Thin-film multichamber structures made of collagen element of tissues regeneration containing it and method for its production

FIELD: medicine.

SUBSTANCE: thin-film multichamber structure, made of collagen is used as an element for tissues regeneration, thus it is possible to enhance the stimulation of regeneration, to reduce treatment period, to accelerate the functional recovery and to achieve similar effects with regard to body tissues such as nervous tissue, subdermal tissue submucosa tissue, membranous tissue, adipose tissue, muscle tissue, skin tissue and gum tissue. Moreover, when the structure is used for patients with neuropathic pain, it leads to disappearance of pain.

EFFECT: obtaining new structure made of collagen to increase the stimulation of regeneration of nerve tissue, healing and regeneration of the soft biological tissue having defects, etc without the use of laminin, or nerve growth factor (NGF), and an element for the regeneration of tissue, including it.

12 cl, 21 dwg, 12 ex

 

The technical field

The invention relates to multi-cell thin-film structure made of collagen, the member for tissue regeneration containing it, the various props used for this item for tissue regeneration, and to the way it was received. More specifically, the present invention relates to an element for the regeneration of nerve tissue containing thin-film multi-cell structure made of collagen and the way it is received, including lyophilization of a solution of collagen.

Prior art

In the United States are already commercially available tube for connection of the nervous tissue through the use of collagen in the form of a guide element for the regeneration of nerves NeuraGen (trade name) from the company Integra NeuroCare LLC, USA, and tubing to connect the nervous tissue through the use of polyglycolic acid (PGA) is available in the form of GEM Neurotube (trade name) from Synovis Micro companies Alliance, USA. These tubes to connect the neurons are not filled inside the hollow tube, and can be used for regeneration of peripheral sensory nerve, in which the length of having the defect part of the nerve tissue is up to 2 cm When the hollow tube implanted in the defect part of the fabric of the nerves, with the defect parts of the tissue regenerated nerve fibers.

However, when having the defect part of the fabric longer than 2 cm, the tube for the connection of the nerves is limited. This is because the hollow tube has a low potential for promoting nerve regeneration, it is quickly destroyed and therefore there are problems, because the hollow tube cannot be used for a longer having the defect parts of the fabric. In addition, available in the US hollow tubes there is a problem, which is that if there is a mismatch between the opening end of the hollow tube and the bore of the end of the nerve trunk, between the two holes creates a gap, and therefore a gap is introduced surrounding tissue, inhibiting the promotion of nerve tissue that inhibits the development of nerve regeneration. In addition, there is a problem, which is that when having the defect part of the fabric of the peripheral nerve branches, you cannot use one hollow tube and the operation of implantation becomes problematic. There is another problem, namely that the possibility of preservation of the lumen of the hollow tube is insufficient. Therefore it is impossible to restore the long part of the nerve that has a defect in tissue, the nerve may not increase, and the regeneration is terminated. In addition, there is a problem that depends on the use of the tube, when both ends of the nerve cannot be inserted into the tube for nerve.

N which long ago was made of artificial neural tube made of biodegradable, absorbable material (such as polylactic acid and polyglycolic acid), containing in the tube this sponge-like or gel-like collagen. For example, in patent document 1 (WO 98/22155) disclosed artificial neural tube containing a gel comprising collagen and laminin, in a tube made from a biodegradable, absorbable material, such as polylactic acid and polyglycolic acid).

In patent document 2 (patent application in Japan (Kokai) No. 2003-019196, the examination was not conducted) expands the tube for nerve regeneration, which is made of an outer layer of a biologically absorbable material, such as polylactic acid) and an inner layer made of this sponge-like substance collagen and copolymer of lactic acid/ε-caprolactone.

In patent document 3 (patent application in Japan (Kokai) No. 2004-208808, the examination was not conducted) revealed inductive tube for nerve regeneration, containing this sponge-like collagen inside the tubular body, made of a biodegradable material or a biologically absorbable material (such as a protein, polysaccharide, polylactic acid and polyglycolic acid).

In patent document 4 (application for Japan patent (Kokai) No. 2005-143979, the examination was not conducted) expands the tube d is enerali nerves, in which such fiber synthetic biologically absorbable polymer such as polylactic acid and polyglycolic acid)coated with collagen, is filled inside the tubular body, made of a biologically absorbable polymer material (such as polylactic acid and polyglycolic acid).

In non-patent document 1 (Lee D.Y. et al., Journal of Cranio-Maxillofacial Surgery (2006) 34, 50-56, “Nerve regeneration with the use of a poly-L-lactide-co-glycolic acid-coated collagen tube filled with collagen gel”) is disclosed artificial neural tube containing gel-like collagen, in a tubular casing made of polylactic acid and polyglycolic acid.

In patent documents 1 to 4 and non-patent document 1 collagen with this sponge-like, gel-like or similar to the fiber structure incorporated in biodegradable material of the tubular body and therefore, in comparison with a hollow body that does not contain collagen, collagen serves as a so-called cellular scaffold for the regeneration of nerve tissue, and, through this, has the advantage consisting in the fact that largely stimulated the regeneration of nervous tissue.

However, there is a growing need not only to stimulate the regeneration of nerve tissue and promote tissue regeneration, but also in improving clinical functions by accelerating in which Stanovlenie physiological functions of the nervous tissue. In addition, there are problems lies in the fact that clinical application is impossible, because it uses laminin, which is a physiologically active substance, which has yet to be established; that the tube cannot be used for longer defective parts due to rapid destruction of the tubes; it creates a gap, if there is a difference openings between artificial nerve and cut off the end of the nerve; that the handset cannot be used if there is a fork; the preservation of the lumen of the hollow tube is insufficient; that in some cases both ends cannot be inserted in the neural tube.

Description of the invention

The present invention was created to resolve the above problems, and an object of the present invention is the provision of a new structure made of collagen, to improve the stimulation of regeneration of nerve tissue healing and regeneration of having the defect part of the soft biological tissue, and so forth without the use of laminin or nerve growth factor (NGF).

In addition, the present invention is the provision of an element for tissue regeneration to facilitate or, preferably, essentially eliminating at least one of the problems lies in the fact that the tube cannot be used for more than the long defective parts due to rapid destruction of the tubes; it creates a gap, if there is a difference openings between artificial nerve and cut off the end of the nerve; the tube cannot be used if there is a fork; the ability to save lumen of the hollow tube is insufficient; in some cases both ends cannot be inserted in the neural tube.

Another objective of the present invention is the provision of a support used for such element for tissue regeneration, and to the way it was received.

In addition, another objective of the present invention is the provision of a new structure made of collagen, the member for tissue regeneration containing it, a support used for a member for tissue regeneration, and the method of obtaining the above-described member for tissue regeneration.

The applicants have carried out extensive studies to solve the aforementioned problems and, as a result, surprisingly found that the collagen has a specific form that you can use to improve the stimulation of regeneration, shortening of the period of recovery, functional recovery, or similar effects in relation to body tissues, such as nervous tissue, subdermal tissue, submucosal tissue, membranous tissue, adipose tissue, muscle tissue, skin tissue and the tissue of the gums, and the above problems can be solved by using collagen with such specifications shall ical form, and thus was established the present invention.

That is, in one aspect the present invention provides a new structure made of collagen, and this structure is a thin-film, multi-cell structure made of collagen.

In another aspect the present invention provides an element for tissue regeneration containing the above-described thin-film, multi-cell structure.

In one embodiment, the present invention provides an element for tissue regeneration, in addition, includes a biodegradable support.

In a preferred embodiment, the present invention provides a member for tissue regeneration having the above-described thin-film, multi-cell structure inside the tubular biodegradable support.

In addition, the applicants have carried out extensive studies and, as a result, found that by using biodegradable support having a broken U-shaped or C-shaped form (namely, in the General shape of the gutter), the tubular structure is not required for the regeneration of nerve tissue in the fascia or on the floor of the body or in similar areas, and easier operation with suturing, and shortened the duration of the operation.

That is, in another preferred embodiment, Khujand is the implementation of the present invention provides an element for tissue regeneration, with the above-described thin-film, multi-cell structure inside the tubular biodegradable support having the form of a trough with a U-shaped or C-shaped in cross section.

In addition, the applicants have carried out extensive studies and, as a result, found that by using biodegradable support having branching in the defective part of the peripheral nerve, for defective parts sufficient one hollow tube.

That is, in another embodiment, the present invention provides the above-described member for tissue regeneration, in which the biodegradable support is branching.

In addition, the applicants have carried out extensive studies and, as a result, found that when using tubular or shaped gutter supports, having the distinction of holes between the hole at one end biodegradable support and opening its other end, a gap between the element for tissue regeneration, in which the bearing is used, and nervous tissue is not generated.

That is, in another embodiment, the present invention provides the above-described member for tissue regeneration having the distinction of holes between the hole at one end biodegradable support and opening its other end.

In addition, applicants who polnyi extensive research and as a result, found that when using a biodegradable support, in which the rate of decomposition of the biodegradable support having a tubular or globoidal form, is modified so that the rate of destruction of the ends is higher than the rate of destruction of the Central part, the outer wall around the part, in which occurred the regeneration of nervous tissue, successively decomposes, and therefore nutrients enter the regenerated nerve from the environment, and the item is removed by repeated operation is not required.

