KR20030074660A - Method of making demineralized bone particles - Google Patents

Abstract

Demineralized bone particles are obtained by demineralizing the entire bone and then subdividing the demineralized bone to provide the demineralized bone particles.

Description

METHOD OF MAKING DEMINERALIZED BONE PARTICLES}

The manufacture of demineralized bone particles and compositions, materials and devices comprising demineralized bone particles, and their use in the correction and orthopedic use of bone defects are known.

The microstructure of the cortical bone consists of bundles or fibers of mineralized collagen oriented parallel to the long axis, and known methods for making demineralized bone particles are treated with acid. Subdividing the entire, ie, mineralized sections of the bone by mechanical operations such as threading, milling, saving, machining, etc. to provide particles which are subsequently demineralized. The resulting demineralized bone particles exhibit osteoinductive properties that make them useful as or in implants for use in bone correction and other orthopedic applications. One drawback of known methods of making demineralized bone particles is that only a portion of the bone stock produces, for example 45-65% by weight, demineralized bone particles. Also, due to the mechanical limitations of bone milling machinery, such as the need to hold stock seen in the jaws of the machine, only quite significant donor bones, such as intact cortical shafts, can be used to demineralize bone particles. Can be used as a source.

The limited amount of demineralized bone particles obtained by the prior art methods is important because of the limited utility of the donor bone. At this point, the adjustment does not allow pooling of the donor bone material. Since the amount of demineralized bone particles that can be obtained is limited by the usefulness of the donor bone and the size of the bone, there is a need for a method of making demineralized bone particles that are not subject to the constraints imposed by these limiting factors.

The present invention relates to a method of making demineralized bone particles useful for or as an implant for a variety of orthopedic applications. More specifically, the present invention relates to a method of making particles from demineralized bone and produces more wood than is provided by the prior art methods of producing such particles.

It is an object of the present invention to provide a method of making demineralized bone particles that optimally uses donor bone.

It is another object of the present invention to provide a method of making demineralized bone particles that will produce more particles for a given amount of total bone compared to that provided by the prior art methods.

It is still another object of the present invention to provide demineralized bone particles in the form of fibers or fiber bundles of bone collagen by applying mechanical pressure to demineralize bone stocks.

Still other objects of the present invention will be apparent to those skilled in the art in view of the above objects and the specification to be described later.

In accordance with these and related objects of the present invention, a method of making demineralized bone particles comprising demineralizing the entire bone and then subdividing the demineralized bone into demineralized bone particles Is provided.

In general, the yield of demineralized bone particles obtained by the method of the present invention is to first subdivide the whole bone into mineralized bone particles and then to mineralize the bone particles to prepare the demineralized bone particles. Significantly greater from about 5 to about 20 wt.% Than that obtained by demineralization.

The term "particles" as used herein refers to fibers that may or may not be completely separated from one another with regular, irregular or random geometric arrangements, bundles of loosely connected fibers, threads, fine strips, sheets, chips ), Relatively small bone fragments such as shards, powders, and the like.

As used herein, the term "whole bone" refers to a bone that includes its completely naturally occurring mineral content and that includes anatomically complete bone and fragments thereof.

As used herein, the term “demineralized” refers to a bone comprising less than about 95% of the original mineral content of the bone. As used herein, the expression “sufficiently demineralized” refers to a bone comprising less than about 5% of the original mineral content of the bone.

As used herein, the term "osteogenic" refers to the ability of a material or substance to cause new bone formation through the involvement of living cells from within the substance, and "osteogenesis" refers to its mechanism or outcome. Will be understood as.

The term "osteoinductive" as used herein refers to the ability of a material or substance to replenish cells from a host with osteogenic capacity and the ability to form ectopic bones and to "osteoinduction". Will be understood as the mechanism or result.

As used herein, the term "osteoconductive" refers to the ability of a material or material to provide a surface to accommodate the growth of new host bones and "osteoconduction" will be understood as its mechanism or outcome.

The terms "allogenic" and "xenogenic" are used herein in reference to the final recipient of bone tissue.

The whole bone suitable for making the demineralized bone particles of the present invention can be a donor bone from any source. Thus, autogenic, allogeneic or xenografts may be used with preferred autologous and allogeneic bones. Particularly useful sources of heterologous tissue may be porcine, equine or bovine. The bone may be cortical, cancellous or corticocancellous. Preferred bones are the cortical allogenic bones such as the femur, fibula, radius, and ulna.

