for manufacturing the osteoimplant. More specifically this invention relates to an osteoimplant 10 made from a solid aggregate of elements obtained from bones that are joined together through chemical bonds formed between their collagen exposed on the surface.

Description of the Related Art lz The use of self-tapping bone, allografted bone or xenografted bone in human and veterinary medicine is well known. See, Stevenson et al., Clim cal Orthopedics and Related Research, 323, p. 66-74 (1996) In particular, it is known that transplanted bone provides support, promotes healing, fills bone cavities, separates bone elements as vertebral bodies, favors fusion and stabilizes fracture sites. Currently, processed bone has been developed in forms for use in new surgical applications, or as novel materials for? implants that were traditionally made from materials obtained not biologically. U.S. Patent No. 4,678,470 discloses a non-stratified bone graft material produced from bone by a process that includes tanning with glutaraldehyde. The bone can be pulverized, used as a large block or machined in a precise manner. Tanning or hardening stabilizes the material and renders it non-antigenic. The bone material can also be demineralized. Collagen is a structural biomaterial that occurs in nature and is a component of connective tissues, including bone, in vertebrate species. Native collagen is a glycine-rich amino acid chain arranged in a triple helix and can be cross-linked by a variety of procedures. Tissue transglutaminase is described as effective in increasing adhesive strength in a cartilage-cartilage substrate. See Jurgensen, J., et al., The Journal of Bone and Joint Surgery, 79-A (2), 185-193 (1997) U.S. Patent No. 5,507,813 discloses a sheet that can be surgically implanted, formed from elongated bone particles, optionally demystified, containing biocompatible ingredients, adhesives, plasticizing fillers, and so on. U.S. Patent No. 4,932,973 describes a artificial matrix of organic bone with holes or perforations extending towards the organic bone matrix. The holes or perforations are indicated to be centers of induction of cartilage and bone after implanting the bone matrix. U.S. Patent No. 4,394,370 discloses sponge-like bone graft material, one-piece made from completely demineralized bone powder or icroparticle bone, and reconstituted collagen. The sponge type graft is optionally crosslinked with glutaraldehyde.

Another one-piece porous implant is described in U.S. Patent No. 5,683,459. The implant is constituted by a biodegradable polymetallic macrostructure, which is structured as a polygonal network of interconnected open cells, and a biodegradable polymetallic microstructure composed of crushed chemotactic substances such as hyaluronic acid.

SUMMARY OF THE INVENTION The present invention provides an osteoimplant which, due to the chemical bonds that are formed between the collagen exposed on the surface of the partially de-meralized, adjacent osseous elements, of which the osteoimplant is manufactured, has good mechanical strength, is biocompatible and, in a preferred embodiment, Due to its activity of bone healing and ability to contain bone growth-inducing substances, it can favor and / or accelerate the growth of new bone. So, an object of the present invention is to provide an osteoimplant made of a solid aggregate of elements obtained from bone, elements obtained from adjacent bone being joined together through chemical bonds between their exposed collagen on the surface, and which possesses good resistance mechanics and bio-packing. Another object of the invention is to provide an osteoimplant that can optionally include another component such as a reinforcing particle or fiber, fillers, bone growth-promoting substances such as substances useful for medical and surgical use and combinations thereof. . Another object of the invention is to provide an osteoimplant that possesses a network of pores, perforations, openings, channels or spaces that allow and stimulate the penetration of endogenous and exogenous bone healing materials and the blood supply, and simultaneously provide a means for incorporate one or more bone healing substances. Yet another object of the present invention is to provide an osteoimplant that can be modeled in a variety of shapes and sizes that is not limited by the restrictions imposed by the size and / or types of donor bone that are available for the construction of the osteoi plante. It is also an object of the invention to provide a manufacturing method that will provide a strong, biocompatible osteoimplant of any size and / or shape for implantation. In accordance with these and other objects of the invention, there is provided an osteoimplant containing a solid aggregate of bone elements obtained with elements obtained from adjacent bone being joined together through chemical bonds between their collagen exposed on the surface. In addition, according to the invention, there is provided a method for the manufacture of an osteoimplant which consists of providing a quantity of elements obtained from bone that present collagen exposed on the surface and which form chemical bonds between the collagen exposed on the surface to join the elements in a solid aggregate. The osteoimplant of the present invention has a significant advantage over the prior art in its ability to be biocompatible, non-antigenic and provide good mechanical strength. Another important advantage of the present osteoimplant over the implants of the prior art lies in its ability to function as a carrier for, and effectively diffuse, one or more bone growth promoting substances that promote the growth of new bone and / or accelerate healing. The term "osteogenic" as used herein should be understood as referring to the ability of a substance to induce new bone formation through the participation of living cells from within the substance. The term "osteoconductive" as used herein should be understood as referring to the ability of a substance or material to provide biologically inert substances that are receptive to the growth of the new host bone. The term "osteomductive" as used herein should be understood as referring to the ability of a substance to recruit host cells that have the potential to repair bone tissue. The use of the term "elements obtained from bone" should be understood as referring to the pieces of bone in any of the different sizes, thicknesses and configurations including particles, fibers, strips, thin or thick sheets, etc. that can be obtained by grinding, slicing, cutting or machining whole bone. The expression "collagen exposed on the surface" should understood as referring to the result obtained by the demystification of the aforementioned elements obtained from bone, the demineralization ranging from practically complete (in which case the elements obtained from bone are mainly collagenic) to partial or superficial (in which case only the surfaces of the elements obtained from bone show exposed collagen). The partial or surface demyelination produces elements obtained from bone having a surface binding region, namely, exposed collagen, while retaining a reinforced region, namely, the mineralized, unaffected region of the elements obtained from bone.