That is, in another embodiment, the present invention provides the above-described member for tissue regeneration, in which the rate of decomposition of the biodegradable support having a tubular or globoidal form, is modified so that the rate of destruction of the ends is higher than the rate of destruction of the Central part.

In addition, the applicants have carried out extensive studies and, as a result, found that when using a biodegradable support, in which the structure having a hollow internal space, continuing the mixing of raw material, which is slowly degraded in vivo, with raw material, which is rapidly degraded in vivo to delay its degradation in vivo, the degradation rate of biodegradable support becomes IU is feudal (or inactive), and the structure having a hollow interior space is maintained for a longer period if the defects are part of the fabric long.

That is, in the preferred embodiment, the present invention provides a member for tissue regeneration including biodegradable support, in which the structure having a hollow interior space, with tubular or globoidea form, supported by mixing raw material, which is slowly degraded in vivo, with raw material, which is rapidly degraded in vivo to delay its degradation in vivo.

Preferably, biodegradable bearing, in which the structure having a hollow interior space that is saved by delaying decomposition in vivo, was used in combination with the above-described biodegradable support, the rate of decomposition is higher than the rate of decomposition of the material located closer to both ends from the Central part. That is the preferred element for tissue regeneration, including biodegradable support, in which the rate of decomposition of biodegradable support the higher, the closer to both end portions from the Central portion, and in which the structure having a hollow interior space, supported by the mixing of raw material, which slowly once Agueda in vivo, with raw material, which is rapidly degraded in vivo to delay its degradation in vivo. Thus, there is a member for tissue regeneration including biodegradable support, in which the structure having a hollow interior space remains in the Central part with the Stripping element for tissue regeneration with ends in vivo.

That is, in one preferred embodiment, the present invention provides the above-described member for tissue regeneration, in which the rate of decomposition of the biodegradable support having a tubular or globoidal form changed so that the rate of decomposition of the ends was higher than the rate of decomposition of the Central part of in vivo and in which the structure having a hollow interior space inside the tubular or globoidea form, supported by mixing raw material, which is slowly degraded in vivo, with raw material, which is rapidly degraded in vivo to delay its degradation in vivo.

Member for tissue regeneration according to the present invention are not specifically limited in relation to be using cloth until the item can be used for body tissues and may contribute to tissue regeneration. More preferably used for the regeneration of nerve tissue.

In others the GOM aspect of the present invention provides a method of obtaining the above-described thin-film multi-cell structure, providing for the lyophilization of a solution of collagen.

In another preferred aspect of the present invention is a method of obtaining element for tissue regeneration involves the immersion of biodegradable support, retaining the above-described thin-film multi-cell structure in a solution of collagen and then lyophilization of a solution of collagen.

Structure made of collagen according to the present invention has a multi-cell thin-film formation (structure or form) and therefore a new structure that is different from the shape of the colloid, the form of gel and form fibers. Therefore, when a new structure made of collagen according to the present invention, is used as the element for tissue regeneration, then, amazingly, can improve the stimulation of regeneration, shortened the treatment period, to accelerate functional recovery, or you may have similar effects on the body tissues, such as nervous tissue, subdermal tissue, submucosal tissue, membranous tissue, adipose tissue, muscle tissue, skin tissue and tissue of the gums.

In addition, when the above-described member for tissue regeneration includes biodegradable support, it is possible to protect the underlying tissue regeneration.

When the member for regeneration in accordance with the present what Subramaniam has the above-described thin-film multi-cell structure inside the tubular biodegradable support, the more effectively can be regenerated fibrous and long linear fabric.

When the member for regeneration in accordance with the present invention has the above-described thin-film multi-cell structure within the biodegradable support having the form of a trough with a U-shaped or C-shaped cross-section, can easily be tissue regeneration, available on the flat parts, such as the muscle fascia or on the capsule body.

When biodegradable bearing has a branching element for tissue regeneration in accordance with the present invention, the fabric having a fork, can be regenerated one element for tissue regeneration.

If there is a difference openings between the opening of one end of the biodegradable support and opening its other end the member for tissue regeneration according to the present invention, it is possible to avoid the formation of a gap between the hole of the member for tissue regeneration and the opening of the defective portion of tissue.

When the member for tissue regeneration according to the present invention includes a biodegradable support having a tubular or globoidal the form in which the rate of decomposition of biodegradable support is modified so that the rate of destruction of the ends is higher than the speed destroyed the I Central part, the tissue regeneration is improved and does not require removal of the element of re-operation.

Preferably, for tissue regeneration, has long defective part, the member for tissue regeneration according to the present invention include biodegradable support, in which the structure having a hollow interior space inside the tubular or globoidea form, was preserved by mixing raw material, which is slowly degraded in vivo, with raw material, which is rapidly degraded in vivo to delay decomposition in vivo, because the structure having a hollow interior space, is stored for a long period.

Member for tissue regeneration according to the present invention can be used for nervous tissue, subdermal tissue, submucosal tissue, membranous tissue, adipose tissue, muscle tissue, skin tissue, gum tissue, etc. and, in particular, it is preferable to use an element for the regeneration of nervous tissue.

In addition, in accordance with the method of obtaining the above-described new structure of collagen in accordance with the present invention, the structure can be obtained by lyophilization of a solution of collagen and therefore it is very simple and easy to get new collagen structure.

In addition, in the method of obtaining a new item for the reg is erali fabric in accordance with the present invention can obtain a very simple and easy to implement by lyophilization of a solution of collagen in the state, when the above-described bearing is immersed in a solution of collagen.

Brief description of drawings

In Fig. 1(a) shows a micrograph obtained by scanning electron microscope at low magnification (about ×80), thin-film multi-cell structure made of collagen according to the present invention.

In Fig. 1(b) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×250), a thin-film multi-cell structure made of collagen according to the present invention.

In Fig. 1(C) shows a micrograph obtained by scanning electron microscope at high magnification (about ×5000), thin-film multi-cell structure made of collagen according to the present invention.

In Fig. 1(d) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×400), a thin-film multi-cell structure made of collagen according to the present invention.

In Fig. 1(e) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×300), multi-cell thin-film patterns made of to the of Laguna, in accordance with the present invention.

In Fig. 2(a) shows a micrograph obtained by scanning electron microscope (magnification of about ×20), cross section of one example of the tubular member for tissue regeneration including the thin-film multi-cell structure made of collagen according to the present invention.

In Fig. 2(b) shows a micrograph obtained by scanning electron microscope (magnification of about ×100), a longitudinal section of one example of the tubular member for tissue regeneration including the thin-film multi-cell structure made of collagen according to the present invention.

In Fig. 3 shows one example of the member for tissue regeneration globoidea shape having a U-shaped cross-section.

In Fig. 4 shows one example of compounds having the defect part (or defect) with a length of 1 cm of the sciatic nerve in rats using element for tissue regeneration having U-shaped cross-section.

In Fig. 5 shows one example of the tubular member for tissue regeneration having a Y-shaped branching.

In Fig. 6 shows a narrowing of the tubular member for tissue regeneration as one example of the member for tissue regeneration having the difference between the CTE is rstam one end and a hole on the other end.

In Fig. 7 schematically shows the tubular element for tissue regeneration, which is rapidly degraded at both ends and slowly in the Central part, and schematically illustrates the regeneration of tissue by use of the element.

In Fig. 8 shows the dependence of the tensile strength (average) of the deformation element of the PGA-PLA for tissue regeneration (including 50% PLA).

In Fig. 9 shows the dependence of the tensile strength (average) of the deformation element of the PGA for tissue regeneration.

Fig. 10 is a schematic view for explaining deformation and strength, as shown in Fig. 8 and 9.

In Fig. 11(a) shows a micrograph obtained by scanning electron microscope at low magnification (about ×80), one example of collagen in the form of a sponge.

In Fig. 11(b) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×150), one example of collagen in the form of a sponge.

In Fig. 11(c) shows a micrograph obtained by scanning electron microscope at high magnification (about ×3000), one example of collagen in the form of a sponge.

In Fig. 12(a) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×400), one example of collagen in the form of a sponge.

On the IG. 12(b) shows a micrograph obtained by scanning electron microscope at high magnification (about ×1000), one example of collagen in the form of a sponge.

In Fig. 13(a) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×125), one example melkopomolotogo collagen.

In Fig. 13(b) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×400), one example melkopomolotogo collagen.

On Fig(a) shows a micrograph obtained by scanning electron microscope at low magnification (about ×30), one example melkopomolotogo collagen.

On Fig(b) shows a micrograph obtained by scanning electron microscope with an average magnification (about ×300), one example melkopomolotogo collagen.

The best way of carrying out the invention

Further, the present invention will be more specifically and in detail explained with reference to the accompanying drawings. These descriptions are intended only to explain the present invention, and it should be understood that these descriptions have no intention to limit the present invention.

The present invention provides a structure made of collagen which, and it is a thin-film, multi-cell structure.

In the present invention "collagen" in General is called "collagen" and is not specifically limited as long as possible to get "thin-film, multi-cell structure desired in accordance with the present invention. Such a "collagen" includes collagen derived from cows, pigs and people, but especially preferred atelocollagen having low antigenicity.

