JPH0459899B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides connective tissue forming patches (medical patches).
More specifically, the present invention relates to a material suitable for obtaining an innovative medical patch that has connective tissue derived from a living body and has excellent biocompatibility and ease of handling.

(Prior Art) The medical patch referred to in the present invention refers to a sheet-like material for repairing biological organs, and conventionally, such a patch has mainly been a fibrous sheet mainly made of woven, knitted, or non-woven fabric. has been used. However, in the conventional case, it is an artificial product that has no relation to the living body, and when it is implanted in the living body, the reaction of the living body causes unexpected problems such as inflammatory reactions, scar tissue formation, blood clot formation, and infection depending on the site. I was often caught in the middle of nowhere. For example, in conventional atrial septal or ventricular septal defect repair surgery,
Even if a patch is applied to repair this area, thrombus formation and detachment will occur in this patch area, and this detached thrombus will be carried to other, more narrow parts of the body, where it will become clogged and cause serious damage. It is often reported that it causes As a solution to this
Vigorous studies continue to be conducted from the perspective of antithrombotic materials. However, even with the use of materials that are currently considered to have the highest antithrombotic properties, it is difficult to say that this problem has been completely solved. In other words, when using that material, there may be cases in which no traces of blood clots are observed on the surface of the material itself, but there are many cases where thrombotic occlusion disorders are clearly recognized in other parts of the body. We cannot help but think that instantaneous thrombus formation and detachment are occurring for some reason.
In addition, when conventional patches are used to repair blood vessel walls, for example, porous patches with as low density as possible are desirable in order to organize them with living tissue, but porous patches tend to leak blood significantly. Also,
If it is densely packed in order to prevent blood leakage, the organization of biological cells through adhesion formation will be hindered. A sufficient balance of this has not yet been developed.

Other types of patches as prior art
The use of other living tissues or organs is called bioprosthesis. A typical example of this is a sheet made from the pericardium of pigs, cows, horses, etc. treated with glutaraldehyde. this
A major drawback of bioprosthesis is that it is difficult to obtain one with sufficient strength, desired size (size, thickness), and uniform quality. In addition, in common with the conventional products mentioned above, satisfactory handling aspects such as ease of anastomosis, ease of sewing, and resistance to fraying (no cutting of the seams) are not achieved.

(Problems to be Solved by the Invention) The present invention aims to provide a material for forming an epoch-making new medical patch that improves the above-mentioned conventional drawbacks. That is, the present invention has a fiber base material in which connective tissue of biological origin is firmly and uniformly integrated, and has excellent biocompatibility, sufficient strength, homogeneity and sufficient size,
Furthermore, it is an object of the present invention to provide a material for forming a patch that has good handling properties.

(Means for solving problems) The present invention has the following configuration.

(1) A mandrel having a thickness comparable to the inner diameter of the fibrous cylindrical body and non-adhesive to biological cells is fitted over substantially the entire length direction. A medical material for connective tissue forming patches characterized by:

(2) The medical material for a connective tissue forming patch according to (1), wherein at least the inner surface of the fibrous material is made of ultrafine fibers of 0.8 denier or less.

(3) The medical material for connective tissue forming patch according to (1), wherein the mandrel is made of silicone-based, fluorine-based, or olefin-based plastic.

(4) The medical material for connective tissue forming patches according to (2), wherein the ultrafine fibers are polyester fibers.

(5) Fray resistance value T and water permeability Q of the cylindrical fibrous material
The medical material for connective tissue forming patch according to (2), wherein T×Q>300.

(6) The medical material for a connective tissue forming patch according to (2), wherein the fibrous material has a hydrophilic surface.

(7) The medical material for a connective tissue forming patch according to (1), wherein the patch material is covered with a bioabsorbable polymer.

As described above, the gist of the present invention is to first use a mandrel made of a material to which biological tissue is relatively difficult to adhere when implanted into a living body, and to cover the mandrel with a fibrous material so as to surround it in a ring shape along the length of the mandrel. It is something that As for the material that can be used for this mandrel, it is necessary to select a material to which living tissue is difficult to firmly adhere. The extent of this adhesion will be understood in accordance with the next objective of the present invention. That is, in order to form a patch using the product of the present invention, first the product of the present invention is implanted into a living body, and then it is quickly and uniformly applied to the inside and surface of the fibrous material (fiber base material) and firmly attached to the fiber base material. After forming an integrated living tissue, it is taken out of the body, the outer part that is raised like a lump of flesh is scraped off, the mandrel is removed, and a cylindrical object made by integrating the fiber base material and living cells is made. A common method is to cut it open, make it into a sheet, and then patch it. The order of removing the mandrel and scraping off the raised flesh on the outside may be changed as appropriate.