BRIEF DESCRIPTION OF THE DRAWINGS l-? In the following, different modalities are described with reference to the drawings, wherein: FIGURE 1 is a cross-sectional view of the bone from the diaphyseal region that has been sliced longitudinally into several sheets of cortical bone. FIGURE 2 is an enlarged, perspective view of an osteoimplant of the invention presenting the partially demineralized bone sheets on its surface and an interior comprised of mineralized or partially demineralized bone; -? FIGURE 3 is a view of a human femur showing a osteoimplant of the invention, as shown in FIGURE 3a, cast as a femoral bone replacement. FIGURE 4 is a partial view of the human spinal column showing a disk-shaped osteoimplant of the invention installed at a midvertebral site; FIGURES 5 and 5a are views of a human skull showing an osteoimplant of the invention molded as a replacement of parietal bone; FIGURE 6 is a perspective, amplified view of an osteoimplant of the invention presenting alternating layers of the bone sheets and cubes with channels between the cubes.

FIGURE 7 is a partial view of a human spine showing the installation of the osteoimplant of FIGURE 6 at a mtrtransverse posterolateral fusion site; and FIGURE 8 is an enlarged, perspective view of an osteoimplant of the invention presenting layers of bone laminae bound together by chemical bonds formed by tissue transglutammase catalysis, as shown in FIGURE 8.

