DE60029492T2 - Deformable bone composition for filling bone defects - Google Patents

Description

FIELD OF THE INVENTION

The The present invention relates generally to a surgical Bone product and more specifically represents: a flowable gel and a deformable putty based on demineralized allograft bone particles, in a liquid Carrier, comprising a hydrogel, in particular chitosan, are mixed.

BACKGROUND OF THE INVENTION

deformable Kitt is used to correct surgical defects caused by Trauma, pathological diseases, surgical intervention or Other situations can be caused in which defects by means of the bosar Surgery must be treated. It is important to have the substance to fill the defect in the mold a stable, viscous putty to facilitate placement of bone growth medium into the surgical field, usually from uneven shape and depth is present. The surgeon) brings the putty on a spatula or other instrument and spatulate put him in the place or take him in his / her finger to the bone-inducing Material in the right configuration to shape it into the to be corrected.

It Many products exist to cover this surgical need. An example is autologous bone particles taken from the patient or segments. When removed from the patient, they are due to the blood associated with it, it causes moist and viscous. This works very well when healing the defect, but requires it a significant secondary Surgical intervention designed to prolong surgery renewal the time while the patient is under anesthesia and increase costs. In addition, this procedure goes associated with a significant increase in morbidity of the patient since The surgeon removes bones from an unaffected area of the patient must be taken to ensure adequate healthy bones, bone marrow and Blood to carry the surgical filling to win the defect. this leads to Significant postoperative pain.

A other product group involves the use of inorganic Materials Providing a Matrix for New Bone Growth in the Surgical field. These inorganic materials include hydroxyapatite one derived from sea coral or synthetically derived becomes. One way or another can be with the blood and / or bone marrow of the patient to form a gel or putty. Calcium sulfate or gypsum can to similar ones Be mixed to form a putty with water. These Inorganic materials are osteoconductive, but bioinert and are neither absorbed nor remodeled into natural bone. They thus remain indefinitely as a brittle foreign body in back in the tissue of the patient.

Allograft bone represents a logical substitute for autologous bone. It is readily available and closes as noted above, those associated with autologous bone surgical complications and morbidity of the patient. Allograft bone essentially constitutes a collagen fiber reinforced hydroxyapatite matrix, Contains active Bone Morphogenic Protein (BMP) and can be used in sterile form. The demineralized form of the Allograft bone is both osteoinductive by nature osteoconductive. The demineralized allograft bone tissue is going over a well established biological mechanism completely in the tissue of the Patients incorporated. It has been in bone surgery for many years to fill the previously discussed osseous Defects used.

It is in the state of the art everywhere known to surgeons for several decades of one's own blood Patients have used as a vehicle in which they have bone fragments or bone powder of the patient or demineralized bone powder mix in this way to make a paste for filling the Defect. Blood poses due to its availability from the bleeding surgical field, a useful carrier for the patient is not immunogenic and contains Bone Morphogenic Protein, causing Wound healing is promoted by new bone growth. Stored blood from other patients, however, entails the deficiencies that Any blood transfusion, such as blood type compatibility, would have the potential the disease transmission and the unknown concentration of BMP that is largely of age depending on the donor are.

Although containing blood from forty percent (40%) to fifty percent (50%) cell mass, it provides a satisfactory carrier for demineralized bone powder because it is both mono- and polysac Charide contains, which contribute to the viscosity of the blood and impart the bulk viscosity to the paste, which was brought about by mixing the bone powder and blood. Specific monosaccharides in the blood represent glucose in a concentration of 60-100 mg / 100 ml (0.1%) and polysaccharides, such as hexose and glucosamine at about 0.1%. Glucuronic acid in the amount of about 0, 4-1.4 mg / 100 ml (mean 0.01%) is also present.

The the use of the patient's blood as a carrier for demineralized bone powder inherent problems consist of the following difficulties: the mixing of the same in the surgical field, the difficulty in terms preserving a bone paste consistency that is easily applied to the surgical field can be the guess when mixing a useful composition at the point and the problem of having a bone paste or gel which promotes optimal bone replacement growth, but from the body fluids is not taken from the surgical field or simply falls out of the bone defect site. In an attempt at the solution These and other problems were subject to a number of other attempts Use of other alternative mixtures and compositions.

Demineralized allograft bone is usually available in lyophilized or lyophilized and sterile form to provide extended shelf life. The bone present in this form is usually very coarse and dry, and its manipulation may be difficult for the surgeon. A solution for use of such a freeze-dried bone has been provided in the form of a gel, GRAFTON ^®, a registered trademark of the company. Osteotech Inc., which is a simple mixture of glycerol and lyophilized, demineralized bone powder of a particle size in the range of 0.1 cm to 1.2 cm (1000 microns to 12,000 microns) as disclosed in U.S. Patent No. 5,073,373.

