DE10357460A1 - Bioresorbable material - Google Patents

Abstract

The present invention relates to a bioresorbable material and its use. DOLLAR A The object of the invention, a material which has a paste-like or wax-like consistency, remains dimensionally stable in the moist medium of the body and bioresorbable and to indicate the use of this material is achieved in that the bioresorbable material of at least two different surface-modified particles the particles consist of biodegradable ceramics and / or glasses and / or salts in their pure form or in the form of mixtures or blends or alloys or composites or composite materials or of biodegradable synthetic and / or natural polymers and / or their mixtures and / or derivatives, Copolymers or block polymers in their pure form and / or in the form of mixtures or blends or alloys or composites or composites and that this material is used to occlude cancellous bone, to fill bone defects or to bond bone and / or cartilage and / or other tissues is used.

Description

The The present invention relates to a bioresorbable material and its use.

since For some time, the use of bioresorbable material for Hemostasis known in cancellous bone.

at Operative procedures in the hard tissue lead to bleeding from the spongy cancellous bone. Unlike bleeding in soft tissue There are no vessels in the cancellous bone, which by means of drug delivery be narrowed or sealed by electrocautery can, so as to reduce the bleeding and thus the blood loss.

According to the state The technique is currently a wax-like substance consisting from the main ingredients of purified beeswax and synthetic Grow pressed into the cancellous bone used to the Limit blood loss. This bone wax remains after the OP in the body. The currently used bone waxes are not bioresorbable.

Other paste-like Substances are disclosed in document WO 03/055531 A2. These Include gelatin in combination with salts and thrombin to prevent bleeding to reduce. The disadvantage of these paste-like substances is that With the gelatin animal products are used, which is a risk of infection include.

Also has been the use of bioresorbable materials for some time as a filler for bone defects known.

there The bone defects are filled up with bone-like materials.

For this are often disclosed as in the document WO 98/16268 A2, calcium phosphate compounds used. These can, as known from the document WO 98/43685 A2, also therapeutic agents contain.

The writings DE 39 37 361 A1 and EP 0 166 263 A1 disclose that in order to increase the strength of these bone filling materials, fibrin or proteins are incorporated into the filling material.

Of the Disadvantage of these materials, however, is that the proteins used Cause for protein-induced diseases, for example by containing prions are.

The Alternatively, biotechnologically produced proteins require elaborate Manufacturing process, resulting in increased costs for this Reflecting materials.

Known is also the use of bioresorbable material as a tissue adhesive in hard tissue.

The Problem of the tissue adhesive used so far, however, is that these either are not bioresorbable, such as. Cyanoacrylate adhesive, or that these have insufficient strength in hard tissue contact, such as fibrin glue.

consequently Therefore, for smaller fractures, the mechanical fasteners the fragments with screws or wires, which in a second operation after reaching a sufficient stability the bones need to be removed, something in increased expenses for precipitates this second intervention.

Therefore, for some time degradable adhesive, such as in the Scriptures DE 101 52 407 A1 disclosed used. The adhesives consist of two liquid components.

adversely At these two-component adhesives is that the mixing of the two Components must be done before the application and that it is in the course this mixing by the reaction of the components with each other to inhomogeneities come can, whereby a reduced adhesive effect and thereby a reduced Durability arise.

Of the The invention is therefore based on the object, a material which a paste-like or waxy Has consistency, remains dimensionally stable in the moist environment of the body and bioresorbable and indicate the use of this material.

These The object is achieved by a material according to claim 1 and by Use according to claims 18 to 20 solved. Advantageous embodiments of the material according to the invention are in the subordinate claims 2 to 17 indicated.

• a) zum Verschluss der Spongiosa und damit zur Verminderung oder Vermeidung des Blutaustrittes verwendet werden kann,
• b) und/oder als Füllstoff bei Knochendefekten einsetzbar ist,
• c) und/oder die Kompakta und/oder Spongiosa des Knochen kleben kann,
• d) und/oder Knorpel und andere Gewebe kleben kann.

