DE3435771A1 - BONE MATRIX AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

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Bone matrix and process for making it

The present invention relates to an improved bone matrix and a method of making it, wherein this improved bone matrix is designed so that it stimulates the reconstruction, regeneration and ingrowth of bone, tooth and cartilage material and promotes. The bone matrix of the present invention is useful and useful in the fields of surgery and dentistry has a structure and composition similar to that of natural bones and teeth. The inventive Bone matrix can be used in healing procedures for the orthopedic reconstruction of bone parts.

Compared to a known type of bone matrix, the bone matrix according to the invention solves the task of ingrowth and to better stimulate the restoration of the natural bone structure.

This object is achieved by a bone matrix as described in the claims. The procedure too their production is characterized by the features given in the claims, with the following Further details can be found in the description.

The present invention is that in a bone or a bone matrix prior to their surgical

go implanting a multitude of artificial holes or perforations designed to facilitate cell and blood vessel ingrowth after implantation and the ability of the implanted material to induce bone and cartilage formation.

QC increase significantly and bone regeneration too stimulate.

As is well known, bones and teeth are composed of a matrix - an organic material that is composed of collagen-like Pibrils and a binding substance consists of mucopolysaccharides, as well as of the inorganic component, namely calcium phosphate in the form of hydroxyapatite. The organic matrix is made of filiform Molecules formed, which are arranged parallel to each other. Furthermore, the tissue is made up of numerous microscopic capillaries .through which opposite the thread-like molecules in different directions are oriented.

It is known that when the inorganic component is partially or completely from the bone or Tooth is removed, the remaining organic bone material called the bone matrix is another 'Living animals or human bodies can be transplanted without causing any significant harm Impact is coming. Consequently, due to its ability to stimulate and stimulate reconstruction, the bone matrix is Regeneration and ingrowth of bone tissue after its implantation in a body part used in modern medical procedures.

While in the prior art the need for methods and materials for stimulation and excitation Reconstruction, regeneration and ingrowth of bone was recognized, it has not yet been recognized that the artificial creation of holes or perforations provided according to the invention is useful for these goals.

U.S. Patent 3,458,397 (Myers) relates to a method for making an osteogenic material from animal bone tissue. The osteogenic material is injected into an animal for the purpose of inducing bone formation. In this procedure, the bone is put in with pepsin

an acidic solution grind and digested, extracted and pleases. In the patent mentioned there is no suggestion whatsoever to create artificial holes in the bone matrix Mistake.

U.S. Patent 4,294,753 (Urist) discloses a method that uses morphogenic bone proteins for the separation of proteins from bone tissue. As in the previous one In this case, the bones are ground and the bone tissue is demineralized. The demineralized Bone tissue is then in an aqueous solution with a water-soluble neutral salt and an agent for Treated increase in solubility. The neutral salt and the solubilizing agent are then separated, and that Morphogenic bone protein is precipitated. Again there is no evidence of the creation of artificial ones Holes.

U.S. Patent 2,621,145 (Sano) relates to bone mat compositions and includes bone particles which are then bound in a fibrous network. That leads to Making a bone mat or matrix supported by a carrier strip that is said to be that it consists of a flexible plastic material. The one described in this publication. Process results in the production of a flexible tape for use in US Pat bone surgery and bone regrowth promotion, and it includes a variety of so-called "Uncooked" particles of ground whole go bones held in a fibrous network. This reference does not see the creation of holes in the bone mat composition or the fibrin network as described below.

U.S. Patent No. 2,968,593 (Rapkin) describes a method of making an inorganic bone material by

. l heating an animal bone material in a liquid to a temperature of about 8O ⁰ C to about 100 ⁰ C, drying of the heated bone material, the most extensive degreasing with a fat-extracting solvent, and removing the organic matrix from the defatted bone material, for example by extraction with ethylenediamine> to get the inorganic matrix. Such an inorganic bone material, free of organic matter, is used for transplantation from an animal of one species to an animal of another species without any negative effects being obtained. However, there is no provision for holes or perforations to be formed in the inorganic bone material produced in this way.