GRAFTON works well to give the surgeon the placement of the allograft bone material to allow in the place. The carrier, Glycerol, however, has a very low molecular weight (92 Dalton) and is in water, the primary component flowing in the surgical field of the blood, highly soluble. Glycerol experiences also a significant viscosity reduction, when its temperature is from room temperature (in an operating room usually 22 ° C) to the temperature of the patient's tissue, usually 37 ° C, increases. This combination of high water solubility and reduced viscosity causes that the allograft bone material "runs" and almost immediately after placement flows away from the place; this prevents proper retention the surgeon carefully placed bone in place.

It An attempt was made to address these problems with the GRAFTON gel using allograft bone with a much larger particle size, specific Bone lamellae or splinters that are made by grinding or by the Slicing the bone before mixing with the glycerol carrier to be solved. This improves both the bulk viscosity and the handling characteristics of the Mixture, but dissolves still not the problem of the fast dissipation rate of the carrier and part of the bone due to the solubility of the glycerol carrier. The larger particles of demineralized bone also delay the development of new bone by the patient, because the big ones Bone fins do not pack as well as the smaller granular bone particles to let. This leaves more open space, which prolongs time could, to grow new bone and to properly fill the Defect is required. Another deficiency in use of bone lamella is that the ends of the bone fragments are uneven and when they are packed into the surgical defect, uneven bony Leave filaments behind, which protrude from the defect, causing the cure rate if necessary can be compromised.

US Patent No. 5,290,558 discloses a flowable demineralized bone powder composition below Use of an osteogenic bone powder with a large particle size in the range from about 0.1 to about 1.2 cm, with a polyhydroxy compound is mixed with a low molecular weight ranging from 2 to about 18 carbons, including a number of classes of different compounds, such as Monosaccharides, disaccharides, water-dispersible oligosaccharides and polysaccharides.

The Advantages of using smaller bone particle sizes, such as in Patent 5,073,373 for Gel were thus revealed by the use of bone lamellae in the form of threads or filaments and the retention of the glycerol carrier with the low molecular weight compromised. This later state The technique is disclosed in U.S. Patent Nos. 5,314,476 and 5,507,813 disclosed and the tissue forms described in these patents are commercially known as GRAFTON-Putty or -Flex.

The Use of the glycerol carrier with the very low molecular weight required to obtain the bulk viscosity also the use of a very high glycerol concentration. glycerol and other similar ones organic solvents low molecular weight are toxic to the surrounding tissues and irritant. It was also reports that glycerol is specifically neurotoxic, and this Problem is compounded when the concentration of glycerol as disclosed in patent 5,073,373, at a height from 20-95% is present.

One another attempt to solve the problem with the bone composition is described in US Pat. 4,172,128 which discloses demineralized bone material, that with a carrier for the reconstruction of dental or bone material by adding a Mucopolysaccharide to a mineralized bone colloid material is mixed. The composition is demineralized, coarsely ground bone material that differs from human Bones and teeth can derive, dissolved in a solvent, the one colloid solution forms a physiologically inert polyhydroxy compound, such as Example, mucopolysaccharide or polyuronic acid is added in an amount the orientation causes if the hydrogen ions or polyvalent Metal ions are added to form a gel. The gel is at increased Temperatures of over Flowable at 35 ° C and solidifies when it is lowered to body temperature becomes. Example 25 of the patent indicates that mucopolysaccharides pronounced cause ionotropic effects and that hyaluronic acid especially for the spatial Networking is responsible. Unfortunately, this bone gel is heavy produce and needed a preformed gel form.

The U.S. Patent No. 4,191,747 teaches the treatment of a bone defect with coarsely ground, denatured bone meal that removes grease and ground to a powder. The bone meal comes with a Polysaccharide in a saline solution mixed and applied to the site of the bone defect.

One Another product in the prior art is the formulation of demineralized allograft bone particles in collagen. Both Bovine as well as human collagen were used for this application. Bovine collagen carries the risk of an immunogenic reaction for the accompanying patients. Recently was found to be a disease of livestock, the bovine spongioforme Encephalopathy (BSE) from bovine tissue is transmitted to humans becomes. Consequently, the bovine tissue is at risk of disease transmission Afflicted and does not provide desired carrier for allograft tissue represents.

human Collagen is free from these diseases of the animal. Collagen is but slowly in the human body, especially in one osseous Absorbs site with a generally low level of vascularity. The slow absorption of collagen can restart the growth Delay and bones at this point cause the formation of scar tissue. This could to a non-bony Lead healing and result in much lower tensile strength.