DESCRIPTION OF THE PREFERRED MODALITIES The osteoimplant of the present invention consists of a solid aggregate of elements obtained from bone having chemical bonds between its exposed collagen molecules on the surface thus joining adjacent bone elements together. To expose the collagen located on the outer surface of the bone, the bone elements must be at least partially demystified. The demyelination methods separate the mineral component of the bone using acid solutions. Methods such as those used by the present invention are well known in the art, see, for example, Reddi et al., Proc. Nat. Acad. Sci. 69, pp 1601-1605 (1972), which is incorporated herein by reference. The concentration of the acid solution, the shape of the bone and the duration of the demineralization treatment will determine the degree of demyelination. Reference is made in this regard to Le andro ski et al., J. Biomed Materials Res, 31, pp 365-372 (1996), also incorporated herein by reference. The sources for the elements obtained from bone herein include cortical and cancellous bone and are preferably allogenic but also include xenogenic sources such as bovine and porcine bone. When prepared from elements obtained from bone that are only superficially demineralized, the osteoimplant will tend to have a very high compressive strength, for example, approaching that of natural bone. Accordingly, when an osteoimplant is desired that exhibits compressive strength relatively high, for example, in the order of from about 10 to about 200 MPa, and preferably from about 20 to about 100 MPa, it is necessary to employ elements obtained from bone that retain a high proportion of their original mineral content or, said of another way, that have only been superficially demystified. In addition to containing elements obtained from bone, the osteoimplant of this invention can optionally possess one or more other components such as reinforcing particles, fillers, fibers, bone growth-inducing substances, adhesives, plasticizers, flexibilizing agents, agents that facilitate hydration. , biostatic agents / biocides, substances that impart radio opacity, metallic meshes or similar. Examples of the reinforcing particles include completely mineralized cortical and cancellous bone, and cortical and cancellous bone partially demymballized in any form, including particles, sheets and pieces of bone formed; graphite or pyrolytic carbon. Examples of the fillers include mineral material such as hydroxyapatite, tpcalcic phosphate and other calcium salts, bone powder, cortical and cancellous bone completely mineralized and partially or completely demymballized in any form, including particles such as demystified bone powder (or matrix of demystified bone "as it may also be called) molded bone sheets and pieces, graphite or pyrolytic carbon," bioglass "or other bioceramic or natural or synthetic polymers, for example, bio-absorbable polymers such as polyglycolide, polylactide, glycolide-lactide copolymer, and the like, and non-bioabsorbable materials such as starches, polymethyl metacrate, polytetrafluoroethylene, polyurethane, polyethylene and nylon Suitable plasticizers, flexibilizing agents and hydration facilitating agents include liquid polyhydroxy compounds such as glycerol, monoacetma, diacetma and mixtures thereof. Suitable biostatic / biocide agents include antibiotics, povidone, sugars and mixtures thereof; Suitable surface agents include non-ionic surfactants, cationic, ammonium and biocompatible amphoteric and mixtures thereof. The osteoimplant may also possess substances that induce bone growth that includes any of a variety of substances for medical and / or surgical use described below. The osteoimplant can have one or more cavities that, if desired, can communicate with the surface of the implant through pores, openings, perforations or channels provided for this purpose and covering an average diameter from some microns to several millimeters.

These cavities and their pores, openings, perforations and associated channels can be partially or completely filled with one or more substances for medical or surgical use that favor or accelerate the growth of new bone or bone healing due, for example, to some effect osteogenic, osteoconductive and / or osteoconductive [sic]. Useful substances of this class that can be incorporated in the osteoimplant of this invention include, for example, collagen, collagen derivatives, insolubles, etc., and soluble solids and / or liquids dissolved therein, eg, antiviral agents, particularly those that are effective against HIV and hepatitis; antimicrobials and / or antibiotics such as erythromycin, bacitracma, neomicma, penicillin, polymyxin B, tetracyclines, viomicma, chloromicetham, and streptomycins, cefazolma, ampicilma, azactam, tobramicma, clmdamicma, and gentamicma, etc .; biocide / biostatic sugars such as dextrose, glucose, etc .; amino acids, peptides, vitamins, inorganic elements, co-factors for the synthesis of proteins; hormones; endocrine tissue or tissue fragments; smtetizadores; enzymes such as calagenase, peptidases, oxidases, etc .; structures of polymepca cells with parenchyma cells; angionegic drugs and polymeric carriers containing such medicaments; Collagen reticles, antigenic agents, agents cytoskeletal; fragments of cartilage, living cells such as condorcytes, bone marrow cells, primordial mesenchymal cells, natural extracts, tissue transplants, bone, bone demystified, autogenous tissue such as blood, serum, soft tissue, bone marrow; etc.; bioadhesives, morphogenic bone proteins (BMP), transforming growth factor (TGF-beta), insulin-like growth factor (IGF-1); growth hormones such as zomatotropma; bone digesters; antitumor agents; immunosuppressants; angiogenic agents such as basic fibroblast growth factor (bFGF); permeation enhancers, for example, fatty acid esters, laureate, miptate, and monoesters of polyethylene glycol stearate, enamma derivatives, alpha-ketoaldehydes, etc., nucleic acids. These and similar medical / surgical use substances can be incorporated in the osteoimplant of this invention or its elements obtained from bone constituents or other components during any stage of the implant assembly. Suitable methods of incorporation include coating, saturation by immersion, packing, etc. The quantities of the substances for medical or surgical use used can vary widely with optimal levels being easily determined in a specific case by routine experimentation.