In the present invention, thin-film, multi-cell structure is essentially composed of thin collagen in the form of a film and has a structure that includes multiple cells<or cameras) between thin films. In Fig. 1(a)-1(e) are shown obtained with a scanning electron microscope micrograph of thin-film, multi-cell structure made of collagen according to the present invention. For the Fig. 1(a)-1(C) accelerating voltage scanning electron microscopy is 20 kV. In Fig. 1(a) shows the image with a small increase (approximately h), Fig. 1(b) shows the image with a medium magnification (about ×250), and Fig. 1(C) shows the image with high magnification (about ×5000). In addition, for Fig. 1(d)-1(e) accelerating voltage scanning electron microscopy is 18 kV. In Fig. 1(d) shows the image with the average increase is observed (approximately ×400), and in Fig. 1(e) shows the image with a medium magnification (about ×300). "Thin-film, multi-cell structure made of collagen, made from a variety of thin films, the surfaces of which are flat, such as "pie of Western confectionery", and it should be understood that it is not included collagen formed in the form of fibers.

The film thickness of the thin film is preferably from 0.01 to 200 microns and preferably from 0.1 to 50 μm and particularly preferably from 0.5 to 5 μm. In addition, the intervals between films, "thin-film, multi-cell structure" includes, for example, from about 50 μm to about 3 mm, and preferably from 300 μm to 2000 μm. Botryoidal a space formed by a thin film may be continuous or closed.

In the prior art as a structure made of collagen, a famous structure in the form of a sponge structure in gel form and structure in the form of fibers, but the above thin-film, multi-cell structure is unknown and was first discovered by applicants.

Examples of patterns in the form of sponges and patterns in the form of filamentous collagen fibers, which are known from the prior art shown in Fig. 11-14. Accelerating voltage scanning electron microscopy for illustrations Fig. 11(a)-11(C) is 20 kV accelerating the e voltage scanning electron microscopy for illustrations Fig. 12(a) is 8 kV accelerating voltage scanning electron microscopy for illustrations Fig. 12(b) is 9 kV accelerating voltage scanning electron microscopy for illustrations Fig. 14(b) is 18 kV, and accelerating voltage scanning electron microscopy for illustrations Fig. 13(a), 13(b) and 14(a) is 25 kV.

Fig. 11(a)-11(C) are obtained using a scanning electron microscope micrograph of collagen in the form of a sponge, which is used clinically at present as an artificial dermis (PELNAC (trademark), manufactured Gunze Co., Ltd. and sold by Johnson & Johnson Inc.). Fig. 11(a) represents the image at low magnification (about ×80), Fig. 11(b) represents the image at the middle magnification (about ×150), and Fig. 11(C) represents the image at high magnification (about ×3000).

In addition, Fig. 12(a) and 12(b) are obtained using a scanning electron microscope micrograph of collagen in the form of a sponge. Fig. 12(a) represents the image at the middle magnification (about ×400), and Fig. 12(b) represents the image at high magnification (about ×1000). The collagen in the form of a sponge was prepared as follows. Atelocollagen (collagen with normal melting temperature PSN (chamber of trade names is), manufactured by Nippon Meat Packers, Inc., derived from porcine dermis) was mixed with water (about pH 7,0), so that its content was 1 wt.% and was stirred for about 30 minutes at 12000 rpm and then injectively framed and frozen at -196°C and dried for 24-48 hours at -80°With lyophilization for evaporation of moisture, and then subjected to the processing of cross-linking by heating for 24 hours at 140°C under vacuum, and thereby was obtained collagen in the form of a sponge.

It is clear that the collagen has a spongy hollow structure due to filamentous fibers of collagen. Therefore, the basic unit constituting a spongy collagen is a fiber.

Fig. 13(a) and 13(b) are obtained using a scanning electron microscope micrograph of a commercially available fibrous collagen as a local hemostatic agents (Aviten (trade name), produced by Alcon (Puerto Rico) Inc., Humacal, Puerto Rico, and imported and sold Zeria Pharmaceutical Co., Ltd.). Fig. 13(a) represents the image at the middle magnification (about ×125), and Fig. 13(b) represents the image at the middle magnification (about ×400).

Fig. 14(a) and 14(b) are obtained using a scanning electron microscope micrograph of a commercially available fibrous call the gene as absorbable local hemostatic agents (Integran (trade name), produced Koken Co., Ltd., and sold by Nippon Zoki Pharmaceutical Co., Ltd.). Fig. 14(a) represents the image at low magnification (about ×30), and Fig. 14(b) represents the image at the middle magnification (about ×300).

In both cases, small collagen fibers form a structure similar to the non-woven material. It is clear that the structure is formed from bundles of collagen fibers and their disorderly location. The basic unit constituting melkopyatnistoy collagen is a fiber.

When comparing Fig. 1(a) Fig. 1(e), 11(a) 14(b) can be understood that the "thin-film multi-cell structure made of collagen according to the present invention clearly differs from collagen formed gel and collagen formed by the fibers.

Thin-film multi-cell structure made of collagen according to the present invention can be used for tissue regeneration. In this case, the fabric is a fabric body of the animal, such as human, rat, dog, cat, monkey, horse, cow and sheep, and, in particular, it is suitable for use in human tissue. Tissue from animals can include nervous tissue, subdermal tissue, submucosal tissue, membranous tissue, adipose tissue, muscle tissue, skin tissue and cloth the gums, and, in particular, they can be used for the regeneration of nerve tissue. Therefore, the present invention provides a member for tissue regeneration including the thin-film multi-cell structure made of collagen. In this case, as the tissues of the body can be illustrated by the following tissue: nervous tissue (such as the Central nerve, peripheral nerve, sciatic nerve, median nerve, facial nerve, cranial nerve, brachial plexus, ulnar nerve, radial nerve, femoral nerve, a perineal nerve and sural nerve); subdermal tissue, submucosal tissue, submucosal tissue of the oral cavity, submucosal tissue of the digestive tract, submucosal tissue of the genital organs, the membranous tissue (such as Dura mater, peritoneum, pleural membrane, fascia, capsule body); adipose tissue (such as the so-called fat), muscle tissue (such as the so-called muscle); skin tissue (such as the so-called skin); the tissue of the gums (such as the tissue of the periodontium, alveolar bone, tissue dental alveoli); tissues of vital organs (such as liver, kidney, pancreas, thyroid gland); and other tissues (such as blood vessels, tendons, ligaments, cartilage and bone).

In addition, the present invention provides an element for tissue regeneration, in addition, including the Mering biodegradable support. In the present invention "biodegradable support tends to degrade in vivo, and may form a frame structure element for tissue regeneration, and is not specifically limited, while it is able to attach and hold the multi-cell thin-film structure made of collagen, and can get the item for tissue regeneration in accordance with the present invention. Materials for the manufacture of such biodegradable supports include polyglycolic acid (PGA), polylactic acid (PLA), copolymers of lactide and glycolide (such as Polyglactin 910), poly-ε-caprolacton and a copolymer of lactic acid and ε-caprolactone.

In Fig. 2(a) and 2(b) shows a micrograph obtained by scanning electron microscope cross section (magnification of about ×20) and in longitudinal section (magnification of about ×100), one example of the tubular member for tissue regeneration including the thin-film multi-cell structure made of collagen according to the present invention. Accelerating voltage scanning electron microscope is 20 kV. This is also one example of the member for tissue regeneration having the above-described thin-film multi-cell structure made of collagen inside the tubular biologically razloga is my support. By using a tubular biodegradable support, you can get the item for tissue regeneration having a tubular shape. In the case shown in Fig. 2(a) and 2(b), it is clear that inside the tubular biodegradable support made of PGA, the structure having a multitude of cells (or cells) is formed by a thin film made of collagen. As described above, it is preferable that the thin-film multi-cell structure made of collagen, was included inside the tubular biodegradable support, and in this case, the element can appropriately be used for the regeneration of nerve tissue, subdermal tissue, submucosal tissue, membranous tissue, adipose tissue, muscle tissue, skin tissue and gum tissue.

Usually used tube for connection of nerves, having a tubular shape. Applicants have found that the elements for tissue regeneration, having various forms, can be used in accordance with the fabric, and that such elements for tissue regeneration having different forms have corresponding characteristic advantages. Such forms include forms with a sectional U-shaped or C-shaped form (namely, in General globemallow form), the form of a plate, a branched form and shape, with different holes on one and the other end (tapered shape).

To the Yes used biodegradable support, with a sectional U-shaped or C-shaped, you can get the item for tissue regeneration, with a sectional U-shaped or C-shaped form (namely, in General globemallow form). In Fig. 3 shows one example of such a member for tissue regeneration having broken U-shaped or C-shaped. In Fig. 4 shows one example of the connection parts of the sciatic nerve of the rat when the defect size of 1 cm with the use of such elements for tissue regeneration, with a sectional U-shaped or C-shaped. Both elements shown in Fig. 3 and Fig. 4, are cut in the whole globemallow form. When the element is used for tissue regeneration having such a shape, when the subject of regeneration of tissue is fascia or capsule body, it is easier to perform the operation with suturing. In the modern method of surgical treatment tube for nerve implanted with microscopic surgery. However, it is preferable to use a support of the present invention, because of its implantation can be easily and safely performed under endoscopic control even deep inside the body where microscopy is not possible and, in addition, it is possible to shorten the operation time. Preferably, the inside of the biodegradable support having a broken U-shaped or C-shaped, was included tancap nocna multi-cell structure, made of collagen, in accordance with the present invention, and may include a collagen having various other shapes such as the shape of the gel and form fibers.