As a result, is the state of the art, as in glycerol and other carriers Technology to deliver demineralized allograft bone a bony one Operating field embodied, plentiful with problems and speaks the correcting The problems inherent in surgical defects are only partially

SUMMARY OF THE INVENTION

A sterile deformable bone composition, such as bone sealant, with a useful one Bulk viscosity, was made using chitosan having a molecular weight of one hundred thousand to three hundred thousand daltons.

It is therefore an object of the present invention to provide a sterile deformable bone cement composition for application to the site of a bone defect for promoting new bone growth at the site comprising a mixture of demineralized osteogenic bone powder in a hydrogel carrier;
wherein the bone powder has a particle size of about 100 to about 850 microns;
wherein the bone powder comprises from 30 to 40% by weight of the composition;
wherein the carrier is chitosan in an aqueous solution, wherein the chitosan has a molecular weight in the range of one hundred thousand to three hundred thousand daltons and in the range of 1 wt .-% to 5 wt .-% based on the carrier solution.

The mixture preferably includes a sterile deformable bone composition according to claim 1, wherein said mixture includes Bone Morphogenic Proteins beyond the amount which occurs naturally in allogenic bone.

The aqueous solution includes preferably a sterile deformable bone composition according to claim 1 or 2, wherein the aqueous solution a sodium chloride based phosphate buffer.

The Bone powder closes preferably prefers a sterile deformable bone composition after one of the preceding claims wherein said bone powder is cortical allograft bone powder or corticospongous Allograft bone powder represents.

The Composition closes preferably antimicrobial agents and / or antibiotics, such as, for example, Erythromycin, bacitracin, neomycin penicillin, polymyxin B, tetracycline, Viomycin, chloromycetin and streptomycin, cefazolin, ampicillin, Azactam, tobramycin, clindamycin, gentamicin and vitamins.

In an embodiment the bone powder comprises from 30% to 35% by weight of the composition, and the chitosan component comprises about 3% by weight of the carrier solution.

In another embodiment, a sterile deformable bone cement composition is provided for application to a bone defect site for promoting new bone growth at the site, comprising: a novel bone growth-inducing demineralized lyophilized allograft bone powder having a particle size in the range of about 100 to about 850 microns in high molecular weight chitosan and a water carrier solution wherein the bone content of the putty composition ranges from 30% to 35% and the chitosan component comprises about 3% by weight of the carrier solution, the chitosan having a molecular weight in the range from about 1.0 × 10 ⁵ to 3.0 × 10 ⁵ daltons.

The Compositions of the invention shut down prefers living cells, such as chondrocytes, bone marrow cells or mesenchymal stem cells.

The aqueous solution preferably comprises a sodium chloride-based phosphate buffer, the toxic problems with high concentrations of organic solvent low molecular weight avoids in the prior art.

It can thus be seen that the prior art is trying has obtained by mixing blood with bone particles Putty / preserved gel, without the need, the two in the surgical field in uncontrolled proportions and under time and space constraints to mix together, to replicate.

The Selection of chitosan with the present molecular weight allowed the use of granules with the preferred small particle size of demineralized Allograft bone. These small particles can be better in pack the wound defect and are absorbed faster, thereby allowing that the bone defect to the natural Bone of the patient can be remodeled.

• (i) Verwendung von demineralisiertem pulverförmigem Knochen in einer Partikelgröße, die zum Erreichen der Verformbarkeitsmerkmale, welche die Menge des Knochens in der Formulierung maximiert, ohne körnige, weniger verformbare Merkmale herbeizuführen, nützlich ist.
• (ii) Einen nicht toxischen Träger für die Knochenpartikel, der sich nicht nachteilig auf den Patienten auswirkt.
• (iii) Ein Knochendefektmaterial, das vom Arzt leicht gehandhabt werden kann und bei Kontakt mit dem Blutstrom im Operationsfeld nicht abgebaut wird.

By the use according to the invention, one or more of the following advantages can be achieved:

• (i) Use of demineralized powdered bone in a particle size useful for achieving the ductility characteristics that maximizes the amount of bone in the formulation without causing granular, less deformable features.
• (ii) A non-toxic carrier for the bone particles that does not adversely affect the patient.
• (iii) A bone defect material that can be easily handled by the physician and will not dissipate upon contact with the bloodstream in the surgical field.

In some embodiments of the invention becomes a calcium salt with the demineralized bone composition for support healing used at the site of the bone defect.