In taking such measures, the advantage of using a cylindrical shape with a core as in the present invention is that when implanted in a living body, it does not take up space and reduces unnecessary stimulation to the living body. , prevents the exhaustion of the body's physical strength. The cylindrical shape has a substantially linear effect, rather than a planar expansion, and the attachment of living tissue takes place in a more limited location within the body, resulting in a uniform overall appearance. On the mandrel,
An extremely smooth and uniform biological tissue plane is formed.
That is, because of the cylindrical shape into which the mandrel is inserted, tissue attachment formation is first performed from the outside toward the inside, and as the tissue formation progresses, the tissue formation passes through the fibrous material base material and reaches the top of the mandrel. At this time, by leaving an appropriate gap between the mandrel and the cylindrical base material, it is possible to form a biological tissue layer having a uniform and substantially constant thickness from the base material surface without impairing tissue formation.

On the outside, which is not in contact with the mandrel, the thickness of tissue attachment is irregular, and lump-like protuberances can be seen. Therefore, when used as a patch, the outer tissue layer is appropriately scraped off and smoothed.

In the present invention, at least the inner surface in contact with the mandrel is extremely uniform and forms a thin smooth tissue surface, so even if the outer surface is partially scraped off, a uniform and flexible sheet-like patch can be obtained as a whole. It is. The resulting patch can be flat and homogeneous without undulations or wrinkles. This is because the cylindrical object is fixed by the mandrel, so uneven shrinkage caused by scar tissue or uneven cell formation, which tends to occur when implanted in sheet form, does not occur.

In the present invention, an extremely important point is how to remove the mandrel without damaging tissue as much as possible when it is taken out of the body. Therefore, the material that can be used for the mandrel is one that can fill the inner space of the cylindrical fiber base material and control the tissue formation on its surface in a geometric sense due to its function. In addition, the mandrel must be easily removed without damaging the tissue, that is, it must have low adhesion to the tissue.

It is also important that when implanted into a living body, it does not give the living body a sense of discomfort (feeling like a foreign body). For this purpose, it is desirable that it be as flexible as possible and that there is no risk of damaging the living body during movement. From this point of view, as materials for the mandrel, inorganic materials such as aluminum, stainless steel, steel, ceramics, etc., and organic materials such as silicone-based, fluorine-based, vinyl-based, polyester-based, polyamide-based, and other general plastics are used as appropriate. It is possible. When using such materials, those that have weak adhesion to living tissue can be used as is, but for those that have strong adhesion, measures must be taken to weaken the adhesion, such as making the surface as smooth as possible, or removing biological tissue from the surface. It is effective to treat it with a treatment agent that weakens its properties. As such processing agents, it is effective to subject silicone, fluorine resin, generally known antithrombotic agents such as heparin, urokinase, hydrogel, aspirin, etc. to simple treatment, ionic bonding, or covalent bonding. Plastic is particularly preferred when a flexible material is required. Also, in this case, it is possible to make it more flexible by forming it into a hollow tube shape. Particularly preferable examples of the mandrel material include silicone, fluorine, vinyl-based plastics, and the like.

In the present invention, the term cylindrical should be understood merely in a figurative sense. In other words, although it is desirable that the cylindrical cross section be circular, it is not necessarily necessary to stick to this, and it may be elliptical,
Naturally, applied cross-sectional shapes based on triangular, rectangular, etc. are also included.

The thickness of the mandrel varies depending on the purpose, so it cannot be determined unambiguously. However, in general, it is better if it is slightly thinner than the cylindrical object. If the gap between the mandrel and the cylinder is too tight, the biofilm layer formed on the inner surface of the cylinder will not develop sufficiently, and if it is too loose, the film thickness will be uneven and a uniform sheet surface will not be formed. . It is preferable that the distance is such that the cylindrical objects can be shifted relatively smoothly, and that the gap is not too large. As a more specific guideline, the equivalent diameter D(i) of the mandrel with respect to the equivalent diameter D(t) of the cylindrical body is preferably about 0.1 mm<D(t)-D(i)<3 mm.

However, the present invention is not necessarily limited to this.