U.S. Patent 4,172,128 (Thiele et al) relates to a method for degrading / regenerating bone and tooth material. This document describes a method for producing a bone material which is implanted in a specific area in order to stimulate bone growth. According to this document, the bone material is first ground, after which the organic matrix of the bone is demineralized. ¹ A colloidal solution of the organic matrix is formed, after which ions are diffused into the colloidal solution to produce a gel. Although it appears that the substance produced in this process is used for osteogenesis, no teaching is given to artificially cover such a substance with holes or openings

3Q provided.

As already mentioned in the introduction, it is an object of the present invention to provide a new method for Making a bone matrix to promote bone 3g formation with ingrowth and stimulation of bone regeneration indicate if the bone mass produced

trixin orthopedic restoration procedures will. The solution consists in the formation of a large number of artificial holes or perforations in the the bone matrix, creating the artificially perforated bone matrix is well accepted by the body and is natural in terms of its composition and structure Corresponds to bones and teeth.

The bone matrix according to the invention can be used in a new Method for the orthopedic restoration of skeletal parts can be used in an advantageous manner.

Further tasks and solutions will become apparent to those skilled in the art from the description below.

In principle, according to the invention in a method for Production of a bone matrix for surgical implantation carried out an additional improvement step, which consists in that, prior to surgical implantation of the bone matrix by a surgeon, in this forms a multitude of artificial holes or perforations.

The invention will now be described with reference to several Figures explained in more detail.

Show it:

1 shows a side view of a bone matrix with 3Q a plurality of artificially created holes;

1a. A side view of an alternatively designed Bone matrix with a multitude of artificially created holes;

Fig. ' 1b is a side view of a further alternative

executed bone matrix with a multitude of artificially created holes, which with regard to their sizes and shapes vary;

Fig. 2 is a side view of an artificially perforated one

Bone matrix, as well as a bone with a defect in the form of a cavity, is shown is like the bone matrix according to the invention

IQ for tamponade or to close the bone

defective or void can be used;

Fig. 3 is a side view showing a bone with a

Gap defect and one arranged in this gap artificially perforated bone matrix

shows bridging the bone gap; and

Fig. 4 is a side view showing a bone with

shows a break at which an artificially per-2Q forated bone matrix is arranged to

induce bone repair and reconstruction to close the fracture.

Referring to the figures, wherein like numerals indicate like elements, the present invention relates to Invention an improved method for producing a bone matrix for surgical procedures, wherein in the method according to the invention an additional step for forming a plurality of artificial holes QQ in the bone, bone material or the bone matrix is provided prior to its implantation.

The bone matrix may be prepared using any known method of the prior art O ₅ have been that any arbitrary combination can include the following steps.

- ΟΙ A bone or bone material is obtained from any vertebrate animal. It can then be preserved by any known preservation method. To achieve decalcification, partial or complete demineralization of the bone or bone material is carried out, treatment with various acids, gelling agents, by electrolysis or with any combination of these measures being carried out. Finally, either before or after the demineralization of the bone, bone material or the bone matrix, fixation and various physical and chemical processing takes place. The produced bone, bone material or bone matrix 2 shown in Fig. 1 is then processed so that a plurality of artificial holes 4 are formed therein.

The multiplicity of holes 4 can be made in the bone matrix 2 by drilling, with the aid of a laser, by puncturing or by a similar process. The holes 4 can have various shapes, such as for example circular, triangular, polygonal, irregular, slot-like or combined in any way be, this list is not exhaustive

The number of holes 4 in the bone matrix 2 can vary. However, a large number of holes work a substantial increase in the ability of the perforated bone matrix to induce bone formation or stimulate bone regeneration, which, within a specific range, proportional to the number, Appear to be the size and location of the individual holes in the bone matrix.

The individual holes in the bone matrix also do not have to be of uniform size or shape. Figure 1b shows an alternatively shaped bone matrix 6 with a multiplicity of holes 8 of different shapes and sizes. It should be noted, however, that holes with a maximum diameter of 0.25 mm to 1.0 mm holes are more optimal Size represent, 'umi a considerable increase in Ability of the artificially perforated bone matrix to induce bone formation or stimulate the To effect bone regeneration.

