Biologically absorbable implant material, and method for its preparation.

The invention relates to a biological resorbable implant material for filling and closing soft tissue cavities and for the replacement of soft tissues and a method of manufacturing the same.

In the field of orthopedic implant materials for filling bone cavities are known, which are produced by partial deproteinization and denaturation of the protein residue from cancellous bone tissue (DE-C 961 654). This known as the "Kieler spongiosa" material has substantially the same calcium content as native spongiosa. It is therefore hard and completely inelastic and unsuitable for application in soft tissue.

In bone surgery is furthermore a known from cortical bone, ie bones, produced by descaling material (Journal of Surgical Research 37, 487-496 (1984) having an osteoinductive effect which is its content of "Bone Morphogenetic Protein" attributed . Because of these osteoinductive property is contraindicated a use outside of a bone.

In EP-A-0171176 a composition for the treatment of bone defects is described which is made from bone collagen by decalcifying and lyophilizing and forms a gel after reconstitution. Because of the desired osteoinductive effect of this material is taken to ensure that no cross-linking of the collagen takes place during the preparation.

Furthermore, a bone substitute material based on collagen is known from DE-B 28 54 490, which is made of bone by removing the blood pigment and other water-soluble proteins, degreasing and dissolution of mineral components by complexing or ion exchanger and a concluding freeze drying. The material is insufficiently elastic after reconstitution and not suitable for application in soft tissue.

For application on or in soft tissues only collagen fleeces are known as capping and implant materials so far. However, these fabrics have when wet no form stability and no elasticity; they are for a firm anchoring in a moving tissue, such. as in the lungs, only conditionally suitable. Synthetic materials such as acrylates, which have also been proposed, have again other disadvantages of which are massive foreign body stimulus, isolation, lack of healing and possible release of toxic degradation and by-products in the foreground.

As prior art also prosthetic implant materials are known which are prepared from body tissues by treatment with protein crosslinking agents. Such materials are used to increase the stability of certain institutions, such. As heart valves or vascular prostheses. Such implants are described, for. Example, in EP-B 0 174 737 and in US-A-4,120,649.

The invention has as its object to provide a well-tolerated implant material that can be a part used to close tissue cavities, but on the other hand also for the replacement of specified tissues and the adverse or therapeutic use limiting properties of the known products do not have.

After lung resections and also for other diseases of the lungs bronchopleural fistulas may occur. These are septic holes or cavities between the bronchial tree and pleura, which are filled with secretions or pus. They are continuously flows through breathing and coughing of air and secretions, their size can be a few millimeters in diameter to several centimeters. It's been an unsolved problem in thoracic surgery to close such bronchial fistulas and bring to healing, especially if the introduction of the implant should be done endoscopically, which would be the fastest and most gentle way. At an implant material to be endoscopically inserted and fixed, special requirements. It must firstly enable mechanical bracer, on the other hand it must be brought through the bronchial tree to the fistula.

The implant must be deformable and compressible. It has its original shape can again take in the presence of moisture, ie, have a high memory effect. Furthermore, the material must have a considerable strength, but remain absorbable because germs adhere to non-resorbable materials and can always lead to abscesses or fistulas new. Furthermore, it shall be possible according to a further aspect of the invention to achieve an immediate gas- and liquid-tight seal after insertion of the implant. Finally, it should be possible to incorporate bactericidal or stimulating the healing of wounds or other pharmaceutical substances in the material.

The invention with which these objects are achieved, is in a biological resorbable implant material for filling and closing soft tissue cavities and for the replacement of soft tissues that it - Made of molded into moldings bone tissue of human or animal origin, which - Is decalcified, - Whose native proteins are cross-linked with a protein cross-linking agent in order to avoid an osteoinductive effect, - Wherein the moldings have high resilience at low hysteresis between loaded and unloaded state. The invention thus provides the original protein content of decalcified bone hard tissue is left and causes the high elasticity and resistance through the networking of the native proteins.

The molded bone tissue moldings can have, for example Blöckchen-, conical or spherical shape.

For replacement of tubular soft tissue, such as trachea pieces, the implant material is preferably made of cortical bone parts.

For filling and closure of tissue cavities, the implant material may be made of cancellous bone parts and having spongy consistency, wherein the pore volume of the material 55 - should be 95%. The material is compressible in a dry state; However, in the presence of humidity it takes the original shape, ie, it has a pronounced "memory effect".

The descaling is carried out as far that the remainder calcium content max. 80 mmol / g wet weight amounts.

According to a preferred embodiment, the implant material may comprise a tissue adhesive based on fibrinogen or collagen.

The invention further comprises a method for the preparation of the implant material, which is characterized in that native proteinaceous bone material decalcified with a decalcification agent, washed free of descaling agent, then treated with a protein crosslinking agent, washed to remove the protein crosslinking agent repeated, optionally with pharmaceutical solutions, such as solutions of tissue adhesives, brought together on fibrinogen or collagen, is finally dried and sterilized.

As the crosslinking agent, in particular glutaraldehyde, polyepoxide compounds, or Isodicyanatderivate carbodiimides, aldehydes can be used.

The bone material can be degreased expediently before or after decalcification with an organic solvent such as chloroform-methanol.

