JPWO2019054407A1 - Neuroprotective material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a neuroprotective material which is excellent in operability, strength, kink resistance and shape retention during surgery and can be expected to have an effect of suppressing neuroma and scarring and pain and numbness considered to be associated therewith. I will provide a. SOLUTION: The tubular body is made of a bioabsorbable polymer material and has slits over the entire length along the axial direction, and the gap between the slits is 0 with respect to the length of the outer surface of the tubular body in the circumferential direction. % Or more and 25% or less, the inner diameter of the tubular body is 0.1 mm or more and 20 mm or less, the length is 1 mm or more and 100 mm or less, and the thickness is 150 μm or more and 1000 μm or less. [Selection diagram] None

Description

The present invention relates to a neuroprotective material made of a bioabsorbable polymer material used to protect nerve tissue.

Conventionally, as a reconstruction technique for nerve injury accompanied by a defect, autologous nerve transplantation has been used when the defect is large, and direct suturing has been used when the nerve stumps can be sutured to each other. In recent years, nerve reconstruction surgery has also been performed in which a tubular nerve regeneration tube made of a bioabsorbable polymer material is introduced into a peripheral nerve rupture / defect portion to promote regeneration of the ruptured or defective nerve. On the other hand, there have been reports of cases in which autologous nerve transplantation and direct suturing cause scarring of the sutured part and pain that seems to be caused by neuroma.

As a material for protecting nerve tissue, Patent Document 1 discloses a roll of a porous sheet made of collagen fibers. Rolled sheets can wrap and protect damaged tissue. Patent Document 2 discloses a nanofiber sheet made of a biocompatible material, and describes wrapping nerve tissue.

U.S. Pat. No. 9061464 U.S. Patent Application Publication No. 2017/0595591

The conventional roll-shaped sheet that can be used as a material for protecting nerve tissue is insufficient in terms of strength in the compression direction and kink resistance. Further, when suturing a sheet covering an injured nerve, it is difficult to suture the rolled and overlapping sheets, which may further damage the nerve, which is not preferable in terms of operability. Further, the non-rolled sheet-shaped neuroprotective material has problems in operability when wound around nerve tissue and sutured, strength in the compression direction, kink resistance, and cylindrical shape holding force.

In view of these problems, the present invention is considered to be excellent in operability, strength, kink resistance, and shape retention during surgery, and to be associated with neuroma and scarring observed at nerve injury sites and nerve suture sites. An object of the present invention is to provide a neuroprotective material that can be expected to have an effect of suppressing pain and numbness.

Based on the above problems, the present inventors have completed the inventions represented by the following.
[1] It is a tubular body made of a bioabsorbable polymer material and having slits over the entire length along the axial direction, and the gap between the slits is 0% with respect to the length of the outer surface of the tubular body in the circumferential direction. A neuroprotective material having an inner diameter of 0.1 mm or more and 20 mm or less, a length of 1 mm or more and 100 mm or less, and a thickness of 150 μm or more and 1000 μm or less.
[2] The neuroprotective material according to [1], wherein the bioabsorbable polymer material contains collagen and / or polyglycolic acid.
[3] The neuroprotective material according to [1] or [2], wherein the bioabsorbable polymer material contains fibrous collagen and / or fibrous polyglycolic acid.
[4] The neuroprotective material according to any one of [1] to [3], which further has a collagen layer on the inner surface and / or outer surface of the tubular body.
[5] The neuroprotective material according to any one of [1] to [4], which contains collagen having a sponge structure and / or linear collagen fibers in the lumen of the tubular body.
[6] The neuroprotective material according to [1], wherein the tubular body is made of a braided fibrous polyglycolic acid.
[7] The neuroprotective material according to [6], which further has a collagen layer on the inner surface and / or outer surface of the tubular body.
[8] The neuroprotective material according to any one of [1] to [7], wherein the maximum thickness of the tubular body is 1.5 times or less the minimum thickness. [9] Compression strength in the radial direction The neuroprotective material according to any one of [1] to [8], wherein the content is 50 Pa or more and 5000 Pa or less.
[10] A neuroprotective material characterized in that fibers made of a bioabsorbable polymer material are alternately knitted to prepare a tubular body, the tubular body is cut over the entire length along the axial direction, and a slit is provided. Manufacturing method.
[11] After alternately knitting fibers made of a bioabsorbable polymer material to prepare a tubular body, a collagen solution is applied or impregnated on the outer surface of the tubular body, and then the tubular body is axially applied. The method for producing a neuroprotective material according to [10], wherein a slit is provided by cutting along the entire length.