In other embodiments of the invention provided a premixed bone cement / pre-mixed gel in an oxygen-protected carrier, to protect the putty / gel from drying out or removal.

DESCRIPTION OF THE INVENTION

object The present invention is a demineralized bone powder composition for Healing of bone defects. The preferred embodiment of the examples and other alternative embodiments of the invention address the two basic deficiencies of the glycerol carrier and the flowable Compositions of bone particles known in the art used: first, those of low molecular weight glycerol; and secondly, the use of large particles or fins to obtain the preferred bulk viscosity. In the invention used Types of demineralized bone are cortical and corticospongous Bone powder.

The Combination of demineralized, lyophilized allograft bone with a particle size of 100-420 microns produced surprisingly when mixed with very low concentrations of this chitosan high molecular weight in a suitable carrier deformable putty with clinically useful Bone inducing properties. The ductility property allows the surgeon to increase the amount of bone cement or gel Precise fitting to shape the surgical defect. The manipulation of the "lump" of bone putty Can be done without him wearing the gloves of the surgeon sticking, in a sense, as in modeling used wet clay behaves.

The ideal carriers for the deformable putty are chitosan having a molecular weight of about 1.0 × 10 ⁵ to 3.0 × 10 ⁵ daltons.

The molecular weight of the chitosan used in the examples is 2.0 × 10 ⁵ daltons.

A other embodiment of the invention is the induction of the presence of soluble calcium at the bone defect site. This is over the normal biochemical mechanism of new bone growth. soluble Calcium can be made using a sodium phosphate buffer of pH 6.8 to 7.2 instead of the physiological saline in the surgical field are attracted. The phosphate buffer pulls Cations of calcium from the surrounding healthy bone to the Place and produces an equilibrium concentration of calcium exactly at the healing point where the growth of new bone most desired is.

any Number of medically useful Substances can according to the invention by inflict the substances for composition at any stage of the mixing process or directly to the final composition. Such substances shut down Collagen and insoluble Collagen derivatives, hydroxyapatite and soluble solids and / or dissolved in it liquids one. Also included are virucides, such as those that are effective against HIV and hepatitis; antimicrobial agents and / or antibiotics, such as erythromycin, bacitracin, Neomycin, penicillin, polymyxin B, tetracycline, viomycin, chloromycetin and streptomycin, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamycin. It is also conceivable that the composition Added the following can be: amino acids, peptides; Vitamins, cofactors for the protein synthesis; hormones; endocrine tissue or tissue fragments; Synthesis tools; Enzymes, such as Collagenase, peptidases, oxidases; Polymer cell scaffolds with parenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; Collagen lattice; biocompatible surfactant Means, antigenic agents; cytoskeletal agents; Cartilage fragments, Live cells, such as chondrocytes, bone marrow cells, mesenchymal stem cells, natural Extracts, tissue grafts, bioadhesives, transforming growth factor (TGF-β), insulin-like growth factor (IGF-I); Growth hormones, how to Example somatotropin; Bone digestion aids; Antitumor agents; fibronectin; Cell attractants and addition agents; immunosuppressants; Permeation enhancers, e.g. B. fatty acid esters, such as Laureat, myristate and stearate monoesters of polyethylene glycol, enamine derivatives and α-ketoaldehydes.

The invention may be further understood by the following examples, wherein the percentages are by weight. For some samples, a penetration test was used to measure the mass consistency of the formulation. In principle, the test measures the depth of penetration of a metal cone of known mass inserted into a sample of the formulation for a specified period of time. The heavier a formulation, the lower the penetration that occurs, and this test is done according to ASTM Method D 1403-96: Standard test procedure for cone penetration of a grease using 1/4 and 1/2 scale tapering equipment , All examples could if necessary, in an aseptic environment to maintain a sterile final product.

Examples according to the invention

In the examples, the molecular weight of the chitosan used is 2.0 × 10 ⁵ daltons.

Example I:

One malleable putty made from a 3% chitosan 100-300 micron solution cortical allograft bone powder at 33%.

507 mg freeze-dried cortical allograft bone with a particle size of 100-300 microns was mixed in 1002 mg of a 3% chitosan solution in physiological saline. The bone component becomes a bone concentration of 33 wt .-% added. The solution was mixed well and 2-3 Hours at room temperature. This represented a deformable Putty with good formability properties ready.

Example II:

One malleable putty made from a 3% chitosan 420-850 micron solution cortical allograft bone powder at 33%.

518 mg freeze-dried cortical allograft bone with a particle size of 420-850 microns was mixed in 1038 mg of a 3% chitosan solution in physiological saline. The bone component becomes a bone concentration of 33 wt .-% added. The solution was mixed well and 2-3 Hours at room temperature. This represented a deformable Putty with good moldability properties.