Osteoimplants of any desired size and / or configuration can be prepared, for example, by machining or other mechanical shaping operations such as in a pressure die. The computerized modeling of a specific implant followed by the computerized control of the implant conformation can be used to provide a difficult osteoimplant which can be specified according to the proposed application site with great precision. Where the invention comprises aggregates of elongated bone elements which, in appearance can be described as filaments, fibers, strands, rods or thin ribbons, etc., an osteoimplant can be formed from these elements by a variety of methods . For example, forming a solution or slurry in a suitable medium that may contain the crosslinking agent, and any proportion of the elements from bone, elongated being partially or completely demystified completely mineralized. This solution can be formed in an osteoimplant in any way according to the configuration of a mold in which it is poured. The mold is preferably formed as a bone or section thereof, or as an implant for graft formation. Once contained in a mold, the solution of the elements coming from bone can be solidified in a Solid osteoimplant by known techniques. It is within the scope of the invention to supplement or increase the preservation characteristics of the shape and / or mechanical strength of the osteoimplant, for example, by the addition of mechanical fasteners such as pins, screws, dowels, etc., which may be manufactured of natural or synthetic materials and bioasorbable as well as non-bioabsorbable materials, through the use of tissue laser welding or ultrasonic bonding, and others. In these osteoimplant modalities that are assembled from relatively large bone-derived elements such as laminae, these elements can be provided with characteristics of mechanical coupling, for example, tongue and groove characteristics or box-and-pin junction, which facilitate their assembly in the final product and / or to adjust the elements to each other in a safer way. The osteoimplant herein is proposed to be applied at the site of the bone defect, for example, resulting from injury, defect during the course of surgery, infection, malignancy or malformation during development. The osteoimplant, with the appropriate size and shape as required, can be used as a graft or replacement in a wide variety of orthopedic, neurosurgical and oral surgical procedures.