In addition, usually in the tube for the connection of the nerves was known tubular form with 2 end, but applicants have found that when defects nerves with branching, excellent effect tube having three or more late. When using biodegradable tubular bearing or globoidea shape having a fork, you can get the item for tissue regeneration tubular or globoidea form. In Fig. 5 shows one example of the tubular member for tissue regeneration having a Y-shaped branching. The number of branches, the shape of the branches (such as Y-shaped or T-shaped) and the shape of the cross section (such as a circle, ellipse, U-shape or C-shape) (such as a generally tubular or globulina form) can appropriately be modified depending on the fabric on which the item will be put. Member for tissue regeneration having such branching can be used, for example, for recovery of branches in the distal part of the median nerve, branching on the finger nerves in the periphery or part of the sciatic nerve branching on the peroneal nerve and bolser rcopy nerve. In particular, the element can be used, because using a single element for regeneration is possible to ensure the regeneration fan-out segment of a peripheral nerve to the periphery. Preferably, the thin-film multi-cell structure made of collagen according to the present invention was incorporated in biodegradable support having a fork, but can be enabled collagen having various other shapes, such as a form or gel form fibers.

However, it is usually for the connection of the nerve trunk was previously used tubular element having a constant diameter, but the applicants have found that when, in accordance with the nature of the fabric on which it is necessary to use an element for regeneration, the ends of the element have different diameter holes, achieved an excellent effect of regeneration. Such an element can be obtained when using biodegradable support having a different bore diameter of its two ends. In Fig. 6 shows a narrowing of the tubular member for tissue regeneration. The element can have in the context of U-shaped or C-shaped form, namely as a whole globemallow form. With regard to the size of all the segments of tissue to be regenerated, it is possible to find elements with corresponding different hole sizes. Member for reg is the generation of tissue with such a difference of the holes in the ends, can be used, for example, a cranial nerve, such as the facial nerve, brachial plexus, ulnar nerve, radial nerve, median nerve, femoral nerve, sciatic nerve, branches, and other areas in which nerves extend from the spinal cord to the periphery, and, in particular, the element can be used for the reconstruction of peripheral nerve having a different diameter of the Central part and the peripheral part. Preferably, the thin-film multi-cell structure made of collagen according to the present invention was incorporated in biodegradable support having different holes on both ends, but may be included collagen having various other shapes, such as a form or gel form fibers.

In addition, for the connection of the trunk of the nerve plate element is unknown and is not normally used, but applicants have found that for tissue regeneration can also use the plate element. By using biodegradable plate support you can get this item for tissue regeneration. Such a plate element for the regeneration of tissue can be used, for example, to restore tibial nerve defect part of the skin defect part of the dermis, the gum tissue defect part of mahmoudkhani and essentially defect part of the body. Preferably, the main surface of one side of the biodegradable support was enabled multi-cell thin-film structure made of collagen according to the present invention, but may be included collagen having various other shapes, such as a form or gel form fibers.

In addition, when placed inside the body is the preferred element for tissue regeneration, which is destroyed with the ends of the element for tissue regeneration, because the outer wall around the part in which the regenerated tissue is destroyed afterwards and therefore nutrients enter the regenerated tissue from the surrounding tissue. In addition, such an element is preferable, because it does not require the removal element for tissue regeneration re-operation.

In Fig. 7 schematically shows the tubular element for tissue regeneration, which is rapidly degraded at both ends and slowly in the Central part and schematically illustrates the regeneration of tissue by use of the element. As a fabric, having the defect, illustrated by nervous tissue. The gap is caused by a defect of fabric connected by a tubular element for tissue regeneration. The regeneration of nervous tissue occurs from both ends toward the center, and the member for tissue regeneration is destroyed, starting from both ends, is absorbed.

In particular, from both ends of the tubular biodegradable support to the centre of the rate of destruction of the polymer, for example, is reduced (i) by heating, or (ii) by irradiation with ultraviolet or radioactive radiation or the rate of destruction of the element for tissue regeneration can be adjusted (iii) the reduction in the degree of cross-linking with collagen that will be described below, or similar methods, in order to regulate the rate of destruction of the element for the regeneration of tissue.

Preferably, the thin-film multi-cell structure made of collagen according to the present invention was incorporated into the lumen of such a biodegradable support, but can be enabled collagen having various other shapes such as the shape of the gel and form fibers.

In addition, applicants have found that for the regeneration of the long tissue defect, it is important that the rate of destruction of the element for tissue regeneration was controlled by the use of biodegradable support, in which the structure having a tubular or globoidal form, supported by the mixing of raw material, which slowly breaks down in vivo, with raw material, quickly destroyed in vivo to delay the destruction of the pillars in vivo.

In this case, the "raw material, which is rapidly destroyed in vivo" is from the battle of the raw material, which is destroyed and absorbed in General within three months after implantation in the body and may include polyglycolic acid (PGA) (its tensile strength is reduced by half after 2-3 weeks), Polyglactin 910 (Vicryl), politician (PDS) and PGA + trimethylantimony (TMC), which usually are often used as supports.

In addition, the "raw material, which slowly breaks down in vivo" is a raw material that breaks down and is absorbed in the whole three months after implantation in the body, preferably destroyed and absorbed through 6-24 months and may include polylactic acid (PLA) and polybutylene (PBS).

When regenerated long defect, it is preferable that the fibers of polylactic acid (PLA) slower destroyed in vivo than PGA, mixed to obtain a biodegradable support. Shows an example in which PLA is used as the only material support, but this example is not considered to be preferred, as an example, in which the PGA and PLA are mixed and used as a support, is unknown. When mixing PLA speed of destruction of the bearing approaches zero, and you can get biodegradable support, in which the structure having a hollow interior space (such as the structure of tubular shape with a lumen), can support the I in vivo for a long period.

In Fig. 8 shows the dependence of the tensile strength (average) of the deformation tube, made of PGA and PLA, for tissue regeneration (including 50% PLA). In Fig. 9 shows the dependence of the tensile strength (average) of the deformation tube, made in the whole of the PGA, for tissue regeneration. Fig. 10 is a schematic view for explaining deformation and strength, is shown in Fig. 8 and 9. It is clear that in the tube, made in the whole of the PGA, following the insertion of the tube into the body is immediately reduced mechanical strength, but the strength is increased by the combination of PLA and PGA. In Fig. 8 and scheme 9 (d0-d/d0) plotted on the graph along the horizontal axis, the force applied (f per unit length) are plotted on the graph along the longitudinal axis, and one can see that the structure of Fig. 8, in which is mixed 50% PLA, has greater strength than the structure of Fig. 9, when the same strain. It has been found that by mixing 50% PLA fibers can increase the mechanical strength of the tube and stop the decrease in strength after implantation tube in vivo. Therefore, it is preferable to use a support, which combines PGA and PLA. It is preferable that the mixing ratio of PGA and PLA (PGA/PLA) (the ratio of the number of fascicles) was 10-90/90-10, and particularly preferably 50/50.

As this combination can be, for example, to omnitele example PGA and PBS, etc. Preferably, the thin-film multi-cell structure made of collagen according to the present invention, was included inside this biodegradable support, but can be enabled collagen having various other shapes such as the shape of the gel and form fibers.

For regeneration of the long tissue defect, it is preferable to use biodegradable support having a tubular or globoidal the form in which the speed of the biodegradable support is adjustable so that the rate of destruction of the ends was higher than the rate of destruction of the Central part of the in vivo and in which the structure having a hollow inner space, supported by the mixing of raw material, which slowly breaks down in vivo, with raw material, which quickly breaks down in vivo to delay the destruction in vivo. Such biodegradable support can be obtained by combining PLA to PGA to obtain, for example, tubes and then use the above methods (i)to(iii) or the like to reduce the speed of destruction.

More preferably, the thin-film multi-cell structure made of collagen according to the present invention was incorporated in such a biodegradable support. Can be enabled collagen with other various f is RMI, such as the shape of the gel and form fibers.

Thin-film multi-cell structure made of collagen according to the present invention, can be obtained without limiting in any way get it while you can to obtain the desired structure, and, for example, the structure can be obtained by lyophilization of a solution of collagen. More specifically, for example, an aqueous solution of atelocollagen freeze using the freezer to the deep freeze, and then dried by lyophilization and processed thermal cross-linking under vacuum. Preferably, the concentration of the diluted hydrochloric acid solution of atelocollagen ranged from 0.5 to 3.5 wt.%, and preferably, from 1.0 to 3.0 wt.%, especially preferred concentration of from 1.0 to 2.0 wt.%. Preferably, the concentration of diluted hydrochloric acid ranged from 0.0001 to 0.01 N, and particularly preferred concentration of 0.001 N. Preferably, the pH of the diluted hydrochloric acid was 2-4, and particularly preferably pH 3. Preferably, the temperature of the freezing ranged from -70 to -100°C., and especially preferred temperature is from -80 to -90°C. Preferably, the lyophilization was carried out for 24 hours under reduced pressure of 5.0 PA or less at a temperature of from -80 to -90°C. Preferably, to process thermal cross-linking was carried out during the onset 6 to 48 hours at 100 to 150°C. under reduced pressure of 1 Torr or less, and more preferable to perform processing within 12-48 hours at 120-145°C., and particularly preferably processed within 48 hours at 140°C. In particular, such a thin-film multi-cell structure can be used for nervous tissue.