Example III:

One malleable putty made from a 3% chitosan 420-850 micron solution cortical allograft bone powder at 50%.

518 mg freeze-dried cortical allograft bone with a particle size of 420-850 microns was mixed in 522 mg of a 3% chitosan solution in physiological saline. The bone component becomes a bone concentration added by 50 wt .-%. The solution was mixed well and 2-3 Hours at room temperature. This represented a deformable Putty with poor moldability properties.

Example IV:

One malleable putty made from a 3% chitosan 100-300 micron solution cortical allograft bone powder at 50%.

518 mg freeze-dried cortical allograft bone with a particle size of 100-300 microns was mixed in 522 mg of a 3% chitosan solution in physiological saline. The bone component becomes a bone concentration added by 50 wt .-%. The solution was mixed well and 2-3 Hours at room temperature. This represented a deformable Putty with poor moldability properties.

The following Table I sets forth the examples I-IV given above in comparative form:

Table I summarizes that:
a putty having good mouldability may consist of about 30-40% of the bone powder (particle size in a range of 100-850 microns) mixed in a hydrogel solution, such as 3% chitosan (Examples I and II).

Examples III and IV of the test results, both no successful flowable putty are included. These show the concentration limits the respective examples. Absorb particle sizes below about 100 microns too fast.

To the Exclusion of oxidation degradation and loss of viscosity should the composition mixed and in an oxygen-free environment be packed. The mixing of demineralized bone powder in a hydrogel solution is in an enclosed sterile glove chamber with an oxygen-free Environment, such as in one with nitrogen, argon or another inert gas filled chamber carried out. The mixed deformable bone composition is then placed in a sterile container, such as an impermeable one Syringe plunger or vial given, sealed and placed in a sterile tightly closed Packed, filled with an inert gas or sealed by vacuum becomes.

The Principles of the invention preferred embodiments and effects were described in the above description. However, the invention should not be construed as meaning that Limits the above-described specific embodiments. Instead of however, the embodiments described herein should rather be taken as illustrative of restricting be considered. Variations and changes may be made by third parties be without coming out of the scope of the invention, as by the following claims is defined:

Claims (10)

Sterile deformable bone cement composition for application to a bone defect site for promotion of new bone growth at the site, comprising a mixture of demineralized osteogenic bone powder, in a hydrogel carrier; in which the bone powder has a particle size of about 100 to about 850 Having micron; the bone powder is from 30% to 40% the weight of the composition; the carrier is chitosan in an aqueous solution wherein the chitosan has a molecular weight in the range of one hundred thousand to three hundred thousand daltons and in the Range of 1 wt .-% to 5 wt .-% based on the carrier solution. Sterile deformable bone composition according to claim 1, wherein said mixture of Bone Morphogenic Protein on the Amount that occurs naturally in allogenic bone. Sterile deformable bone composition according to claim 1 or 2, wherein the aqueous solution has a sodium chloride based phosphate buffer. Sterile deformable bone composition after one of the preceding claims, wherein said bone powder is cortical allograft bone powder or corticospongous Allograft bone powder represents. Sterile deformable bone cement composition according to Claim 3 or 4, the antimicrobial agents and / or antibiotics, such as erythromycin, bacitracin, neomycin penicillin, Polymyxin B, tetracycline, viomycin, chloromycetin and streptomycin, Cefazolin, ampicillin, azactam, tobramycin, clindamycin, gentamycin and vitamins. Sterile deformable bone composition after one of the preceding claims, wherein the bone powder is from 30% to 35% of the weight of the composition and the chitosan component comprises about 3% by weight of the carrier solution. A sterile deformable bone kink composition for application to a bone defect site for promoting new bone growth at the site, comprising: a new bone growth-inducing, demineralized, lyophilized allograft bone powder having a particle size ranging from about 100 to about 850 microns , in a carrier solution of high molecular weight chitosan and water, wherein the bone content of the putty composition is in the range of 30% to 35%, and the Chitosan component comprises about 3 wt .-% of the carrier solution, wherein the chitosan has a molecular weight in the range of about 1.0 × 10 ⁵ to 3.0 × 10 ⁵ daltons. A composition according to claim 6, wherein the aqueous solution comprises a sodium chloride-based buffer. A composition according to any one of claims 5 to 8, wherein said bone powder is added to Bone Morphogenic Protein includes. A composition according to any one of claims 1 to 9, wherein the composition comprises live cells, such as chondrocytes, Bone marrow cells or mesenchymal stem cells.