Maxillofacials such as the repair of simple and compound bills and fixation without joints, external and internal, reconstruction of joints such as arthrodesis, general arthroplasty, arthroplasty in the dome of the hip joint, replacement of the femoral and humeral head, replacement of the Femoral head surface and total joint replacement, spinal cord repairs including spinal fusion and internal fixation, tumor surgery, etc., deficient filling, disectomy, lamectomy, excision of spinal cord tumors, anterior cervical operations and thoracic, repair of spinal cord injuries, scoliosis treatments, lordosis and kyphosis, fixation of intermaxillary fractures, mentoplasty, replacement of the temporomandibular joint, augmentation and reconstruction of the alveolar crest, onlay bone grafts [sic], placement and implant revision, breast elevations, etc. Specific bones that can be repaired or replaced with the osteoimplant of the present include the ethmoid, frontal, nasal, occipital, parietal, temporal, mandible, maxilla, zygomatic, cervical vertebra, thoracic vertebra, lumbar vertebra, sacral bone, ribs, sternum , clavicle, scapula, humerus, radius, ulna, carpal bones, metacarpal bones, phalanges, ilium, ísquion, pubis, femur, tibia, fibula, kneecap, calcaneus, tarsal bones and metatarsus. The method of manufacturing the osteoimplant of the present invention consists in providing a quantity of elements obtained from bone initially presenting collagen exposed on the surface and subsequently forming chemical bonds between the collagen exposed on the surface and the elements obtained from adjacent bone to join the elements in a solid aggregate. These chemical bonds can be formed using a variety of methods including chemical reaction, the application of energy such as radiant energy, which includes irradiation by UV light or microwave energy, drying and / or heating and photo oxidation mediated by dyes; hydrothermal treatment in which the water is slowly removed while the bone tissue is subjected to vacuum; and enzymatic treatment to form chemical bonds in any of the collagen-collagen metastases. The preferred method for forming chemical bonds is by chemical reaction. Chemical crosslinking agents include those which contain bifunctional or multifunctional reactive groups, and which react with functional groups on the amino acids such as the epsilon-amine functional group of the lysine or hydroxy-lysine, or the carboxyl functional groups of the aspartic and glutamic By reaction with multiple functional groups thereof or different collagen molecules, the reactive chemical crosslinking agent forms a strengthening bridge. Suitable chemical crosslinking agents include: mono- and dialdehydes, including glutaraldehyde and formaldehyde; polyepoxy compounds such as glycerol polyglicital ethers [sic] polyethylene glycol diglycide ethers [sic] and other polyepoxy and diepoxiglicidal ethers [sic]; tanning agents including polyvalent metal oxides such as titanium dioxide, chromium dioxide, aluminum dioxide, zirconium salt, as well as organic tannins and other phenolic oxides from plants; chemical substances for the esterification of carboxyl groups followed by the reaction with hydrazide to form activated azide acyl functionalities in the collagen; dicyclohexyl carbodnide and its derivatives as well as other heterobifunctional crosslinking agents; hexamethylene dusocyanate; sugars; including glucose, will also crosslink the collagen. Bio-matepals cross-linked with glutaraldehyde have a tendency to over-calcify in the body, in this situation, calcification controlling agents that can be used with aldehyde cross-linking agents should be considered necessary. These calcification controlling agents include: dimethyl sulfoxide (DMSO), surfactants, diphosphonates, amino acid oleic and metal ions, for example, iron and aluminum ions. The concentrations of these calcification controlling agents can be determined by routine experimentation by those skilled in the art. Chemical crosslinking includes exposing the bone elements that exhibit collagen exposed on the surface to the chemical crosslinking agent, placing the elements in a solution of the chemical crosslinking agent or exposing them to the vapors of the chemical crosslinking agent under conditions suitable for the reaction type of the chemical. specific crosslinking. These conditions include: pH and suitable temperatures, and for times ranging from minutes to days, depending on the level of crosslinking desired, and the activity of the chemical crosslinking agent. The osteoimplant is then washed to remove all leachable traces of the chemicals. When enzymatic treatment is employed, useful enzymes include those known in the art which are capable of catalyzing cross-linking reactions in proteins or peptides, preferably collagen molecules, eg, transglutammase, as described in Jurgensen et al., The Journal of Bone and Jomt Surgery, 79-A (2), 185-193 (1997), which is incorporated herein by reference. The formation of chemical bonds can also be carried out through the application of energy. One way to perform the chemical bonds by applying energy is to use the known methods to form highly reactive oxygen ions generated from the atmospheric gas, which in turn favors the crosslinks of oxygen between collagen exposed on the surface. These methods include the use of energy in the form of ultraviolet light, microwave energy and the like. Another method that uses the application of energy is a process known as photo oxidation mediated by dye in which a chemical dye under the action of visible light is used to crosslink the exo collagen on the surface. Another method for the formation of chemical bonds is by hydrothermal treatment that uses combined heat and slow removal of water, preferably by vacuum, to obtain crosslinking of the elements obtained from bone. The process includes the chemical combination of a hydroxyl group of a functional group of a collagen molecule and a hydrogen ion from a furnace group of another collagen molecule reacting to form which then separates giving rise to the formation of an > It forms between the collagen molecules. With reference to the drawings, as shown in Figure 1, the cortical portion of the bone 10 taken from the diaphyseal region is cut into bone pellets. cortical 11 of different width slicing the bone longitudinally. If desired, cortical bone sheets 11 may also be cut to a uniform size and shape, as in the laminae from bone 21 of osteoimplant 20 shown in Figure 2. Figure 2 illustrates an osteoimplant 20 consisting of in sheets coming from cortical bone 21 having an external surface completely or partially demineralized with collagen exposed on the surface, a nucleus not demystified or partially demystified 22. Otherwise, it is possible to make one or more sheets obtained from bone from almost completely demineralized bone. Likewise, another component such as demystified bone powder can be coated on the sheets obtained from bone. The entire structure has crosslinked collagen in the sheets obtained from adjacent bone to provide greater adhesion between these. The total thickness of the osteoimplant will usually be at least about 2 to about 20 mm. The osteoimplant can be cut, machined and / or otherwise formed in any desired shape or dimension for implantation in the body. Thus, as shown in Figure 3, it is possible to make an osteoimplant of practically cylindrical shape 30 for use as a bone segment replacement. long for a femur 32 of Figure 3. To form a cylinder, the practically square or rectangular osteoimplant can be formed on a lathe with the required diameter. It is possible to form a cavity to separate bone material with, for example, a hole or, otherwise, a cavity can be formed by suitably assembling configured layers of bone elements. As shown in Figure 4, the disc-shaped osteoimplant 40 is formed inserted at the medvertebral fibrocartilage site 41 on the anterior side of the spinal column 42. In Figure 5, the parietal osteoimplant 50 has the size and shape to take part of the parietal bone for the skull 51 of Figure 5A. In Figure 6, the osteoimplant 60 is constructed of lamellar sections obtained from bone 61 of the desalinated cortical bone on the surface, and forms cubic sections derived from bone 62 of the superficial demiralized cancellous bone of uniform square section. These constituents sheets and cubes are arranged in alternate layers as shown. After assembly, the structure is subjected to treatment for crosslinking. Due to the open structure of the osteoimplant 60 resulting from the channel pattern 63, the osteoimplant allows vascular penetration or internal growth of the host bone in it and / or diffusion of one or more substances for medical use and surgical from these. The osteoi plante 60 is shown installed as a graft superimposed on the spine joined by insertion of the transverse process 71 into the channels 63 for fusion in the posterolateral mtertransverse process on the vertebral column 70 of Figure 7. In Figure 8A, the osteoimplant 80 consists of sheets obtained from bone 81 having a complete or partially demystified outer surface. As shown in Figure 8, a sheet obtained from bone has a side coated with tissue transglutammase 83 and, the corresponding surface of the adjacent sheet is coated with CaCl2 82 solution. As the osteoimplant 80 is installed, the contact between the two complementary sides of the bone-derived sheets gives rise to the transglutammase of tissue 83 catalyzing the cross-linking of collagen at the interface of the sheets obtained from adjacent bone 81. The following examples also show the osteoimplant of this invention.