A fibrous material that is biocompatible and does not substantially deteriorate in the living body is one that causes less rejection by the living body when implanted in the living body, and shows less deterioration in strength even after long-term use. Specifically, synthetic fibers in a general sense that do not easily deteriorate in vivo, fibers that are fibrillated by stretching plastic tubes, and even natural fibers that are special. Biocompatibility has been imparted through a process. Particularly preferred are polyester, polyurethane, polysulfone, polyamide,
Polyolefin, polyvinyl chloride, fluorine resin,
It is composed of a fibrous material consisting of. Among these, polyester is particularly preferred. Furthermore, in the present invention, when implanted in a living body, the key point is how quickly and uniformly the tissue can be formed so that the fiber base material and the tissue are firmly integrated. In order to more effectively perform cell formation and fixation and integration with the fiber base material, it is more preferable that the fiber base material is made of a hydrophilic material. Such hydrophilic materials include, for example, those having hydrophilic functional groups, such as copolymers with sulfone groups, polyethylene glycol, vinylpyrrolidone, and acrylamide, and physical means such as hydrophilic treatment by plasma treatment at high electric field pressure, There are other ways to develop this, such as those that use naturally derived hydrophilic fibers such as collagen and cellulose. By appropriately using these means, the present invention exhibits its effects even more.

Further, as another means for carrying out the present invention more effectively, it is preferable to add a polymer having good biocompatibility and bioabsorption. Such bioabsorbable polymers include purified or regenerated collagen, gelatin, fibrin, chitin, chitosan, polyaminoacids, cellulose, starch, polyglycolic acid, polylactate acid, polyvinyl alcohol, and the like. By adding such a polymer, it is possible to further accelerate biocompatibility, and when cells are sufficiently formed and the patch is organized in the living body, such polymer will be absorbed by the living body, and the adverse effects of the artificial material will be avoided. This is because it can reduce the amount of Appropriate methods such as impregnation, coating, and spraying can be used for application. Furthermore, by applying antithrombotic treatment after applying the polymer, it can be used in areas where thrombus formation is a problem. Such antithrombotic treatments involve directly or indirectly binding an antithrombotic agent to a bioabsorbable polymer. Examples of antithrombotic agents include mucopolysaccharides such as heparin, urokinase, hydrogel, acrylamide, aspirin, styrene-acrylic acid copolymer, and the like. There are methods such as directly applying these, ionically bonding using a mediator, or direct graft polymerization. An example of mediating the intermediary agent is, for example, using an epoxy compound having a quaternary ammonium ion, bonding the epoxy group to the fiber base material constituting the patch, and ionic bonding between the ammonium ion and heparin. It is. An example of direct graft polymerization is grafting acrylamide onto a plasma-treated patch substrate. Such means may be carried out by appropriately using known means depending on the purpose.

Flexibility and resistance to fraying of the patch thus obtained are also very important properties required of the patch.
To achieve this, the thickness of the fibers of the fibrous material is preferably 1.4 denier or less, preferably 0.8 denier or less, more preferably 0.5 denier or less.
Further, by setting the denier to 0.1 denier or less, more uniform cell formation may be possible. The manufacturing and processing methods for such ultrafine fibers have already been described.
As seen in USP 3531368, USP 3350488, etc., there is a method of forming multicomponent fibers and removing or peeling one of the components to form ultrafine fibers. This ultra-fine treatment can be performed in advance and then processed into a cylindrical shape.
Alternatively, it is also possible to process the material into a cylindrical shape and then process it to make it extremely fine. Of course, it is also possible to use microfibers directly formed into ultrafine fibers without going through such a method. In the case of direct miniaturization, in order to obtain a continuous filament, the thickness must be restricted to some extent. Currently commercially available fibers have a denier of 0.1 denier or more, and in order to obtain a fiber of less than 0.1 denier, it is better to use multicomponent fibers.

If such microfibers are available in the form of filaments, they can be used to form tubes into tubes by conventional tube-forming means such as weaving, knitting, braiding, etc. If it is in the form of a staple, it can be made into a cylindrical body by first spinning it into a thread and then performing the same process, or by processing it with a nonwoven fabric, needle punching, high-pressure fluid, heat, or the like. Such means are already within the range of known techniques, and these techniques can be used in combination as appropriate. It is also possible to form a cylindrical object even more directly. An example of this is melt blowing,
By extruding molten polymer through tiny holes at high speed,
Alternatively, it can be taken and blown onto a mandrel to form a cylindrical body. With such a direct method, the fiber denier can be relatively small. However, it should be noted that in this case, the degree of crystallinity of the polymer cannot be increased in many cases, and the physical properties of the fibers often deteriorate.
Therefore, polymers that are easily crystallized by slight shear stress or have relatively high strength even without stretching are likely to be limited to, for example, polybutylene terephthalate, polyurethane, and even liquid crystal-forming polyesters. Furthermore, even if it is in the form of plastic, it is also possible to use a material that can be fibrillated into fibers by stretching. This can be achieved by making a plastic tube and then stretching it.