The essence of the invention is that the material according to the invention has a paste-like or wax-like consistency, remains dimensionally stable in the moist environment of the body, is bioresorbable and in hard tissue contact

• a) can be used to occlude cancellous bone and thus to reduce or prevent blood leakage,
• b) and / or can be used as a filler in bone defects,
• c) and / or the Kompakta and / or cancellous bone can stick to the bone,
• d) and / or cartilage and other tissues can stick.

According to the invention the material consists of at least 2 different, surface-modified Particles.

Essential is that the particles of biodegradable materials, preferred made of biodegradable ceramics, glasses, Salts in their pure form or in the form of mixtures, blends, alloys, Composite materials, composites exist.

Advantageous According to the invention, the particles are biodegradable Materials, preferably of synthetic or natural Polymers and mixtures thereof and / or derivatives, copolymers, Block polymers, in pure form or in the form of mixtures, blends, Alloys, composites, composite materials exist.

Besides that is according to the invention the coating of the particles of degradable natural polymers and / or degradable synthetic polymers, copolymers, block polymers, or their derivatives and mixtures.

According to the invention, that the particles are formed by covalent bonding or non-covalent interactions, such as adhesion, connected to the coating material.

Advantageous For the purposes of the invention, the coatings are multi-layered on the surface is applied.

Farther According to the invention that the coatings have functional groups on their surface, preferably aldehyde groups, amino groups, carboxyl groups, keto groups, unsaturated Compounds or derivatives of these groups are present.

in the The invention relates to the functional groups on the surface of the Particles by adding liquids (preferably water-based) with or without chemical reactions initiating reagents crosslinkable, the reactions between the functional groups of the surface-coated particles can be controlled by the influence of temperature.

The Reactions between the functional groups of the surface-coated Particles may also be enzymatically initiated.

in the The sense of the invention is that the material of the invention medically effective Substances, preferably active substances from the groups of growth factors, Interleukins, prostaglandins, anti-inflammatory drugs, steroids, peptide hormones, anesthetics, antimicrobial chemotherapeutic drugs, antirheumatics, Antihistamines, cytostatic drugs, enzymes, vitamins and substances, affecting blood coagulation and / or platelet aggregation, may contain.

Farther is according to the invention that the surface modified Particles of the material by adding liquids in their consistency are adjustable, so that the material preferably as a paste or waxy Material is formed.

Also the material is surface modified Particles by selecting the coating and / or by adding liquids adjustable in consistency, so that the material preferably as a paste or wax-like Material is formed.

in the The sense of the invention is also that the application of the pastes suitable application systems can take place.

• • Verwendung zum Verschluss der Spongiosa zur Verminderung oder Beseitigung des Blutaustrittes,
• • Verwendung zur Auffüllung von Knochendefekten,
• • Verwendung zur Klebung von Knochen und/oder Knorpel und/oder anderen Geweben.

For the purposes of the invention, the material according to the invention can be used as follows:

• Use to occlude cancellous bone to reduce or eliminate blood leakage;
• Use for filling bone defects,
• • Use for bonding bones and / or cartilage and / or other tissues.

The Invention will be explained in more detail with reference to the embodiments.

1st embodiment

Production of a powder A)

It becomes strength with periodic acid oxidized to produce polymer-analogous aldehyde groups. On the surface of Hydroxylapatite powder particles become amine groups by means of silane coupling agents generated. These amino groups are oxidized by 4 times Strength and ethylenediamine reacted one more time with oxidized Strength reacted.

This produces the following following layer structure on the particles:
"Powder Surface (Oxidized Starch Ethylenediamine) ₄ - oxidized starch "with aldehyde groups.

Production of a powder B)

It becomes strength with periodic acid oxidized to produce polymer-analogous aldehyde groups. On the surface of Hydroxylapatite powder particles become amine groups by means of silane coupling agents generated. These amino groups are oxidized by 4 times Strength and ethylene diamine reacted.

This produces the following following layer structure on the particles:
"Powder Surface (Oxidized Starch Ethylenediamine) ₄ "

The Powders A and B are dry blended together. By adding Water creates a paste-like mass. The terminal aldehyde groups of the powder A react with the amino groups of the powder B. under formation of covalent bonds. It creates a three-dimensional Structure. The cancellous bone of a broken bovine bone gets through push in the paste is closed or a bone defect is mixed with the material refilled.