EXAMPLE 1 A cortical bone section of the diaphyseal region was cut in the longitudinal direction while wetting continuously with water in sheets of approximately 1.5 mm thickness using a closure with diamond blade. Laminas from cortical bone were then frozen at -70 ° C and freeze-dried for 48 hours and then placed in excess 0.6N HCl solution for 1.5 to 5 hours with constant agitation, washed in water for 5 minutes and rinsed for 1.5 hours in buffered saline with BupH phosphates. The laminae coming from bone were assembled in a stratified structure and fastened with a clamp. The clamped structure was then placed in a buffered, neutral formalized 10% solution for 48 hours to crosslink the surfaces of exposed collagen. After cross-linking, the clamp was removed and the structure was placed in a container and left in rinsing under running water for several hours. The osteoimplant was cut to the shape on a band saw, and then placed in an aqueous solution in excess of glycerol. After 7 hours, the excess solution was removed and the osteoimplant was freeze-dried.

Example 2 Fibers obtained from bone, elongated, were crushed from cortical bone completely demymbedded in excess 0.6N HCl solution. These fibers were washed with water, and rinsed in an aqueous solution of glycerol. In addition, the t fibers obtained from completely mineralized bone were added to the solution that was stirred and left for 12 hours at room temperature. The solution containing the mineralized and desmmeralized, rinsed bone fibers was emptied through a sieve of 106 microns to recover the fibers. The mixture of mineralized and demineralized fibers was placed in a cylindrical matrix, and pressure treated at 10,000-50,000 psi in a press for 15 minutes, and then heated for 2 to 12 hours at 37-55 ° C. The resulting osteoimplant package was freeze-dried and placed in diglyceryl polyethylene glycol ether [sic] for 12 hours at room temperature.

EXAMPLE 3 Laminas from bone obtained from human cortical bone, approximately 1 mm thick by 7 mm wide by 50 mm long were treated for 10 minutes in 0.6 N HCl to expose the surface collagen. The cubes from bone obtained from human cancellous bone, 10 mm by 10 mm, were treated to expose the surface collagen on the outer edges of the cubes. All the sheets and cubes from bone were washed in water. The pieces were assembled together with the sheets coming from bone at the ends of the cubes, and fastened in place. The construction was later placed in a 10% formally buffered solution until neutrality for 3 hours to crosslink the collagen exposed on the surface. The resulting osteoimplant was then washed in water and cut to size on a band saw. See Figure 6.

Example 4 Laminas from human cortical bone approximately 1 mm thick were demineralized on the surface for 15 minutes in 0.6N HCl, then washed in running water. The tissue transglutammase was reconstituted to obtain a solution of 1 mg / ml. For each sheet from bone, demineralized in the construction, the surface was dried with blotting paper, then 40 μl / cm2 of the tissue transglutammase was applied to one side and an equivalent volume of a 0.1M solution of CaCl was applied to the corresponding surface of the next sheet coming from bone, demystified. This was repeated sequentially. The resulting osteoimplant was held and placed in a humidity chamber to promote cross-linking for approximately 30 minutes, then washed in water.