Although the present description has been limited to a cylindrical shape for convenience, it is not necessarily limited to this. After the fiber sheet is formed, it may be formed into a cylinder, or the fiber sheet may be simply wound around a mandrel to obtain a substantial effect. What is more desirable for such a fibrous cylindrical body is that the porosity is as high as possible and that it is resistant to fraying.

Porosity (Q) is defined as the amount of water permeation (ml) per minute per 1 cm ² area under a pressure of 120 mmHg.

This value is usually 300ml or more preferably 1000ml
From the above, preferably 2000 ml or more. This range is delicately related to the thickness of the fiber, and as the fiber becomes thinner, the porosity tends to show better results even if the porosity becomes smaller. The most preferable value for general fibers is 4000ml or more.

Further, even in the case of the same porosity, it is preferable that the fibers are uniformly and finely dispersed throughout because the cell formation state is good. However, in the case of such hyperporosity, fraying is a problem, and when sutured to a living body as a patch, sufficient fraying resistance is required. As a measure of this fraying resistance, the fraying resistance value (T) is defined as follows: Surgical thread was passed in a half loop at a distance of 3 mm from the cut end of the fibrous cylindrical body, and the thread was pulled with a tensile tester. Let T be the maximum load (g) at the time.

In the present invention, it is desirable that the relationship between T and the above-mentioned porosity Q is T×Q>300. Also, in this case, it is preferable that Q>500.

The value of T can be controlled by improving the weaving, knitting, and braiding structures. As a means to increase T, it is also possible to improve the weave by using, for example, weaving in the case of weaving, warp knitting with increased loop density in the case of knitting, and torsion lace in the case of braiding.

Partial fusion by heat is also an effective means.

Furthermore, as a means to maintain flexibility and porosity, the value of T can be significantly increased by spraying a high-speed fluid to entangle the fibers with each other. In particular, in order to entangle the fibers with each other using high-speed fluid, it is preferable that the fiber thickness be small.
In this case, a denier of 0.5 denier or less is particularly effective.
Furthermore, by having fiber nape, cell formation can be carried out smoothly, and the effect of preventing fraying by various treatments can be enhanced.

Further, the fibers can be used not only alone but also in combination with thick fibers. As a specific example, other fibers can be placed on a large mesh and entwined.

There is no need to be particular about the size of the cylindrical shape of the present invention, but 3 mm or more is preferable. If it is smaller than this, the yield will be low and it will not be efficient. Moreover, if it is too thick, the stimulation given to the living body will be too strong, which is not preferable. The thickness depends on the size of the living body to be implanted.

As described above, the present invention is an extremely important material for obtaining an ideal patch that has sufficient strength, size, uniformity, and flexibility in which the fiber base material and biological tissue are integrated. be.

When applying the product of the present invention, the patch should be
Most preferably, the product is implanted in an appropriate site of a patient requiring the patch, and cells are allowed to form sufficiently. The best results are obtained by extracting it, processing it, and using it as a patch. However, when forming living tissue, it is not necessary to focus only on the means of implantation into the living body. A feature of the present invention is that ultrafine fibers are used, which allows cell culture outside the body to be performed extremely quickly, smoothly, thinly, uniformly throughout, and firmly attached to the fiber base material. Such means can also be effectively used. When culturing living tissue outside the body, the mandrel in the present invention may not necessarily be necessary, and a sheet-shaped mandrel is also often possible. In particular, when using an extracorporeal cell culture method, the cells can be thinly attached, and the cylindrical shape can be used as an artificial blood vessel, or it can be cut open and made into a sheet to be used as a patch.

However, the most effective method is when implanted into a living body and allowed to form living cells.

When forming a patch by implanting it into a living body, a crucial point is how quickly cell formation occurs after implantation. In the present invention, this adjustment can be achieved extremely smoothly by using ultrafine fibers and by making the porosity relatively high.

Furthermore, in forming a uniform and smooth sheet-like patch, an epoch-making effect can be obtained by forming a cylindrical body into which a mandrel is inserted, attaching biological cells to the cylindrical body, and then cutting it open to form a sheet.

Furthermore, by forming the body into a cylindrical shape, the burden on the living body can be reduced and good organization can be achieved.