The method of the present invention can be applied to all bones of various sizes. Therefore, the bone used as starting or stock material will range in size from relatively small bone fragments to bones of dimensions that are recognizable for anatomical origin. Generally, the pieces or fragments of the entire bone stock have a median length of about 1 to about 400 mm, preferably about 5 to about 100 mm, median thickness of about 0.5 to about 20 mm, preferably about 2 to about 10 mm. And the median width can range from about 1 to about 20 mm, preferably from about 2 to 10 mm.

After obtaining a bone from the donor, it is treated using methods well known in the art such as clarification, disinfection, degreasing and the like. The whole bone can then be demineralized or, if desired, fragmented before demineralization. The entire bone, or one or more fragments thereof, is then reduced to low levels, such as less than about 10% by weight, preferably less than about 5% by weight, more preferably about 1% by weight. It is demineralized to contain less residual calcium.

Demineralization of bone can be accomplished according to known conventional procedures. The demineralization procedure removes the mineral mineral component of bone using an acidic solution. Such procedures are well known in the art, see, for example, Reddi et al., Proceeding of the National Academy of Sciences of the United States of America 69, p. 1601-1605 (1972). The strength of the acidic solution, the shape and size of the bone and the duration of the demineralization procedure will determine the degree of demineralization. In general, larger valleys will require longer and stronger demineralization compared to smaller particles. Guidance on specific parameters for demineralizing bones of various sizes can be found in US Pat. No. 5,846,484, Harakas, Clinical Orthopaedics and Related Research, pp.239-251 (1983) and Lewandrowski et al. , Journal of Biomedical Materials Research , 31, pp. 365-372 (1996), which are incorporated herein by reference.

In the demineralization procedure useful in the practice of the present invention, bone is subjected to a degreasing / sterilization step, followed by an acid demineralization step. A useful degreasing / disinfection solution is an aqueous solution of ethanol, which is a good solvent for lipids and water is a good hydrophilic carrier that allows the solution to penetrate deeper into bone particles. Aqueous ethanol solutions also kill bone by killing vegetative microbes and viruses. For optimal lipid removal and disinfection in the shortest time period, at least about 10 to about 40 weight percent of water (ie, about 60 to about 90 weight percent of degreasing agent such as alcohol) should be present in the degreasing / disinfection solution. do. Useful concentration ranges of the degreasing solution are from about 60 to 85 percent alcohol or about 70 percent alcohol. Other or additional degreasing solutions are made of surfactants such as Triton X-100 at concentrations of 0.1% to 10% in water. After degreasing, the bone is immersed in the acid over time resulting in demineralization. Acids that may be used in this step include inorganic acids such as hydrochloric acid and organic acids such as peracetic acid. After acid treatment, the demineralized bone is rinsed with sterile water for injection to remove the residual amount of acid and thereby raise the pH.

Following demineralization, the bone is subdivided into demineralized bone particles of the desired shape and size. Useful for subdividing demulsified bone is those techniques for threading, milling, pressing, saving, machining, extruding and / or cutting hard or fragile materials such as wood, plastics, soft metals, ceramics, etc. Machines or tools known in the field. Particularly preferred are mills comprising impact mills, grating mills, shearing mills, cutting mills. Many preferred tools for subdividing demineralized bone will break or demineralize bone by cutting or separating the demineralized material in a direction parallel to the underlying collagen fibers.

Particularly preferred forms of devices or machines that can be used to subdivide demineralized bone, useful for threading and cutting hard or brittle materials such as wood, plastics and soft metals, are impact grinders, grinding mills, shear grinders and cutting grinders. Include. Many preferred cutting and grinding tools and / or machines will break or demineralize the demineralized bone by cutting or separating the demineralized material in a direction that is parallel or nearly parallel to the basic collagen fibers. Grinders, presses and extruders are particularly useful in this respect.

The impact mill includes a blunt rotor or vibratory hammer that moves at high speed and impacts the bone to break it into debris particles to subdivide the demineralized bone stock. The bones tend to break along the lines of natural collagen bundles that make up the bone's microstructure. Similar mills with sharp cutting rotors tend to cut the bone into somewhat symmetrical particles as opposed to the fiber particles obtained using an impact mill. Impact velocity is a factor influencing the results. Too low a speed will cause the bone to be deformed formally rather than crushed into the desired particles. Factors similar to this one involved in the operation of certain types or models of impact mills to provide demineralized bone fibers can be optimized by mechanical experimentation.