Example 5 Laminas from cortical bone, from approximately 2 m thick, were demixed on the surface in a 0.6N HCl solution for one hour with constant agitation. The sheets from bone were then coated with de-shredded, anhydrous bone powder having a particle size of 300 microns or less, and assembled in layers. The construction was clamped in place, and then placed in a 10% formal buffered neutral solution for 12 hours to allow crosslinking of the collagen. The resulting osteoimplant was washed in water to remove excess chemicals.

Claims (27)

1. An osteoimplant consisting of a solid aggregate of elements from bone, elements from adjacent bone being linked together by means of chemical bonds between their collagen exposed on the surface.

2. The osteoimplant of claim 1, wherein the elements from bone are superficially demineralized particles, strips or sheets of cortical and / or spongy alogenic, xenogenic.

3. The osteoimplant of claim 1, wherein the elements from bone are particles, strips or sheets practically demineralized completely from cortical and / or spongy alogenic, xenogenic bone.

4. The osteoimplant of claim 1 containing at least one other component.

The osteoimplant of claim 4, wherein the component is selected from the group consisting of fiber reinforcing particles, filler material, bone growth-promoting substances, growth factors, fully mineralized allogenic or xenogenic bone, cellular material, material genetic, controlling agent of calcification, hydration agent, inorganic compounds and polymers.

6. The osteoimplant of claim 1 having a cross section in at least a portion of its length that is, or approaches, a circle, oval or polygon, the implant optionally having a cavity in at least a portion of its length.

7. The osteoimplant of claim 1 configured as a graft.

8. The osteoimplant of claim 1 configured as a replacement for a bone or section thereof.

9. The osteoimplant of claim 8 configured as an intervertebral insert, a long bone, a cranial bone, a pelvic bone or a hand bone or foot or section thereof.

10. The osteoimplant of claim 1, wherein the chemical bonds are formed by chemical crosslinking, energy application, hydrothermal treatment or enzymatic treatment.

11. The osteoimplant of claim 1 having a compressive strength of from about 10 to about 200 MPa.

12. The osteoimplant of claim 1 having a compressive strength of from about 20 to about 100 MPa.

13. The osteoimplant of claim 1, which has a hydration facilitating agent.

14. The osteoi plant of claim 1, wherein the hydration facilitating agent is glycerol.

15. A method for the manufacture of an osteoimplant that consists of: a) providing a quantity of elements from bone micially presenting exposed collagen on the surface; and b) forming chemical bonds between the collagen exposed on the surface of the adjacent bone elements to join the elements in a solid aggregate.

16. The method of claim 15, wherein the elements from bone are particles, strips or sheets practically demineralized completely from alogenic and / or xenogenic cortical bone.

17. The method of claim 15, wherein the chemical bonds are formed by chemical crosslinking, energy application, hydrothermal treatment, enzymatic treatment or any combination of the foregoing.

18. The method of claim 15 carried out in a mold.

The method of claim 18, wherein the forming surfaces of the mold are for providing an osteoimplant configured as a bone or section thereof.

20. The method of claim 18, wherein the mold-forming surfaces are for providing an osteoimplant configured as an intervertebral insert, a long bone, a cranial bone, a pelvic bone or a bone of the hand or foot or section thereof .

The method of claim 17, wherein the chemical bonds are formed by contacting elements obtained from bone with a chemical crosslinking agent to form chemical bonds between the collagen exposed on the surface of the adjacent bone elements.

22. The method of claim 21, wherein the chemical cross-linking agent is selected from the group consisting of aldehydes, dialdehydes, polyepoxy compounds, polyvalent metal oxides, organic tannins, phenolic oxides, sugars, dicyclohexylcarbomide and hexamethylene dnsocyanate.

23. The method of claim 17, wherein the chemical bonds are formed by irradiating the elements obtained from bone in a gaseous environment to provide oxygen ions which then react with the collagen exposed on the surface of the adjacent bone elements. forming chemical bonds between them.

24. The method of claim 17, wherein the bonds are formed by color-mediated photo oxidation.

25. The method of claim 17, wherein the hydrothermal treatment consists of heating the elements from bone to remove water from these and separate the water.

26. The method of claim 17, wherein the chemical bonds are formed by treating the elements from bone with an enzyme that catalyzes the formation of chemical bonds between the functional amino acid groups of the collagen exposed on the surface of the elements originating from adjacent bone.

27. The method of claim 26, wherein the enzyme is a transglutaminase tissue.