2nd embodiment

Production of a powder A)

Calcium phosphate particles are surface-modified with silane coupling agents having carboxyl groups. The terminal ones Carboxyl groups are activated with a carbodiimide and then with Amino groups of heparin reacted. (Heparin possesses through the isolation process up to 10% of free amino groups necessary for the reactions are.) The carboxyl groups of the immobilized heparin become again activated with carbodiimide and reacted with dissolved heparin. These Activation and reaction with heparin is performed several times. The Powder possesses after these multistage modification procedures a multiple layer of carboxyl-terminated heparin and Amino groups.

Production of a powder B)

The Powder B is prepared by the same method as Powder A, however, the carboxyl groups of the outer heparin layer become carbodiimide activated.

powder A and B are mixed in a dry state. By adding isotonic solvents or water the various modified particles together under formation of a paste-like mass. The porous structure inside a bone (cancellous bone) was closed with the mass.

3rd embodiment

Production of a powder A)

Calcium phosphate particles are surface-modified with silane coupling agents having carboxyl groups. The terminal ones Carboxyl groups are activated with a carbodiimide and then with Amino groups of heparin reacted. (Heparin possesses through the isolation process up to 10% of free amino groups necessary for the reactions are.) The carboxyl groups of the immobilized heparin become again activated with carbodiimide and reacted with dissolved heparin. These Activation and reaction with heparin is performed several times. The Powder possesses after these multistage modification procedures a multiple layer of carboxyl-terminated heparin and Amino groups.

Production of a powder B)

It becomes strength with periodic acid oxidized to produce polymer-analogous aldehyde groups. On the surface of Calcium phosphate particles become amine groups by means of silane coupling agents generated. These amino groups are oxidized by 4 times Strength and ethylene diamine reacted. With sodium borohydride, the double bonds reduced the Schiff's bases, resulting in more stable C-N bonds arise. This results in multiply coated calcium phosphate particles, in their outer layer Amino groups are present.

powder A and B are mixed in a dry state. The amino groups of Powders B react with the carboxyl groups of the powder A after a aqueous solution from a carbodiimide was added to a paste-like mass.

4th embodiment

Production of a powder A)

It becomes strength with periodic acid oxidized to produce polymer-analogous aldehyde groups. On the surface of Hydroxylapatite were produced by amine groups using silane coupling agents. These amino groups are changed 12 times with oxidized starch and Implemented ethylenediamine. This results in multiply coated particles, in their outer layer after the last reaction with starch aldehyde groups wear. These are reacted with vinylaniline to form a Schiff base. The Powder carries in the extreme Layer now double bonds.

Production of a powder B)

It becomes strength with periodic acid oxidized to produce polymer-analogous aldehyde groups. On the surface of Hydroxylapatite are produced by amine groups using silane coupling agents. These amino groups are changed 10 times with oxidized starch and Implemented ethylenediamine. The last reaction of the terminal amino groups of the ethylenediamine takes place with the oxidized starch. The now lying on the surface Aldehyde groups are formed to form Schiff's bases with 4-azido-1-fluoro-2-nitrobenzene implemented. Dibenzoyl peroxide is attached to the surface and by photochemical Activation of the azide group chemically coupled.

powder A and B are mixed homogeneously. For transfer into a paste-like Mass becomes isotonic saline added and the mixture kneaded. By increasing the temperature of the mixture to 60 ° C the benzoyl peroxide groups are split and the radical Networking between the outer layers the particle surfaces initiated.

5th embodiment

Production of a powder A)

It becomes strength with periodic acid oxidized to produce polymer-analogous aldehyde groups. On the surface of Calcium phosphate particles become amine groups by means of silane coupling agents generated. These amino groups are oxidized in 10-fold alternation with Strength and ethylene diamine reacted. This results in multi-coated Calcium phosphate particles, in their outer layer of amino groups available.