Similarly, the holes need not be evenly distributed over the surface of the bone matrix. One a higher concentration of the holes in a given surface area of the bone matrix even causes increased stimulation of bone growth or regeneration in this particular area compared to other areas with a lower concentration of holes. This effect is particularly important with orthopedic procedures of use in which the artificially perforated bone matrix rests on the existing bone, as is the case with a Tamponade or when closing any bone defect or a cavity is the case, or in methods of bridging gaps in bones.

'

More precisely, FIG. 2 shows a tamponade situation, 'at

a bone matrix 10 having a plurality of artificial holes 12 which are provided on the sides 14, 16 and 18 of the bone matrix 10, which rest on the bone 20 heaped on. Fewer holes 12 are provided in the bone matrix 10 between the sides 14 and 16.

Similarly, 3 is in surgical procedures for bridging bone voids, as shown in Fig., _Oc a bone matrix 22 is used, comprising a plurality of artificial holes 24 at or near

Pages 26 and 28 are clustered, while between pages 26 and 28 the holes are less concentrated. The bone 30 is also shown.

Fig. 4 shows how part of a perforated bone matrix 40 is used to treat situations in which a bone fracture 42 occurs in a bone 44.

^ ^N these or similar cases, results in a higher accumulation of holes near or in the sides of the bone matrix, which bear against the existing bone structure, an increase in bone formation, ingrowth and regeneration in these more perforated regions of the bone matrix over other less perforated areas. In this way, by increasing bone formation, ingrowth or regeneration in such contact surfaces, the perforated bone matrix will adhere more quickly to the existing bone structure, so that the bone defect, the cavity or the gap are closed in a reliable manner.

The perforated bone matrix produced according to the teaching of the present application can be used in surgery for treatment acute fractures and old non-healing fractures can be used. The perforated bone matrix can also be used for tamponade or the closure of any bone defect or cavity 3Q will be. The following exemplary embodiments illustrate the present invention without describing it in a restrictive manner.

example 1

A laboratory test was carried out to investigate the induction of bone formation by implantation of a perforated To examine the bone matrix in laboratory test animals. A perforated bone matrix was constructed according to the teaching of of the present invention and implanted subcutaneously lateral to the edge of the sternum of each laboratory test rat, which had been selected to form a test group.

A sample of laboratory rats was obtained 4 days after the implantation procedures were completed The experimental group was established and samples were taken from the implantation site. During the microscopic examination it has been found that an accumulation of newly formed in the perforations or holes of the implanted bone matrix undifferentiated cells with high alkaline phosphatase activity in their cytoplasm was created.

7 days after the end of the implantation, another sample of laboratory rats was prepared from the experimental group, and samples were taken from the implantation site. During the microscopic examination it was found that between the young undifferentiated cells filling the holes there were few differentiated cartilage cells and fibroblasts. It was found that in comparison with the previous Observation from the 4th day an increased alkaline phosphatase activity was obtained.

2 weeks after the end of the implantation, another sample was prepared from laboratory rats from the test group, and samples were taken from the implantation site. During the microscopic examination it was found

"Ιοί put that there was some matrix resorption around the edge of the holes with simultaneous replacement of the bone matrix material by cartilage cells and osteoblasts was. The holes were filled with newly formed bone "trabeculae" covered with osteoblasts. The trabecular bone was interspersed with islands of cartilage tissue and newly formed blood vessels. also was the alkaline phosphatase activity in the cells filling the holes is very high.

1 month after the completion of the implantation, a sample of laboratory rats of the experimental group was prepared, and it samples were taken from the implantation sites. During the microscopic examination it was found

IQ that most of the implanted perforated bone matrix had been resorbed and replaced by newly formed trabecular bone interspersed with occasional islets of cartilage tissue. The newly formed trabecular bone was not restricted to the previously implanted perforated bone matrix, but could also be recognized outside this area and was surrounded by a capsule that represented the periosteum.