Shear grinder tears bone to subdivide demineralized bone stock. Tearing is likely to break the bone at its weakest priority. The junctions between the demineralized collagen bundles show weak points and result in the production of fibrous particles.

The spindle element of the lathe bears a rotary grinding wheel in which cutting elements protruding around the surface are embedded. When the bone stock is pressed against a rotating wheel, the cutting element produces fibrous particles. Stainless steel star cutters have been determined to provide particles of useful size. In this type of particle forming action, the resulting fiber particles do not separate along the lines of natural collagen bundles.

Another device useful for grinding bone particles according to the invention is IKA.^R And mills such as the Model A 10 IKA-Cracking Mill or the Model M 20 IKA-Universal Mill available from Works, Wilmington, NC. Such mills include a cooling connection and are suitable for grinding hard and brittle materials with a maximum grain size of 6-7 mm. Other mills useful in the practice of the present invention include drum cutter bone mills such as those available from Tracer Designs, Inc. (Santa Paula, Calif.), Whose bone mill model is BM1000.

A particularly effective method for subdividing demineralized bone stock is to press the bone. The simplest pressing technique is to apply pressure to unbound demineralized bone. Embodiments include pressing a mortar using a mortar and pestle, applying a rolling / pressing operation such as that caused by a rolling pin, or pressing a piece of bone between a plate or a curved plate. Include. These flattening pressures cause the bone fibers to separate. Unlike prior art methods for making fibers in mineralized bone, pressing the demineralized bone in accordance with the present invention is a short fiber fragment (bonded short fibers that can exist long as a fiber in the demineralized bone stock from which it is obtained. Provides complete natural bone collagen fibers, not composite fibers made from.

Another pressing technique involves mechanically pressing the bound mineralized bone in a sealed chamber with holes (or few holes) in the bottom plate or base plate. The separated fibers are extruded through the holes and the pore diameter limits the maximum diameter of the fiber being extruded. Like using an unbound pressing method, this constrained technique produces fibers that are mostly complete but separate bone collagen bundles (as far as length is concerned).

In a combined non-bonded / bound bond pressing technique that produces longer fibers by minimizing fiber breakage, the demineralized bone is first pressed into an unseparated fiber mass first without being bound. These fibers are then bound in a sealed chamber where pressing continues.

Generally, pressing the demineralized bone to provide demineralized bone particles can be performed at about 1,000 to about 40,000 psi, preferably about 5,000 to about 20,000 psi.

Depending on the procedure used to produce the demineralized bone particles, a large amount of bone particles can be obtained, at least about 80 weight percent, preferably at least about 90 weight percent, and most preferably at least about 95 weight percent Phosphorus particles may be from about 2 to about 300 mm or have a long median length, preferably a median length of about 5 to 50 mm, a median thickness of about 0.5 to about 15 mm, preferably a median thickness of about 1 to about 5 mm, about Median width of 2 to about 35 mm, preferably median width of about 2 to about 20 mm, and median length to thickness ratio and / or median length to width ratio of about 2 to 200, preferably about 10 to about 100 . If desired, agglomerates of bone particles may be screened or sorted into various sizes, for example by screening, and / or any less desirable size of bone particles that may be present may be reduced or eliminated.

At this point, depending on their intended end use, the demineralized bone particles can be advantageously stored in sterile, lyophilized or frozen state for use as is or afterwards.

The demineralized bone particles of the ball invention are used as implants or in implants in connection with various orthopedic procedures involved in the bone treatment / repair process through one or more mechanisms such as bone formation, osteoinduction and bone conduction. Demineralized bone particles may be used as they are or may be used in various product forms such as gels, puttys or sheets. Demineralized bone particles are ones such as adhesives, fillers, plasticizers, softeners, biostatic / biocidal agents, surfactants, binders and binders, before, during or after forming the particles into the desired shape. It can be used by mixing arbitrarily with the above materials. Suitable adhesives, binders and binders include bioabsorbable polymers such as acrylic resins, cellulosics, polyesters, polycarbonates, polyarylates and polyfomarates do. In particular, tyrsine, polycarbonate, tyrosine, polyarylate, polyglycolides, polylactides, glycolide-lactide copolymers. Suitable fillers include bone powder, demineralized bone powder, hydroxyapatite and the like. Suitable plasticizers and softeners include liquid polyhydroxy compounds such as glycerol, monacetin, diacetin and the like. Suitable surfactants include biocompatible nonionic, cationic, anionic and zwitterionic surfactants.