(Example) The effects of the present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 Using 50D-48f polyester fiber for the warp,
A cylindrical body with an inner diameter of 14.5 mm and a length of 20 cm was made using a satin weave using a sea-island type multicomponent fiber of 120D-40f, sea component polystyrene 20 parts, island component polyethylene terephthalate 80 parts, number of islands 36/f as the weft. Formed.
This was soaked in toluene, dried, and then lightly brushed. Furthermore, ultra-fine napped fibers formed by spraying high-pressure water through a 0.25 mm hole were entangled. The fraying resistance value of this cylindrical body is 192g, and the porosity is
It was 3600ml. This cylindrical body has an outer diameter of 14 mm and a length of 30 mm.
A cm silicone tube was inserted into the tube, sterilized with ethylene oxide gas, and then implanted subcutaneously into the dog. After 3 weeks, the tube was taken out and the outside was evenly leveled with a scalpel, and then the silicone tube was pulled out. This extraction was relatively smooth. This was then cut lengthwise and trimmed to make a patch. The tissue and fibers were extremely strongly bonded and integrated, and the cut ends did not fray at all during trimming.

A defect of about 9 cm square was created in the experimental dog, including the peritoneum and abdominal muscles, and this patch was sewn to create an artificial abdominal wall.
It was placed in an implanted state by covering the skin above it.

Postoperatively, the experimental dog progressed well, with no abdominal wall hernias and no complications due to foreign body expulsion. When the membrane was collected one month later, it was slightly fused to the subcutaneous tissue, and new small blood vessels were observed to invade from the subcutaneous tissue into the membrane, indicating that it had already become a part of the living body. The membrane retained its original shape, did not collapse or deform, and was confirmed to be an extremely excellent patch as expected.

Examples 2, 3, 4 A polyester plastic rod was used instead of the silicone tube in Example 1 (Example 2), a thin layer of silicone oil was applied to it (Example 3), and a fluororesin tube The emulsion was applied and dried (Example 4) and tested in the same manner.

In both Examples 3 and 4, the mandrel could be pulled out very smoothly, but in Example 2, some adhesion with cells was observed and it was necessary to cut out the entire mandrel.

Comparative Example 1 The cylindrical body of Example 1 was cut into sheets, and the sheet-like shape without a core was similarly implanted into a living body and taken out in the same manner.

However, in this case, the sheet shrunk into a wakame-like shape and biological cells swelled on both sides, making it extremely difficult to form a uniform sheet.

Example 5 A web with a basis weight of 120 g/m ² was formed using the sea-island type multicomponent staple fiber in Example 1.
Waterjet punch treatment was performed at Kg/m ² pressure.
This was soaked in toluene and dried. moreover
Plasma treatment was performed under a voltage of 2.5 kV and in the presence of argon gas. The T value was 130g and the Q value was 590. This was wound spirally around a polytetrafluoroethylene rod with an outer diameter of 10 mm, tied at both ends with polypropylene surgical thread, and implanted subcutaneously into a dog. 2
When removed after a week, extremely good connective tissue had been formed.

(Effect of the invention) The present invention has the following excellent effects.

(1) This is an unprecedented medical material for connective tissue-type patches.

(2) Excellent handling properties such as fraying resistance, flexibility, anastomosis and suturing properties.

(3) There is less discomfort to the living body during implantation, and physical exhaustion of the living body can be prevented.

(4) Patches with high strength, size, and quality uniformity can be obtained. (5) Cell formation is rapid and is strongly integrated with the fiber base material.

Claims (1)

[Scope of Claims] 1 Inside the cylindrical body of the fibrous material, a mandrel having a thickness comparable to the inner diameter of the cylindrical body and non-adhesive to biological cells extends substantially throughout the length direction. A medical material for a connective tissue forming patch, characterized in that the patch is inserted over the entire length. 2. The medical material for a connective tissue forming patch according to claim 1, wherein at least the inner surface of the fibrous material is made of ultrafine fibers of 0.8 denier or less. 3. The medical material for a connective tissue forming patch according to claim 1, wherein the mandrel is made of silicone-based, fluorine-based, or olefin-based plastic. 4. The medical material for connective tissue forming patch according to claim 2, wherein the ultrafine fibers are polyester fibers. 5 The fraying resistance value T of the cylindrical fibrous material and the water permeability Q
The medical material for a connective tissue forming patch according to claim 2, wherein TxQ>300. 6. The medical material for connective tissue forming patch according to claim 2, wherein the fibrous material has a hydrophilic surface. 7. The medical material for a connective tissue forming patch according to claim 1, wherein the patch material is covered with a bioabsorbable polymer.