Example 2

In this experiment, the stimulation of bone regeneration by the implantation of a perforated Examined bone matrix. To form a test group different laboratory rabbits were selected.

₃ Q in each rabbit was a piece of the ulna bone of about 1.5 to 2 cm from the central region of the ulna bone away, and there was einge- a fragment of the perforated bone matrix, the teachings of the present invention was prepared according to the flaw

gc sets. Follow-up x-rays taken immediately after the implantation had been included, left the

-14-Bone Defects Clearly Recognize.

A week after the implantation left an X-ray examination can still clearly see the defect in the elbow bone at the implantation site. It was made from a sample of rabbits of the test group and samples were taken from the implantation site. At the microscopic underestimation it was found that all holes of the implanted perforated bone matrix with young undifferentiated Cells were filled with high alkaline phosphatase activity.

Two weeks after implantation, an x-ray showed some mineralization in the area the implanted perforated bone matrix. A sample of rabbits taken from the test group was prepared and samples were taken from the implantation site. During the ■ microscopic examination it was found that all holes were filled with cartilage cells interspersed with newly formed bone trabeculae was.

One month after the implantation, an X-ray examination showed that mineralization of the implanted perforated bone matrix had occurred. A sample of Experimental group rabbits were prepared and samples were taken from the implantation sites. On microscopic examination it was found that there was resorption of the implanted perforated

QQ bone matrix had come, with the resorption of Centers around the holes spreading. It was also found that the implanted bone matrix by a newly formed trabecular bone that was connected to the trabecular bone that was replaced by grew from the ends of the bone fragments.

Two * months after the implantation, an X-ray examination showed that the fault in the elbow bone of the experimental

rabbit had been replaced by a highly mineralized bone tissue. A final sample from rabbits The test group was prepared and samples were taken from the implantation site. At the microscopic Analysis found that the defect in the elbow bone was now filled, with the bone being new had been shaped.

Example 3

In this experiment, the induction of bone formation by a perforated bone matrix was investigated, the Had holes of various sizes.

As in Example 1, in accordance with the teaching of present invention produced a bone matrix, wherein holes of different diameters produced were: 0.25mm, 0.35mm, 0.5mm, 0.75mm, 1.0mm, 1.25mm, 1.5mm and 2.0mm. The perforated bone matrix was subcutaneously as described in Example 1, laboratory rats implanted. A sample of laboratory rats was taken at different times after the implantation from the experimental group and samples were taken from the implantation sites. the microscopic examination of the implanted bone matrix showed that the most active bone formation process in such specimens could be seen in which the diameter of a hole was in the range of 0.25 to 0.5 mm. At rehearsals with a perforation diameter of 0.75 to 1.0 mm, the osteogenic processes were somewhat less active while in samples with a perforation diameter of 1.25 to 2.0 mm the osteogenesis was even lower than in the last mentioned group.

Example 4

In this experiment the induction of bone formation was used examined through a perforated bone matrix with a different perforation density.

Different test groups were formed, each comprising a number of laboratory rats. As already described, a perforated bone matrix was prepared and each laboratory rat of each corresponding test group implanted subcutaneously.

In the first group, a perforated bone matrix was used, which had perforations with a diameter of 0.25 mm. The number of perforations per cm ² was 25. The calculated sum of the perforated surface was 1.23% of the total surface of the perforated bone matrix. When examined microscopically, this perforated bone matrix showed high osteogenic activity.

For the second group, a perforated bone matrix was used, which had perforations with a diameter of 0.35 mm. The number of perforations per cm ² was about 20. The calculated sum of the perforated surface was 1.92% of the total surface of the perforated bone matrix. When examined microscopically, this perforated bone matrix showed high osteogenic activity.

For the third group, a bone matrix with perforations with a diameter of 0.5 mm was used. The number of perforations per cm ² was about 16. The calculated sum of the perforated surface was 3.14% of the total surface of the perforated bone matrix. When examined microscopically, this perforated bone matrix showed high osteogenic activity.