Production of a powder B)

It becomes strength with periodic acid oxidized to produce polymer-analogous aldehyde groups. On the surface of Hydroxylapatite powder particles become amine groups by means of silane coupling agents generated. These amino groups are oxidized in 8-fold alternation with Strength and ethylenediamine reacted one more time with oxidized Strength reacted. The particles now have aldehyde groups on the outer surface, those with L-dopa (3- (3,4-dihydroxyphenyl) -L-alanine) be implemented.

powder A and B and the enzyme tyrosinase are mixed homogeneously. By adding isotonic solution the enzyme oxidizes the 3,4-dihydroxyphenyl group of L-dopa on the powder B to a quinone derivative, which with the amino groups of the powder A under formation of Schiff's Cross-linking reacts bases.

6th embodiment

For the application the material according to the invention Add the powder mixture (A and B) to a syringe with 2 glass beads given and closed with the splash guard. After sucking of isotonic saline the syringe is closed and shaken. The balls mix the solution with the powder. Subsequently will be the paste-like Mass pushed out of the syringe.

7th embodiment

For the application the material according to the invention the powder mixture is in a sealed foil. The foil contains another foil with water. By mechanical stress on the outer film the inner foil is bursting. The water will now mixed by kneading with the powder. After opening the outer foil may be the paste-like Crowd pushed out become.

Claims (20)

Bioresorbable material consisting of at least 2 different, surface-modified Particles, where the particles are made • biodegradable ceramics and / or Glasses and / or Salts in or out • biodegradable synthetic and / or natural polymers and / or mixtures thereof and / or derivatives, copolymers and block polymers in Pure form or in the form of mixtures or blends or alloys composites or composites. Bioresorbable material according to claim 1, characterized in that that the coating of particles from biodegradable natural Polymers and / or degradable synthetic polymers, copolymers, Block polymers, or their derivatives and mixtures exist. Bioresorbable material according to claim 1, characterized in that that the particles by covalent bond or by noncovalent Interaction with the coating material are connected. Bioresorbable material according to claim 1, characterized in that that the coatings on the surface is multi-layered. Bioresorbable material according to claim 1, characterized in that the coatings have functional groups on their surface has. Bioresorbable material according to claims 1 and 5, characterized in that the functional groups aldehyde groups and / or Amino groups and / or carboxyl groups and / or keto groups and / or unsaturated Compounds and / or derivatives of these are. Bioresorbable material according to claims 1 and 5, characterized in that the functional groups on the surface the particle by adding liquids can be crosslinked with reagents initiating reactions. Bioresorbable material according to claims 1 and 5, characterized in that the functional groups on the surface the particle by adding liquids can be crosslinked without reagents initiating chemical reactions. Bioresorbable material according to claim 7 or 8, characterized in that the reactions between the functional Groups of surface-coated Particles can be controlled by the influence of temperature. Bioresorbable material according to claim 7, characterized characterized in that the reactions between the functional groups the surface-coated Particles enzymatically initiated. Bioresorbable material according to one or more of the preceding claims, characterized in that the material medically active substances contains. Bioresorbable material according to claim 11, characterized characterized in that the medically active substances are active substances from the groups of growth factors and / or interleukins and / or prostaglandins and / or antiphlogistics and / or steroids and / or the peptide hormones and / or the anesthetics and / or the antimicrobial Chemotherapeutics and / or antirheumatics and / or antihistamines and / or the cytostatic drugs are. Bioresorbable material according to claim 11, characterized characterized in that the medically active substances are enzymes and / or vitamins and / or substances that cause blood clotting and / or Are influencing platelet aggregation. Bioresorbable material according to one or more of the preceding claims, characterized in that the material by adding liquids in its consistency is adjustable. Bioresorbable material according to one or more of the preceding claims, characterized in that the material by selecting the coating in its consistency is adjustable. Bioresorbable material according to claim 14 or 15, characterized in that the material is a paste. Bioresorbable material according to claim 14 or 15, characterized in that the material is wax-like is. Use of bioresorbable material after one or more of the preceding claims for closure of cancellous bone. Use of bioresorbable material after one or more of the preceding claims for replenishment of Bone defects. Use of bioresorbable material after one or more of the preceding claims for the bonding of bone and / or cartilage and / or other tissues.