Member for tissue regeneration including biodegradable support, supporting multi-cell thin-film structure made of collagen according to the present invention can be obtained without specific limitations in any way get it while you can get a desirable element for tissue regeneration, and, for example, the element can be obtained as follows. A solution of collagen is applied to biodegradable support, and then a solution of collagen liabilitiesa, and, through this, you can get the item. For example, more specifically, when the support has a tubular shape, the tube having a corresponding size, immersed in 70% ethanol for 24 hours, and the ethanol is then completely dried, and 1.0 to 3.0 wt.% dilute solution of collagen in dilute hydrochloric acid (0,001 N) (pH 3.0) is applied to the surface of the biodegradable support and dried in the air. And the process of application and air drying to repeat the accelerate up to 20 times for the formation of collagen coating on the surface of a support. The item is pre-cooled to -85°C in the freezer, and then from 1.0 to 3.0 wt.% solution of collagen in dilute hydrochloric acid (pH 3.0) at +4°C is poured inside the element with a thin syringe so as not to create a gap, and once the item is placed in a freezer and cooled to -85°C for deep freezing. The item is placed in lyophilizator and dried for 24 hours at -80°C for evaporation of moisture. Then, under vacuum (1 Torr or less), is thermal dehydration treatment cross-stitching within 24-48 hours at a temperature from 120°C to 140°C, and, through this, you can get the item for tissue regeneration.

Tubular biodegradable support, you can get a conventional known method, for example, by forming the tubular wall material around the tubular core.

Tubular biodegradable support having a fork, can be obtained by forming a tubular wall around the core material, having a branched structure (outer diameter of each of the branches is 5 mm). Next obtain will be explained in detail.

The tube is made from a core material having a fork, a device for weaving. As biodegradable fibers can be used fibers of PGA. As the e of the PGA fibers can, for example, to use the PGA fibers obtained plexus five multi-fiber bundles, each of which is obtained by interlacing fibers 28, each of which has noncovalently 2,55 dtex/f 2,55. For example, by using a device for weaving forming tube starting from one end. When the device for weaving reaches the branched part of the core material, the branch branching of the core material on which the formed tube, later given out through the gap in the fibres, and by means of this device for weaving is carried out through the branched portion, and the tube can be formed on one branch of the branching of the core material. Thereafter, the tube is folded to the second end, and the tube is re-formed and superimposed on one end. When the device for weaving again reaches the branching part, the exhaust branch around which was previously formed tube is drained out through the gap in the fibers. The tube is formed on another branch as the core around which has not been previously formed tube. By forming the tube at the second end, you may receive a tubular support having a single branching structure. For the material of the core branching patterns requires the use of soft materials on the WMD that the exhaust branch should be conducted through the gap fibers of the tubular wall.

As another manufacturing method can be illustrated by the following manufacturing method. After the tube is formed with one end on the branching part of the device for weaving, the tubular wall is formed to the second end on the same core material waste branch by using half of the fibers of PGA device for weaving. Then by using the remaining half of PGA fibers of the tubular wall is formed on the third end on a different core material branching part.

In addition, biodegradable support plate can be fabricated, for example, planar weaving raw material of biodegradable support, or receiving a tubular material having a large diameter, and the dissection of the material in the longitudinal direction, and then the expansion of the material.

Biodegradable support globoidea form with a sectional U-shaped or C-shaped, it is possible to make a dissection of the tubular wall of the tubular support in the longitudinal direction or the excision of part of the tubular wall of the tubular support.

Biodegradable support globoidea shape having different size holes one and second ends, can be fabricated, for example, advanced manufacturing core material having different at p is smeru holes and one of the second ends (tapering the core material), and the formation of the tube by use of a material as a core, for example, a device for weaving.

Biodegradable support having a tubular or globoidal form, the rate of decomposition which in vivo is higher closer to the ends than in the Central part, can be manufactured as described above.

In addition, biodegradable support, in which the form has a hollow internal cavity, made by mixing raw material, which is slowly degraded in vivo, with raw material, rapidly degradable in vivo, to delay its degradation in vivo, can be obtained by forming the tubular wall by using such a raw material as described previously.

Biodegradable support, in which is combined a variety of forms, it is possible to make an appropriate combination of the above-described manufacturing methods.

Member for tissue regeneration including the above-described thin-film multi-cell structure made of collagen, you can get a manufacturer having a light thin-film multi-cell structure of collagen by filling with a solution of collagen various biodegradable supports and lyophilization.

Member for regeneration of tissue, including collagen, having various forms, such as gel form or shape of the fiber, m which should be obtained by completing various biodegradable supports collagen in the form of sponges or collagen in the form of fibers by using a well-known method.

The above-described aspects and embodiments of the present invention can, if possible, respectively, to combine.

Examples

Example 1

Obtaining multi-cell thin-film structure made of collagen

Received 1-3 wt.% solution atelocollagen (collagen with normal melting temperature PSN (trade name), manufactured by Nippon Meat Packers, Inc., derived from porcine dermis) in dilute hydrochloric acid (0,001 N) (pH approximately 3,0), and poured into a frame and then liofilizirovanny in the freezer and deep freeze at -80°C To -86°C. The material was dried in 24-48 hours at -80°C in liofilizadora for evaporation of moisture, and thereby was obtained a thin-film multi-cell structure. The processing of cross-linking by heating was performed for 24 hours at 140°C under vacuum. When observing the structure under a scanning electron microscope at an accelerating voltage of 20 kV was visible thin-film multi-cell structure. It is shown in Fig. 1(a)-1(C).

In addition, in the same way it was received, another thin-film multi-cell structure. When examined under the scanning electron microscope using an accelerating voltage of 18 kV was observed thin-film multi-cell structure. It is shown in the IG. 1(d) and 1(e).

Example 2

Receiving element for tissue regeneration, in which the thin-film multi-cell structure made of collagen that is included inside the tubular biodegradable support

The receiver of the PGA obtained in a known manner, cut to the appropriate segments. Cut the tube was immersed in 70% ethanol for 24 hours. The receiver of the PGA extracted from 70% ethanol and then dried. The outer surface of the tube of the PGA covered about 20 times, using 1-3 wt.% solution atelocollagen (collagen with normal melting temperature PSN (trade name), manufactured by Nippon Meat Packers, Inc., derived from porcine dermis) in dilute hydrochloric acid (0,001 N) (pH approximately 3,0), and then dried. By removing the core from the tube of the PGA received tubular support. With a syringe 1-3 wt.% solution atelocollagen (collagen with normal melting temperature PSN (trade name), manufactured by Nippon Meat Packers, Inc., derived from porcine dermis) in dilute hydrochloric acid (0,001 N) (pH approximately 3,0), was poured into the tubular support. This material was frozen in a freezer and deep freeze at-80-86°C. the Material was dried in 24-48 hours at -80°C in liofilizadora. The processing of cross-linking by heating was performed for 24 hours at 140°C under vacuum Torr or less, and through this, has been received by the member for tissue regeneration. When inspecting the element under the scanning electron microscope at an accelerating voltage of 20 kV was visible thin-film multi-cell structure inside the tubular support. It is shown in Fig. 2(a) and 2(b).

When the member for tissue regeneration used for the regeneration of the tibial nerve of the dog, not only histopathological, but also electrophysiological watched the preferred restoration of nerve function.

Example 3

The receiver of the PGA, namely a tubular biodegradable support was obtained by using the device for weaving, and made element for tissue regeneration (referred to as "tube A1"), which was formed by the thin-film multi-cell structure in the form of a new structure made of collagen inside the pylon in the same manner as in example 2 (diameter: 2 mm, length: 10 mm). On the other hand, as a control experiment used the tube from PGA ("referred to as "tube B1"), filled microfiber collagen, which is commercially available in the form of medical devices (integran (trade name), manufactured Koken Co., Ltd.) (diameter: 2 mm, length: 10 mm).

Part of the nerve defect 5 mm of the right sciatic nerve of the rat Wistar (n=2) restored the tube A1. As a control h is the terrain of the left sciatic nerve defect 5 mm was restored tube B1.

One month of Wistar rats were put on their feet, and measured the diameter of the axial fibers and the thickness of the myelin sheath in the distal end of the restored part of the nerve, and measured the number myelination nerve axons. When the tube A1 measurement results respectively were 1.4±0.3 μm/0,4±0,08 µm/60±25 pulses at 100×100 μm2and when the tube B1 they respectively was 1.0±0.4 µm/0,2±0,10 µm/92±31 pulses at 100×100 μm2and therefore, when the tube A1 was observed significantly better regeneration.

Example 4

The receiver of the PGA, namely a tubular biodegradable support was obtained by using the device for weaving, and made element for tissue regeneration (referred to as "the tube A2"), which was formed by the thin-film multi-cell structure in the form of a new structure made of collagen inside the pylon in the same manner as in example 2 (diameter: 2 mm, length: 10 mm). On the other hand, as an experimental control was used tube of PGA ("referred to as "tube C1"), collagen fibers having a diameter of 400 μm, collected into bundles and placed in a tube (diameter: 2 mm, length: 10 mm).

Part of the nerve defect 5 mm of the right sciatic nerve of the rat Wistar (n=2) restored the tube A2. As a control part of the left sciatic nerve defect 5 mm is ostanavlivali tube C1.