Before or after protein cross-linking may also be provided to treat the bone material by means which reduce a possible content of undesired antigens, eg. As detergents or enzymes.

The implant material according to the invention and the method for its manufacture can be modified in various ways, whereby additional pharmaceutical effects or properties can be obtained. Thus, by the above-mentioned concomitant use of a detergent, eg. As the Oktylphenoxypolyethoxyäthanol-Triton X-100 in a one percent concentration, not only the content of undesired antigens are reduced in the washing solutions, but it can reduce the risk of subsequent calcification of the implant can be reduced. Furthermore, it is possible, in the washing solutions a low content (about 0.5 M) to provide ethylendiamintetrasaurem sodium, whereby descaling is improved.

It can also be an intermediate treatment of the implant material with a buffer solution containing enzymatically active substances Example as ficin and / or Neuraiminidase be provided, whereby the antigen content is also reduced in the finished product.

To ensure that the finished product does not contain traces of glutaraldehyde, the material (content about 5 mg / ml) can be rinsed after the crosslinking treatment with a glycine or lysine solution.

If implantation material according to the invention was prepared from cancellous bone, it is advantageous to compress it prior to the filling in the final container, such as to half the volume.

A special application of the material according to the invention is the replacement of tubular tissues such Tracheateilen. As starting material for such an implant femur are used, which are reduced by mechanical surface removal on the lathe tubular to approximately 2 mm wall thickness prior to the combined treatment according to the invention subjected by decalcification and protein cross-linking.

The final product according to the invention is, if it is to be used to fill tissue cavities, suitably placed in Blöckchenform.

The material may be sterilized by gamma rays and in container, the z. B. a 70% ethanol solution, stored. The small blocks are rinsed before application on patients with Ringer's solution.

It is however also possible to mount the small blocks after sterilization with gamma-rays in the dry state, are being impregnated in accordance with a particularly preferred embodiment of the invention, the small blocks with a Fibrinkleberlösung under sterile conditions and then freeze-dried in the final container.

Of course the product, apart from the Blöckchen- or tubular shape already described invention can also be placed in disc or in film form.

In the following example, the inventive method and the product produced thereby will be explained.

1 kg cancellous bone material from the calf was recovered by drafts liges cutting a femoral head.

This spongiosa were rinsed with hot water (50 ° C) and then at room temperature in 0.6 N hydrochloric acid (10 l) with continuous agitation and several changes, squeezing and washing the Spongiosablöckchen decalcified (24-72 hours). Subsequently, the small blocks were rinsed free of acid and for one hour at room temperature with 1% glutaraldehyde in 0.05 M phosphate buffer solution (1 l) at pH 7.4 incubated for the purpose of crosslinking.

By at least five times washing with a sterile washing solution, and squeezing the cancellous bone of the residual glutaraldehyde was removed from the cancellous bone. The small blocks were freeze-dried, filled into the final packaging and sterilized in 2.5 Mrad gamma rays.

A thus produced implant material in Blöckchenform was used in patients as fistula endoscopic approach: The patient was intubated with the rigid bronchoscope and performed a ventilation in the open system with the Injekttimer. After inspection of the fistula a suitable Spongiosastück was cut and compressed, so that it could be carried out through the bronchoscope. With a biopsy forceps, the implant was placed in the fistula, where it is moistened by contact with the bronchial wall, quickly expanded and verspreizte. With a triple-lumen Spray Catheters 1 to 2 ml of fibrin sealant was applied dropwise around the implant immediately after positioning of the implant, thereby further bonded and swelled with the bronchial wall. It has achieved an immediate airtight closure of the fistula.

The implant material according to the invention has no osteoinductive activity, which can be determined by measurement of alkaline phosphatase or by histological examination. Therefore, the material can be used safely for application in soft tissue area.

The implant material according to the invention produced has excellent elastic properties. For comparison with known preparations spongiosa blocks with 1.5 cm was the one hand, without treatment with a protein crosslinking agent and on the other hand described the present invention by a combined descaling and protein cross-linking, as in the above embodiment was prepared. The small blocks were dried and then wetted with a 0.9% NaCl solution. All small blocks were in a load machine (Transducer 0 - 1000 at a loading rate of 1 cm min pond /) tested, with loading or unloading curves revealed as illustrated in the drawing.

The load curve and the discharge curve (motor - way) of spongiosa blocks that have not been subjected to cross-linking treatment are denoted by 1 and 2; 1 'and 2' to give the corresponding curves of the preparations according to the invention again. It can be seen that a relatively low strength and a strong hysteresis occur in the non-crosslinked part of the prior art preparations, while spongiosa blocks according to the invention show no hysteresis and exhibit high strength.

The tissue compatibility invention spongiosa blocks having a dimension of 0.5 x 0.5 x 1 cm, made according to the embodiment has been tested in experiments with rats, the small blocks implanted subcutaneously on the rats back, taken after various times, fixed, and were processed histologically.

It was found that non-crosslinked spongiosa blocks stronger inflammatory reactions, more foreign body giant cells, more fibrosis and already after 14 days showed approaches to absorption and after 4 weeks occurred significant degradation signs. By contrast, could be detected in the inventively treated samples no such side effects.