The neuroprotective material according to the present invention can be used to cover and protect a partially damaged or partially defective site of an unruptured nerve. As another example of use, when the nerve stumps are directly sutured to each other, they can be attached so as to cover the sutured portion and its surroundings, and can be used to protect the sutured portion. As yet another example of use, in nerve reconstruction surgery in which an autologous nerve or an allogeneic nerve is transplanted, it can be worn so as to cover the transplanted nerve including the sutured portion and used to protect the sutured portion and the transplanted nerve. ..

Since the neuroprotective material according to the present invention is not in the form of overlapping rolls, it can be easily attached to a nerve site. If it is in the form of overlapping rolls, it is necessary to pass a suture needle so as to penetrate multiple layers when suturing the material, which may damage nerves. On the other hand, in the neuroprotective material of the present invention, since the ends of the material are exposed at the time of suturing, suturing is easy. Furthermore, since it retains a cylindrical shape rather than a flat sheet-like material, it has excellent shape retention and contributes to operability and strength.

Since the neuroprotective material according to the present invention has a predetermined range in thickness and high uniformity, it has excellent properties in strength and kink resistance in the compression direction. Neuroprotective materials are used by being embedded in the body, but they must withstand external forces such as bending, twisting, pulling, and compression that are applied as the body moves, in addition to pressure from the tissues surrounding the nerve. Since the neuroprotective material of the present invention also has excellent physical properties typified by strength and kink resistance, the shape is maintained over a long period of time, the rate of bioabsorption is uniform, and the excellent neuroprotective effect associated therewith. Can be expected.

Furthermore, the neuroprotective material according to the present invention is expected to have an effect of suppressing the formation of neuromas and scars that are likely to occur at the injured site and the nerve suture site, and can suppress the pain and numbness associated therewith.

The total walking distance in the walking evaluation test of Example 2 is shown. The rate of change of the total walking distance in the walking evaluation test of Example 2 is shown. The Score result in the Score test of Example 2 is shown.

The neuroprotective material of the present invention is characterized by being a tubular body having slits over the entire length along the axial direction. The axial direction can also be said to be the longitudinal direction. That is, it looks like there is a cut from one end to the other in the axial direction. The tubular body is preferably circular, but is not limited to a substantially perfect circle and may be an ellipse.

The present invention is characterized in that the gap between the slits provided in the tubular body is 0% or more and 25% or less with respect to the length of the outer surface in the circumferential direction. The ratio of the gap is calculated from the following equation (1).
Equation (1) [Length of outer circumference of the portion corresponding to the gap when it is assumed that the gap portion in the tubular body is also continuous] / [Cylindrical shape not including the portion corresponding to the gap in the tubular body] Length of the outer surface (outer circumference) of the cylindrical wall that makes up the body] x 100
It can be calculated by the formula of.
Here, "the gap in the circumferential direction of the cylindrical shape is 0% with respect to the length of the outer surface in the circumferential direction" means that one end and the other end are in contact with each other, and the gap is visually confirmed. It is a state that cannot be done, but it is not bonded and can be opened so as to widen the gap.

In the present invention, since the gap between the slits is 0% or more with respect to the length of the outer surface in the circumferential direction, those that overlap in a roll shape are not included. When they overlap in a roll shape, there is a difference in the thickness of the cylindrical wall (or film thickness) between the overlapping part and other parts, and the compressive strength and bending stress are applied unevenly, resulting in pressure resistance. And kink resistance may not be constant. In addition, when the materials are overlapped in a roll shape, it is necessary to pass a suture needle so as to penetrate multiple layers when suturing the material, which may damage nerves. However, in the present invention, since the ends of the protective material are exposed at the time of suturing, suturing is easy. On the other hand, if the gap is greater than 25% of the length of the outer surface in the circumferential direction, a large number of suture points are required to close the gap when suturing the protective material after coating the nerve with the neuroprotective material of the present invention. Therefore, it is not preferable from the viewpoint of operability. In addition, the strength may decrease, which is not preferable. The ratio of the size of the gap to the length of the outer surface in the circumferential direction is more preferably 0% or more and 23% or less. It is more preferably 0% or more and 20% or less.