One month of Wistar rats were put on their feet and measured the diameter of the axial fibers and the thickness of the myelin sheath in the distal end of the restored part of the nerve, and measured the number marinerevenge nerve axons. When the tube A2 measurement results respectively amounted to 1.3±0.5 µm/0,3±0,07 mcm/61±22 pulses at 100×100 μm2and when the tube C1 they respectively accounted for 0.9±0.3 μm/0,2±0,05 µm/103±30 pulses at 100×100 μm2therefore , when the tube A2 was observed significantly better regeneration.

Example 5

Receiving element for tissue regeneration, in which the thin-film multi-cell structure made of collagen incorporated in biodegradable support having globemallow form with a sectional U-shape

By using fibers of PGA (PGA fibers were obtained by linking the two beam multi-fiber bundles, each of which was obtained by linking to the beam 28 of fibers, each of which had noncovalently 2,59 dtex/f, received a tube of the PGA having an inner diameter of 2 mm (length = 10 mm), by using the device to obtain a twisted braid of 48 bobbins (reels), so that the tube is made of Teflon (registered trademark)having an outer diameter of 2 mm was used as the core material. After cutting the tube on the cutting 5 cm together with the core material, it was treated with a coating of 1.0 wt.% solution of collagen in dilute hydrochloric acid (0,001 N, pH approximately 3,0), and the tube was dried, which was repeated 20 times, and through it received tubular support. Then the core material pulled and removed, and a solution of collagen filled inner lumen of the tubular support, conducted lyophilization and thermal cross-linking to obtain a tubular element for the regeneration of tissue, including collagen, inside multi-cell thin-film structure. 1/3 of the outer wall element for the regeneration of tissue was dissected, using sharp scissors for microsurgery under the stereomicroscope for receiving the U-shaped member for tissue regeneration. This is shown in Fig. 3 and 4. In Fig. 4 the member for tissue regeneration including biodegradable support having a generally globemallow form implanted into a portion of the sciatic nerve defect 1 cm at the hip rats weighing 300 g, and the operation time required for implantation, approximately 10 minutes. On the contrary, when the connection element is used for tissue regeneration, comprising a tubular biodegradable support having the same size required for the operation time for a total of about 20 minutes, so the time of surgery, you can save about 50%.

In this case, by ASCS is the treatment of the exterior wall of the tubular member for tissue regeneration, received the item for tissue regeneration having globemallow form, but the member for tissue regeneration having globemallow form, can be obtained by forming a thin film multi-cell structure made of collagen inside the biodegradable support having globemallow form.

Example 6

Manufacture of tubular biodegradable support having a Y-shaped branching, and the member for tissue regeneration including support

First, by using a thermoplastic polyolefin synthetic polymer that is soft at room temperature, was formed Y-shaped core material. The outer diameter of each of the branches of the Y-shaped form was 5 mm, and their length was 10 cm By using it as the core material received Y-shaped tube made of fibers of PGA (PGA fibers obtained plexus in bundles of five multi-fiber yarns of the PGA, each of which was obtained by linking to the beams 28 made of fibers, and each of them had noncovalently 2,55 dtex/f 2,59) device for weaving with 48 guns. This method will be specifically explained hereinafter. The tube was formed on the above-described core material from one end of the Y-shaped structure. After one leg of the core pulled out of the tube in to the achieving the branching part of the Y-shaped structure, the tube is sequentially made to the second end, so that the remaining branch serves as the core material. Through this, has received a tube of the PGA, having the form in which the exposed core material were in the form of branches in the center. In the same way as in the previous production, from one end of the Y-shaped structure again received a tube of the PGA, so that she previously received the tube serves as the core. After manufacturing before branching part, the exhaust branch (core material)having one end around which formed the structure of the PGA, was stretched out. By forming the tube to the third end, so that the exhaust branch, on which the tube has not been previously generated, served as the core material, has been seamless, single Y-shaped tube.

The obtained Y-shaped biodegradable support is applied and liabilitiesa solution of collagen, and thereby is made and is included in "thin-film multi-cell structure of collagen, and through this you can get a tubular member for tissue regeneration with Y-shaped branching, including multi-cell thin-film structure made of collagen.

Example 7

Experiment on the introduction of nerve cells in the tubular element to Regener the tion tissue, having a Y-shaped branching

Y-shaped tube of the PGA, namely Y-shaped biodegradable support was obtained by use of the device for weaving, and received Y-shaped element for tissue regeneration, in which the thin-film multi-cell structure was formed in the same manner as in example 2, as the new structure of collagen. The diameter of each of the branches was 4 mm, and their length was 3 see All three angles formed by the branches was 60°.

Y-shaped element for the regeneration of tissue was placed in a Petri dish for culturing and immersed in the environment for nerve cells (MB-X9501D, produced Dainippon Sumitomo Pharma Co., Ltd,), and nerve cells (MB-X032D manufactured Dainippon Sumitomo Pharma Co., Ltd) from two embryos were divided into three parts and was injectively in three holes Y-shaped element. After culturing it in the incubator for two weeks was examined by the inner surface of the Y-shaped member for tissue regeneration. It was confirmed that nerve cells have penetrated into all parts made of collagen thin-film multi-cell structure, filled inside the Y-shaped member for tissue regeneration, proliferated and spread. Believe that this is due to the fact that the member for tissue regeneration having branched structure, has a high sredstvo cells obtained from nerves, as a guide tube for nerve regeneration.

Example 8

Manufacture of tubular biodegradable support having different size holes and one second end, and the member for tissue regeneration including this support

First heating and processing of thermoplastic polyolefin synthetic polymer having a ductility at room temperature, made 30 pieces of core material, each having a length of 10 cm, the outer diameter of the one end 3 mm, the outer diameter of the other end 1 mm and tapering shape, the diameter of which is linearly decreased from one end to the other end. Then made the long material of the core, connecting 30 pieces of core material so that the narrow ends facing each other, and so that the thick ends were facing each other. By using this long core material made of a tube of fibers of PGA using the device for weaving and cut it to get 30 pieces of biodegradable supports, each of which had different size holes on both ends. In the manufacture of pipes of PGA fibers were preferably, by setting the low-speed folding of the tube in the part having a large aperture, and a higher speed folding t the skirts as the refinement of the core material, the mechanical strength of the tube is not weakened on the thicker side, that is achieved a uniform strength over the entire length.

The obtained tubular biodegradable support having different size openings on both ends, put a solution of collagen and liofilizirovanny, and thus produced is included in support of the "multi-cell thin-film structure of collagen, and through this it is possible to make the tubular member for tissue regeneration having different size openings and including a thin-film multi-cell structure made of collagen.

Example 9

Tubular biodegradable support, the rate of decomposition is regulated so that the rate of decomposition of the ends was higher than the rate of decomposition of the Central part in vivo, and its decomposition in vivo

By using the device for weaving and through the use of fibers of polylactic acid (PGA), which decays slowly, made a tube with a diameter of 5 mm and a length of 4 see Then, in terms of covering the right half of the tube cold insulator, the left half of the tube blew hot air for 30 minutes using a dryer at 1200 W and 105°C. Next, after covering the left half of the tube cold insulator in the same way the hot air blew right end of the tube. Through this, has received greater impact is the influence of high temperatures on the part of the tube, closer to its both ends. When a tube implanted under the skin of the back of the rat, it was confirmed that decomposition had begun in vivo with the ends of the tube, starting with the third week after injection. By processing by heating the decomposition and absorption of both ends of the tube was achieved after about 1 month, and its Central part was decomposed and absorbed through 2 or 3 months. That is, it was confirmed that it is possible to make the tube, namely biodegradable support, the rate of decomposition which in vivo is higher, the closer to both ends.

Example 10

Manufacturer of biodegradable support, in which the tubular structure is maintained by mixing raw material, which is slowly degraded in vivo, with raw material, which is rapidly degraded in vivo to delay its degradation in vivo, and the member for tissue regeneration including support

The receiver of the PGA-PLA produced by the receiving tube in which the fibers of polylactic acid (PLA), which decays slowly, mixed with polyglycolic acid (PGA) (PGA/PLA=30/50 (the ratio of fascicles)) by use of the device for weaving. On the outer surface of this tube was applied to 1 wt.% an aqueous solution of collagen and dried. This process was repeated 20 times to obtain the above biodegradable the pores. Then inside the tubular biodegradable support from PGA-PLA was filled with 1 wt.% an aqueous solution of collagen and immediately liofilizirovanny for forming inside the tube multi-cell thin-film patterns. Then, the handled cross-stitching within 24 hours at 140°C and, thus, received a tubular member for tissue regeneration containing within 1 wt.% thin film mesh of collagen and having a diameter of 5 mm and a length of 40 mm (hereinafter also referred to as "element of the PGA-PLA for tissue regeneration").

Part of the nerve defect with a length of 40 mm of the right tibial nerve dogs-Beagle (n=12) were reconstructed using the element of PGA-PLA for tissue regeneration. As a control part of the nerve defect with a length of 40 mm of the right tibial nerve dogs-Beagle (n=12) was reduced by using a tubular member for tissue regeneration (hereinafter also referred to as "element of the PGA for tissue regeneration")obtained in the same way, except that instead of PGA-PLA PLA was mixed for manufacturing the element for the regeneration of tissue.