3435771 -πι For the fourth test group, a bone matrix with perforations with a diameter of 0.75 mm was used. The number of perforations per cm ² was about 12. The calculated sum of the perforated surface was 5.3% of the total surface of the perforated bone matrix. A microscopic examination of this perforated bone matrix revealed an osteogenic activity which was somewhat lower than in the previous three test groups.

For the fifth experimental group, a bone matrix with perforations with a diameter of 1.0 mm was used. The number of perforations per cm ² was about 8. The calculated sum of the perforated surface was 6.28% of the total surface of the perforated bone matrix. A microscopic examination of this perforated bone matrix revealed an osteogenic activity that was also somewhat lower than in test groups 1 to 3.

For test group 6, a bone matrix with perforations with a diameter of 1.25 mm was used. The number of perforations per cm ² was about 6. The calculated sum of the perforated surface area was 7.36% of the total surface area of the perforated bone matrix. Upon microscopic examination, this bone matrix revealed an osteogenic activity that was considerably lower than that found for test groups 1-5.

For test group 7, a bone matrix with perforations with a diameter of 1.5 mm was used. The number of perforations per cm3 was about 4. Die The calculated sum of the perforated surface was 7.06% of the total surface of the perforated bone matrix. On microscopic examination this showed, per-

formed bone matrix had an osteogenic activity that was considerably lower than that observed for test groups 1 to 5.

For test group 8, a bone matrix with perforations with a diameter of 2.0 mm was used. The number of perforations per cm ² was about 3. The calculated sum of the perforated surface was 9.42% of the total surface of the perforated bone matrix. When examined microscopically, this bone matrix showed very low osteogenic activity.

The present invention thus relates to an artificially perforated bone matrix and a method for its production, those for stimulating the induction of bone formation and for stimulating bone regeneration suitable is. According to the invention, a large number of perforations are made in the bone matrix before it is implanted or holes formed. These perforations facilitate the ingrowth of cells and blood vessels implantation of the bone matrix and increase its ability to induce bone formation and to Significant stimulation of bone regeneration.

While the present invention has been described in this specification by way of example, it should be understood for those skilled in the art that numerous other modifications and Variations are conceivable, all of which fall within the scope of the present invention or the claims.

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Claims (13)

Dipl.-Chem. Dr. Equip ANDRAE DipJ.-Phys. Dieter FLACH Dipi.-mg. Dietmar HAUG 2 8, Sep. 1984 Dtol.-Chem. Dr. Richard KNEISSL PATENTANWÄLTE Steinstr. 44, D-8G00 Munich 80 Note: Dr. El GENDLER Los Angeles, California 90035, V.St.A. . Az: 257 / AS / sc bone matrix and process for their production claims 1. Bone matrix for surgical implantation, thereby characterized 'that it has a plurality of artificially created holes. 2. Bone matrix according to claim 1, characterized in that the holes have a regular cross section. 3. Bone matrix according to claim 1, characterized in that that the holes have an irregular cross-section. 10 Ά. Bone matrix according to one of Claims 1 to 3, characterized in that the holes are distributed evenly through the entire bone matrix. 15. * bone matrix according to one of claims 1 to 3, characterized characterizedι that the holes in at least one Area of the bone matfix are executed heaped. 6. bone matrix according to one of claims 1 to 5, characterized characterized in that the holes have a triangular shape exhibit. ^: 7. bone matrix according to one of claims 1 to 5, characterized in that the holes are polygonal Have shape. 8. bone matrix according to one of claims 1 to 5, characterized in that the holes are irregular Have shape. ' . 9. bone matrix according to one of claims 1 to 5, characterized in that the holes have a slot-like shape. 10. Bone matrix according to one of claims 1 to 5, characterized in that the holes are circular. 11. Bone matrix according to one of claims 1 to 10, characterized in that the diameter of the holes 0.25 to 1.0 mm, preferably 0.25 to 0.75 mm. 12. Method of preparing a bone matrix for surgical use. Implantation, characterized in that a plurality in a bone matrix produced in a manner known per se before it is surgically implanted artificial holes is created. 13. The method according to claim 12, characterized in that that the holes are produced by drilling, puncturing or using a laser.