If desired, demineralized bone particles can be altered in one or more ways, such as their protein content can be increased or altered as disclosed in US Pat. Nos. 4,743,259 and 4,902,296, which are incorporated herein by reference. Any of a variety of medically and / or surgically useful materials may be incorporated into or associated with bone particles before, during or after formation. Thus, for example, one or more such materials may be introduced into the demineralized bone particles by soaking or dipping the bone particles in a solution or dispersion of the desired material (s).

Medically / surgically useful materials that can be readily combined with the demineralized bone particles of the present invention include, for example, collagen, insoluble collagen derivatives, and the like, and are soluble solids and / or solutions dissolved therein, such as killing. Antiviricides, especially those effective against HIV and hepatitis; Erythromycin, Bacitracin, Neomycin, Penicillin, Polymyxin B, Tetracyclines, Biomycin, Chlomycintin, Chloromycetin Antimicrobials and / or antibiotics, such as streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin; Biocidal / biostopping sugars such as dextrose, glucose and the like; Cofactors for the synthesis of amino acids, peptides, vitamins, inorganic elements, proteins; Hormones, endocrine tissues or tissue fragments; Synthesizers; Enzymes such as collagenase, peptidases, oxidases and the like; Polymer cell scaffolds with fragments; Polymer cytoskeleton with parenchymal cells; Angiogenic agents and polymeric carriers comprising such agents; Collagen lattice; Antigen agonists; Cytoskeletal agents; Cartilage fragments; Living cells such as chondrocytes, bone marrow cells, mesenchymal stem cells, natural extracts, tissue implants, bone, demineralized bone powder, blood, serum, soft tissues, endogenous tissues such as bone marrow; bioadhesives Bone growth proteins (BMPs), transforming growth factors (TGF-beta), growth factors such as insulin (IGF-1) (IGF-2); Platelet derived growth factor (PDGF); Growth hormones such as somatotropin; Bone digesters; Antitumor agents; Immunosuppressants; Osmotic enhancers such as laureate, myristate and stearate monoesters of polyethylene glycol, emamine derivatives, alpha-ketoaldehydes Fatty acid esters; And nucleic acids. The amount of such optionally added material can vary widely depending on the optimum level, which is easily determined in certain cases by mechanical experiments.

The method of the present invention will be better understood through the examples. As is often the case throughout this application, all parts are by weight unless otherwise specified. The examples are provided herein as a means of illustrating the invention and are not intended to limit the invention in any way.

Example 1

The right bone shaft (99 g) from the human donor was long divided into four sections. The total weight of all sections was 94 g. Bone sections were placed in a 2-liter container with 1410 ml of 0.6 N HCl solution. After about 6 hours the solution was removed and replaced with another 1410-ml of acid solution. The bone sections and the second aliquot of acid solution were gently vortexed with a magnetic stirrer for 2 days. The bone fragments were demineralized until they were completely translucent without any visible mineralized parts that actually showed complete demineralization. The mineralized bone fragments were then rinsed with water until the pH of the rinse was at least 4.0. The demineralized bone fragments were then immersed in 70% ethanol for 1 hour. The demineralized bone fragments were cut with scissors to fit a model M 20 IKA-universal grinder and processed in the mill for about 30 seconds to produce demineralized bone particles in fiber form (17.98 g, 110 yield). cc). The fibers were then frozen and lyophilized for about 12-15 hours.

Comparative Example

119 g of mineralized human donor bone was ground in a grinding machine disclosed in US Pat. No. 5,607,269 to provide large amounts of mineralized bone particles in the form of fibers. The mineralized fiber was then treated with a demineralization process described below. Allocortical bone is placed in the reactor. 0.6 N HCl solution is introduced into the reactor at 15 ml per gram and the demineralization reaction is continued for 1 to 2 hours. Following HCl drainage, the bone is filled with 0.6 N HCl / 20 ppm-2000 ppm nonionic surfactant solution for 24 to 48 hours.