In the element of the PGA for tissue regeneration tubular structure could not be maintained after 2 weeks of recovery, and it was decomposed and absorbed mainly in the oral cavity, and, on the contrary, in the element of PGA-PLA for tissue regeneration was almost no change is in the structure of the lumen even after two months, and structure of the lumen remained even when assessing the condition of the tissue 6 months after recovery.

The mechanical properties of an element from PGA-PLA for tissue regeneration shown in Fig. 8. Mechanical properties were measured using the device Tensilon RTM-250 (trade name), manufactured ORIENTEC Co., Ltd, in terms of axial compression at 37°C in physiological saline with a pH of 6.4 at the speed of traverse movement 1 mm/min Mechanical properties of an element from the PGA for tissue regeneration was measured in the same way, and the results are shown in Fig. 9. Considering the use of this item for parts with long defect by delaying the degradation rate, it is preferable that this element had a higher mechanical strength. When comparing Fig. 8 and 9, as described above, it is clear that the element of the PGA-PLA for tissue regeneration has a higher strength if the same increase in deformation and therefore can be used over a longer period.

Using the obtained biodegradable support in the future, it is possible to make elements for tissue regeneration involving collagen and having various forms such as gel form and shape of the fiber.

In addition, the applicants have carried out extensive studies and found that when the damaged area perifericheskogo the nerve, causing pain, is restored by the use of element for tissue regeneration, including multi-cell thin-film structure made of collagen according to the present invention, the pain disappears after the operation.

It has been shown that the tube for the connection of the nerve has effect in relation to the loss of the perception of touch and pain sensation or motor paralysis due to a defect of the nervous tissue, but applicants have found that by utilizing the item for tissue regeneration, including multi-cell thin-film structure made of collagen according to the present invention, in the area of the defect in the nerve that causes the pain, the pain disappears and then restored normal sensitivity.

Example 11

Pain relief element for tissue regeneration, including multi-cell thin-film structure made of collagen

A man aged 42 years, 6 months ago at work accidentally mauled by a saw thumb of the left hand with its incomplete clipping, and had surgery the replantation of finger. However repentigny the thumb of the left hand caused intense pain, making the left hand incapacitated and creating inconvenience in daily life. Respectively, were isseen area is established nerve finger, and was conducted by cross-linking of the affected area element for the regeneration of tissue, including multi-cell thin-film structure made of collagen according to the present invention, and therefore, after the operation, the pain disappeared, and it became possible use of the left hand, and after 6 months it was completely restored the sensitivity of the thumb of the left hand.

Example 12

Pain relief element for tissue regeneration, including multi-cell thin-film structure made of collagen

Male aged 37 years, fell from a height of 2 m, received a compound fracture of right radial bone, and as the initial treatment was surgery internal fixation and external fixation. After the initial intensive treatment the pain had spread from the wrist throughout the right upper limb and the use of the upper limb was impossible. On the radiograph, atrophy of the bones of the right wrist, and was diagnosed with complex regional pain syndrome (CRPS - type II). Because of the intense pain for 4 months, the patient lost 12 kg is Usually assumed that such a complex regional pain syndrome is difficult to treat surgically. The applicants confirmed that they had upset one cutaneous branches of the right radial nerve, and environment the nervous tissue was calaminarian, and then the lesion of this nerve is surgically dissected and restored through the cross-linkage element for tissue regeneration, including multi-cell thin-film structure made of collagen. Accordingly, the pain that has been present in the patient before surgery, disappeared immediately after awakening from anesthesia. On the radiograph at 12 months after surgery, it was confirmed that Trofimovna bone recovered and skin temperature returned to normal. After the operation of motor function of the right hand which was broken, was restored, and the patient was able to button and unbutton the buttons of shirts amazed by the brush and returned to normal life.

Industrial applicability

Member for tissue regeneration including the thin-film multi-cell structure made of collagen according to the present invention, has a new structure, non-colloidal form, the form of gel and form fibers. Therefore, when a new structure made of collagen according to the present invention is used for a member for tissue regeneration, it is possible to improve the stimulation of regeneration, to shorten the period of treatment, to carry out functional recovery or similar body tissue, such as nerve tissue, the DBMS is Malina fabric, submucosal tissue, membranous tissue, adipose tissue, muscle tissue, skin tissue and tissue of the gums.

In addition, when the above-described member for tissue regeneration, in addition, includes a biodegradable support, you can further protect the underlying tissue regeneration.

When the member for tissue regeneration according to the present invention includes the above-mentioned thin-film multi-cell structure inside the tubular biodegradable support, primarily to regenerate long and thin fibrous tissue.

As described above, the member for tissue regeneration according to the present invention is extremely useful for the regeneration of body tissues and, in addition, when the patient has neuropathic pain, this item has an effect in the form of disappearance of pain, so this item can be widely used in medicine.

1. Thin-film multi-cell structure for the regeneration of tissue made of collagen by freezing the diluted solution of collagen in dilute hydrochloric acid at the temperature of freezing from -70 to -100°C and freeze-drying with subsequent cross-linking by heating.

2. Member for tissue regeneration containing multi-cell thin-film structure according to claim 1.

3. Member for regeneration TC is neither according to claim 2, where the element includes a biodegradable support.

4. Member for tissue regeneration according to claim 3, where the element has the specified multi-cell thin-film structure inside the tubular biodegradable support.

5. Member for tissue regeneration according to claim 3, where the element has the specified multi-cell thin-film structure inside the tubular biodegradable support having globemallow shape with a U-shaped or C-shaped cross-section.

6. Member for tissue regeneration according to claim 4 or 5, where biodegradable bearing has a branch.

7. Member for tissue regeneration according to claim 4 or 5, where there is a difference openings between the opening of one end of the biodegradable support and opening its other end.

8. Member for tissue regeneration according to claim 4 or 5, where the rate of decomposition of biodegradable support in vivo is modified so that the rate of destruction of the ends is higher than the rate of destruction of the Central part.

9. Member for tissue regeneration according to claim 4 or 5, where the structure having a hollow internal cavity, supported by the mixing of raw material, which is slowly degraded in vivo, with raw material, rapidly degradable in vivo, to delay its degradation in vivo.

10. Member for tissue regeneration according to any one of claim 2 to 5, where the member for tissue regeneration is used in cacheclient for the regeneration of nervous tissue.

11. A method of obtaining a thin-film multi-cell structure according to claim 1, including the freezing of dilute solution of collagen in dilute hydrochloric acid at the temperature of freezing from -70 to -100°C and lyophilization and subsequent cross-linking by heating.

12. The method of obtaining element for tissue regeneration according to any one of any of p-5, including immersion biodegradable support in a dilute solution of collagen in dilute hydrochloric acid, the freezing of dilute solution of collagen in dilute hydrochloric acid at the temperature of freezing from -70 to -100°C and lyophilization and subsequent cross-linking by heating.



 

Same patents:

FIELD: medicine.

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EFFECT: application of the invention in targeted angiogenesis.

1 tbl, 3 ex

FIELD: medicine.

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EFFECT: invention ensures production of bioabsorbable matrix containing native nonreconstructible collagen type I with collagen fibre structure identical to natural collagen-containing tissue, possesses considerable mechanical properties and is applied as a matrix for growth, directional regeneration, improvement of soft and hard tissue trophism and structures.

32 cl, 1 ex, 3 dwg

FIELD: medicine.

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EFFECT: method improvement.

3 cl, 5 ex

FIELD: medicine.

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4 cl, 4 dwg, 3 ex

FIELD: medicine.

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18 cl, 4 att, 4 dwg

FIELD: medicine.

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EFFECT: enhanced effectiveness in recovering combined injuries of cartilage and bone tissue in articulations having defects.

8 cl, 6 dwg

FIELD: medicine.

SUBSTANCE: the present innovation deals with the method to accelerate mucosal healing due to the following technique: one should apply a membrane consisted of purified collagenic material obtained out of natural collagen-containing tissue onto the part of affected mucosa to provide the chance for mucosal reconstruction in this part and, also, it deals with mucosa-regenerating preparation and application of purified collagenic material obtained out of collagen-containing natural tissue for preparing mucosa-regenerating preparation. The innovation provides more modified method that accelerates mucosal regeneration, as a whole, and, particularly, after surgical operations associated with the plasty of oral fornix.

EFFECT: higher efficiency.

12 cl, 3 dwg, 5 ex

FIELD: medicine, ophthalmology.

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EFFECT: higher efficiency.

6 dwg, 3 ex

FIELD: medicine.

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EFFECT: enhanced effectiveness of treatment; reduced risk of postoperative complications.

3 cl

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FIELD: medicine.

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29 cl, 2 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: medical device for elimination of diastasis and restoration of integrity of injured peripheral nerve consists of tube from compatible with tissues and absorbable in tissues biomaterial, containing substance, which stimulates post-traumatic regeneration of nerve fibres and diastasis elimination. As tube, medical device contains fragment of bird feather calamus. As substance, stimulating post-traumatic regeneration of nerve fibres and diastasis elimination bird feather calamus contains hydroxylapatite or fluorohydroxylapatite. Method of manufacturing medical device for diastasis elimination and for restoration of injured peripheral nerve restoration consists in the following: bird feather with hole diametre which is 1.5-2.0 mm larger than diametre of injured nerve is selected, from bird feather calamus fragment with length from 5 to 15 cm, correspondingly 1-5 cm larger than injured nerve diastasis, is cut out, thickness of wall of feather calamus is reduced to 0.8-1.0 mm. Calamus fragment is kept for 2-3 days in 10 per cent neutral water formalin solution. After that feather calamus fragment is kept for from 3 to 5 days in water solutions of ethyl alcohol of increasing concentration from 70 to 90%. Feather calamus fragment is kept for from 1 to 2 days in 10% water solution of salicylic acid in order to change its hystostructure. Hydroxylapatite or fluorohydroxylapatite are precipitated on internal and external surface of feather calamus fragment, after which feather calamus fragment is sterilised. Method of manufacturing medical device for elimination of diastasis and restoration of injured peripheral nerve integrity in accordance with the second version consists in the following: bird feather with hole diametre which is 1.5-2 mm larger than diametre of injured nerve is selected, from bird feather calamus fragment with length from 5 to 15 cm, correspondingly 1-5 cm larger than injured nerve diastasis, is cut out. Bird feather calamus fragment is mechanically cleaned outside and inside, boiled in water for 3-4 hours, kept for 3-4 days in 10% neutral formalin solution, kept for 5-7 days in 70% water solution of ethyl alcohol. Hydroxylapatite or fluorohydroxylapatite are precipitated on internal and external surface of bird feather calamus fragment, after which bird feather calamus fragment is sterilised.

EFFECT: inventions ensure making medical device for diastasis elimination and restoration of injured peripheral nerve integrity simpler and cheaper and method of such device manufacturing.

9 cl, 1 dwg

FIELD: medicine.

SUBSTANCE: unit comprises a porous external wall for vascularisation, an internal space for the storage of an implanted biological material including a selected tissue/cell product, and for the vascular tissue enrichment of the implanted biological material from the external porous wall; a liquid collector for the immunosuppressive and/or growth factor infusion in the specified space. The collector comprises a longitudinal microperforated tube. A pump or medium container is connected to the collector. A method of biological material implantation involves the implantation of said unit, enabled fibrogenesis through the porous external wall into the internal space, arrangement of the biological material including the chosen tissue/cell product in the specified internal space, immunosuppressive and/or growth factor medium infusion in the internal space.

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19 cl, 3 dwg

FIELD: medicine.

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24 cl, 57 dwg, 2 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: method of manufacturing the medical implant from titanium alloy includes precision casting of titanium to the casting mould corresponding the manufactured implant. For casting β-titanium alloy is used, then the resulting product is subjected to isostatic hot pressing, the product is let down in the solid solution area and then is quenched. Medical implant is made of titanium alloy by precision casting. Titanium alloy is a β-titanium alloy with an average grain size of at least 0.3 mm. Inventions enable to produce efficiently products from β-titanium alloy by precision casting method. Thanks to the invention it is possible to combine the advantages of the characteristics of β-titanium alloys, especially their high mechanical characteristics, with the advantages of manufacturing production by method of precision casting. Even implants of complex shape, such as parts of hip joint implant, which are practically impossible to produce, using traditional forging, can now be made from β-titanium alloys due to this invention.

EFFECT: method of manufacturing medical implant from beta-titanium-molybdenum alloy and the corresponding implant.

2 cl, 6 dwg

FIELD: medicine.

SUBSTANCE: there is offered a method for preparing a soft tissue filler composition for injection to relief or treat skin damages caused by mechanical or physiological reasons, including the stages as follows: 1) digestion of autologous dermal tissue recovered from autologous skin of a patient by processing with pancreatine/EDTA solution, and cell isolation; 2) cultivation and proliferation of the recovered dermal cells by serum-free cultivation in vitro in a medium containing a growth factor and activation factor for preparing autologous cellular culture material of dermal nature containing dermal fibroblastic stem cells, dermal fibroblastic "transitional" dividing cells, dermal fibroblasts and collagen; 3) centrifugation of autologous cellular culture material of dermal nature for separation of autologous cellular sediment of dermal nature; and 4) slurrying of autologous cellular culture material of dermal nature in glucose solution for injection or any solution for injection to prepare suspension for injection. There is offered a composition prepared by specified method which contains 1×107 to 8×107 cells/ml of autologous cells of dermal origins and 10 to 100 mg/ml of collagen as an effective ingredient.

EFFECT: invention provides therapeutic effect over a short period of time and maintains it for a long time.

13 cl, 7 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: there is described a method for making a biodegradable ceramic composite of double potassium calcium phosphate that involves preparation of a initial powder containing calcium phosphate with the ratio Ca/P=1 and potassium salt; extrusion and burning, wherein according to the invention, the initial powder is formed by the reaction at pH 5.5-6.0 of aqueous solutions of calcium acetate and potassium hydrophosphate concentrated within 0.6-0.8 M. The powder after the synthesis represents mixed calcium-deficient hydroxyapatite, brushite and acid potassium acetate.

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3 cl, 1 tbl, 2 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: hernial implant of porous polytetrafluoroethylene formed by lamination of balanced polytetrafluoroethylene films. The fibrils pointing direction of each layer of the film is perpendicular to the fibrils pointing direction of each adjacent layer. The implant is perforated in the entire area. The total area of perforation is 30-50% of the implant area. The perforation represents round apertures of diametre 1.6-5 mm.

EFFECT: invention provides reduced number of chronic inflammatory reactions in the postoperative patients.

4 cl, 1 tbl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medical equipment and can be applied for making a biocompatible coating of medical intraosseous and transosseous implant of high engraftment level. The titanium and alloy coating contains titanium and copper oxides in a certain quantitative ratio, and lanthanum. The coating is formed on titanium and titanium alloys (BT 1-0, BT 1-00, BT-6, BT-16 etc.) by the electrochemical method sequentially in two electrolytes; at first, anodic oxidation is used to make a layer of mixed titanium and copper oxides in electrolyte of concentration 200 g/l of sulphuric acid with added 50 g/l of copper sulphate in distilled water with direct anode current; then cathodic incorporation enables generation of a lanthanum layer in the form of fragments in electrolyte of concentration 0.5 M of lanthanum salicylate in dimethyl formamide with direct cathode voltage 3 V.

EFFECT: method allows making the osteointegration oxide biocoating exhibiting bactericidal and anticoagulant properties.

2 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, more specifically the method for surfacing titanium implants that allows forming a bioactive surface. There is described a bioactive coating on the titanium implant exhibiting high adhesion to the implant surface and an extended rough surface sufficient for successful osteointegration of bone tissue and the method for making thereof. The bioactive coating on the titanium implant contains calcium-phosphate compounds and has multilevel porous structure with a rough surface. The coating has thickness 10-40 microns, total porosity 35-45% with average pore dimension 3-8 mcm, roughness 2.5-5 microns, adhesive strength 30-35 MPa. The coating contains calcium-phosphates in roentgenoamorphous condition. There is described method for making the bioactive coating on the titanium implant that involves surfacing by micro-arc oxide coating, but preceded with mechanical and chemical processing of the surface of the titanium implant that is followed with micro-arc oxide coating to make a multilevel porous structure of the calcium-phosphate coating. The mechanical and chemical processing represents sandblasting of the surface of the titanium implant to be exposed to chemical etching. For sandblasting, powdered aluminium oxide AI2O3 or silica SiO2 of fraction 250-380 mcm is used to ensure roughness 1.5-5 mcm. Chemical etching is carried out by staining the surface of the titanium implant in an acid etchant heated to boiling temperature and prepared of hydrochloric and sulphuric acids of the composition as follows: 10 portions of HC1 (30%) and 80 portions of H2SO4 (60%)) and 10 portions of H2O to form pores 1-2 mcm. Micro-arc oxide coating is performed in an anode mode with the following parametres: voltage 250-300 V, pulse duration 50-100 mcs, and pulse repetition rate - 50-100 Hz, within 3-10 minutes in an aqueous solution of electrolyte of orthophosphoric acid, hydroxyapatite and calcium carbonate, of the following composition, wt %: H3PO4 - 20, Ca10(PO4)6(OH)2 - 6, CaCO3 - 9. The implant is made of titanium nanostructure with the average grain-subgrain size 60-110 mcm.

EFFECT: implant for bone tissue improves biological compatibility with a living organism.

13 cl, 3 dwg, 3 tbl, 1 ex

FIELD: medicinal equipment.

SUBSTANCE: the present innovation deals with means for restoring and/or keeping the lumen of blood vessel at treating cardio-vascular diseases due to implanting intravascular prostheses. The latter should be designed as a perforated cylindrical tube with grooves of patterned-cellular type which form at initial state periodically repeated rows of oval open rings connected with longitudinal and cross-sectional crosspieces. Repeated rows consist of the cells which in their initial state are of open oval rings the ends of which steadily come into cross-sectional crosspieces to unite these cells into the row. The second row of cells is developed due to mirror image of the first row being connected with the latter with longitudinal crosspieces. Next pairs of cellular rows are connected between each other with longitudinal crosspieces. By another variant for carrying out intravascular prosthesis, the second row of cells should be developed due to shifting the first row for the half of cellular width being connected with it by longitudinal crosspieces, as for the next cellular rows they are connected with longitudinal crosspieces. The method enables to improve flexibility of intravascular prosthesis at initial state and its rigidity at open state.

EFFECT: higher efficiency.

20 cl, 8 dwg

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