Following draining of the HCl / surfactant solution, 0.6 N HCl was introduced into the reactor at 15 ml per gram of bone and the demineralization reaction was again 40 to 50 minutes until the starting cortical bone was substantially complete demineralized. Continues for a while. Following drainage through a sieve, the demineralized bone is rinsed three times with water for injection at 15 ml per gram bone weight and the water for injection is replaced every 15 minutes. Following drainage of water for injection, the demineralized bone is filled with alcohol and soaked for at least 30 minutes. The alcohol is then drained and the bone is drained with water for injection. The demineralized bone is then subdivided in the grinding apparatus of US Pat. No. 5,607,269 to produce fibrous demineralized large amounts of bone particles. The demineralized bone components are then discharged and transferred to a lyophilization tray and frozen at -70 ° C. for at least 6 hours. After drying, the demineralized bone particles are sorted by size. The yield measured before drying of substantially fully demineralized bone particles made according to this procedure was 15.27 g, 75 cc.

The following table compares the yield between the method of Example 1 illustrating the invention and the prior art methods illustrated in the Comparative Example:

Starting Total Goal Wt. (G) Yield of demineralized bone particles wt. (G) vol. (Cc) Wt. Of demineralized bone particles based on Wt. Of total bone. % output Example 1 99 17.98 110 18.2 Comparative Example 119 15.27 75 12.8

As these data indicate, the method of the present invention prior to demineralization of the entire bone prior to subdividing it into demineralized bone particles (Example 1) results in that the entire bone is subdivided into mineralized bone particles. Only afterwards yielded a useful output of at least 50 wt.% More than the results from the prior art process in which demineralization is carried out (control example).

Example 2

Substantially sufficiently demineralized fibula cross sections about 25 mm long were initially pressed at pressures ranging from 5,000 to about 20,000 psi between the two plates of the Carver press. This initial pressing operation flattened the bone fragments and began to separate their collagen bundles into fibers. This material was then ["fluffed up"] and pressed again using a similar pressure as before. The pressing operation was repeated again to produce a number of coarse fiber bundles that were not completely separated from each other. The yield of fiber was about 50 wt.% Based on the volume of [starting demineralized bone fragments], and many fibers had a length almost as long as the natural fiber of the bone stock. The fibers were in the range of about 10-15 mm in length, some fibers were in the range of 20-25 mm, and were about 2 mm in diameter. Materials not in the form of fibers remained in the bundle of fiber bundles.

The fibers were further subdivided in an impact mill for [30 seconds] and the diameters of many fibers and fiber bundles were reduced without substantially decreasing their length. Thus, the fibers continued to fall within the aforementioned ranges but their diameters ranged from about 0.5 to about 2 mm.

Example 3

Approximately 25 mm long demineralized fibula sections were placed in a series of 29 mm diameter press cells with a single hole in the base having 1, 2 and 3 mm diameters, respectively. Under a pressure of 5,000-10,000 psi, the demineralized bone fragments were subdivided into fibers extruded through the hole. The yield of demineralized fiber was nearly 100 wt.% In almost all cases; Little or no bone remained in the cell.

Example 4

A cell pressing procedure similar to that of Example 4 was performed on demineralized bone sections 4 to 8 mm long in a 29 mm diameter press cell with a single hole of 9.75 mm diameter.

At press loads of 5,000 to 10,000 psi, the bone sections were subdivided into fibers in the length range of 25 to 50% of the length of the bone sections. The yield of the fiber was about 50 wt.%. The fibers were about 1-5 mm long and had a diameter of about 0.5 mm.

Example 5

Substantially sufficiently demineralized fibula sections of about 25 mm length were pressed in the press cells disclosed in Example 4. At pressures from 5,000 to 10,000 psi, the bone fragments were subdivided into fibers with the dimensions shown in the following table.

Diameter of press cell hole, mm Approximate length of fibers, mm Approximate diameter of fibers One 1-5 1.5-2 2 1-5 1.75-2.75 3 1-5 3-3.5

Example 6

The pressing operation disclosed in Example 5 was substantially repeated but preliminary pressing performed on a Carver press of about 15,000 psi was not prioritized. The resulting demineralized bone fibers had a smaller diameter than the fibers obtained in Example 6 and therefore had a greater length to diameter ratio.

Example 7

Substantially sufficiently demineralized complete fibula shafts were subdivided into fiber particles using a Tracer (rotary steel) mill. The fiber length was about 5 mm, the diameter was about 0.5 mm, and the fiber yield was about 70 wt.%.

Example 8

Example 8 was repeated except that non-fragmental pieces of 4-8 mm in length were used. The fiber length was about 3-5 mm, the diameter was about 0.5 mm, and the fiber yield was about 50 wt.%.

Example 9

The model M5A Fitzpartrick grinder produces 4-10 mm of substantially fully demineralized bovine bone fragments with a diameter of about 0.2 mm and a diameter of about 0.2-0.7 mm, yielding about 70 wt. It was used to subdivide the fields.

Example 10

Example 9 was repeated except using a model M20 IKA-universal grinder to break down the demineralized bovine bone fragments. In the fiber-fragments produced by the mill, the fibers had a length of about 1-2 mm, a diameter of about 0.5-1 mm and a fiber output of about 10%.

Example 11

Example 9 was repeated except using a Megatron homogenizer (Glen Mills Inc., Maywood, NJ). The resulting fibers yielded a yield of about 70 wt.% And had a length of about 1-3 mm and a diameter of about 0.2-0.5 mm.

Claims (25)

Demineralizing bone particles after demineralizing the entire bone and then subdividing the demineralized bone into demineralized bone particles. The method of claim 1, wherein the yield of demineralized particles is obtained by subdividing the entire bone into mineralized bone particles and then demineralizing the mineralized bone particles to provide demineralized bone particles. A method of making demineralized bone particles characterized by more than one. The method of claim 1, wherein the entire bone is autologous, homogeneous or heterogeneous cortex, reticular or retinal cortical bone. The method of claim 1, wherein the total bone is demineralized to contain less than about 10% by weight of residual calcium. The method of claim 1, wherein the total bone is demineralized to contain less than about 5% by weight of residual calcium. The method of claim 1, wherein the total bone is demineralized to contain less than about 1% by weight of residual calcium. 2. The method of claim 1 wherein the subdividing of the demineralized bone is performed by milling. 8. The method of claim 7 wherein said milling is performed in an impact mill, a grinding mill or a cutting mill. The method of claim 1, wherein the subdividing the demineralized bone is performed by applying mechanical pressure to the demineralized bone. 10. The method of claim 9, wherein the bone is pressed while not in bondage. 10. The method of claim 9, wherein the bone is pressed while in bondage. The method of claim 9, wherein the method is performed under a pressure of about 1,000 to about 40,000 psi. The method of claim 9, wherein the method is performed under a pressure of about 5,000 to about 20,000 psi. 12. The method of claim 10, wherein the output of pressing is further pressed while constrained. 10. The method of claim 9, wherein the output of pressing is subject to further subdivision. The demineralization of claim 1, wherein the total valleys range from about 1 to about 400 mm in median length, from about 0.5 to about 20 mm in median thickness and from about 2 to about 10 mm in median width. To make broken bone particles. The demineralization of claim 1, wherein the entire valley ranges from a median length of about 5 to about 100 mm, a median thickness of about 2 to about 10 mm, and a median width of about 2 to about 10 mm. To make broken bone particles. The method of claim 1, wherein the demineralized bone particles are elongate in shape. 19. The method of claim 18, wherein the demineralized bone particles have a median length of about 2 to about 300 mm, a median thickness and / or median width of about 0.5 to about 15 mm, a median width of about 2 to about 35 mm, And a median length to thickness ratio and / or a median length to width ratio of about 2 to about 200. 18. The method of claim 18, wherein the demineralized bone particles have a median length of about 5 to about 500 mm, a median thickness of about 1 mm to about 5 mm, a median width of about 2 to about 20 mm, and / or at about 10 And a median length to thickness ratio and / or a median length to width ratio of about 100. Demineralized bone fibers produced by the method of claim 9. Substantially complete natural bone collagen fibers. 23. The substantially complete natural bone collagen fibers of claim 22, wherein the bone collagen fibers have a length substantially equivalent to the length of the fibers when in the demineralized bone from which the fibers are obtained. The demineralized bone fibers of claim 21, wherein the demineralized bone fibers comprise at least one added medically / surgically useful material. 23. The substantially complete natural bone collagen fibers of claim 22, wherein the bone collagen fibers comprise at least one added medically / surgically useful material.