The inner diameter of the tubular body in the neuroprotective material of the present invention is 0.1 mm or more and 20 mm or less, preferably 0.3 mm or more and 15 mm or less, and more preferably 0.5 mm or more and 10 mm or less. Here, the inner diameter refers to the diameter of the internal space when it is assumed that the gap portion is also continuous in the tubular body. The length of the neuroprotective material of the present invention is 1 mm or more and 100 mm or less, preferably 5 mm or more and 80 mm or less, and more preferably 10 mm or more and 60 mm or less.

The thickness of the neuroprotective material of the present invention is in the range of 150 μm or more and 1000 μm or less. That is, the minimum thickness and the maximum thickness of the neuroprotective material are each in the range of 150 μm to 1000 μm. If the thickness is smaller than 150 μm, it may be inferior in terms of compressive strength and kink resistance. On the other hand, if the thickness is larger than 1000 μm, it takes time and effort to suture the material, and there is a concern that the tissue around the nerve may be pressed. The thickness is more preferably 200 μm or more, and the upper limit is more preferably 600 μm or less. As will be described later, the neuroprotective material may be used after being immersed in a physiological saline solution or the like immediately before use during surgery. The above thickness is measured using a dry neuroprotective material before immersion in saline. When a collagen layer is further provided on the inner surface and / or the outer surface of the neuroprotective material, the above thickness is the thickness including the collagen layer. The thickness is measured using a scanning microscope (SEM) image obtained by cutting any one point of the tubular body perpendicularly in the axial direction and photographing the cut surface.

The neuroprotective material of the present invention preferably has a maximum thickness of 1.5 times or less the minimum thickness. Conventional materials include, for example, a collagen sheet or a sheet obtained by molding polycaprolactone into a roll shape, but the thickness is not uniform and the maximum thickness varies by more than 1.5 times with respect to the minimum thickness. It was seen. Variations in thickness tend to affect compression strength and kink resistance. When the thickness variation is large, stress tends to be concentrated on the thin portion, and for example, buckling easily occurs when bending. If the proportion of the thin portion is increased, the buckling strength is lowered and kink is more likely to occur.

As the bioabsorbable polymer material in the present invention, both synthetic bioabsorbable polymers and natural bioabsorbable polymers can be used. For example, polyglycolic acid, D-polylactic acid, L-polylactic acid, DL-polylactic acid, polycaprolactone, lactic acid-caprolactone copolymer, lactic acid-glycolic acid copolymer, collagen, gelatin and the like can be mentioned. In particular, polyglycolic acid, polylactic acid, lactic acid-glycolic acid copolymer and / or collagen are preferable, and collagen and / or polyglycolic acid are more preferable. Further, fibrous collagen and / or fibrous polyglycolic acid is particularly preferable.

The bioabsorbable polymer material can be molded into a sheet shape, a tube shape, or a fibrous shape, but is preferably fibrous. Specific examples of the fibrous form include short fibers, long fibers, nanofibers, filamentous bodies, and cotton-like bodies. The fibers may be either monofilaments or multifilaments. A neuroprotective material can be produced by producing a non-woven fabric, a woven fabric, a knitted fabric, a braid (braid), or a mesh made of the fibrous material. Alternatively, the neuroprotective material can be made from a tubular body around which the fibrous material is wound. The fiber diameter of the fibrous material is usually about 1 to 1000 μm, preferably about 3 to 100 μm.

The following methods are exemplified as a method for producing the neuroprotective material of the present invention from a bioabsorbable polymer material.
[Method of producing from bioabsorbable polymer material molded into sheet]
The bioabsorbable polymer material can be melted and molded into a sheet. Explaining polyglycolic acid as an example of a synthetic bioabsorbable polymer material, it can be produced by forming a film of molten polyglycolic acid into a sheet or extruding into a sheet. As another method, a sheet-shaped bioabsorbable polymer material can be prepared by producing a non-woven fabric, a woven fabric, or a knitted fabric from polyglycolic acid formed into a fibrous form. Taking collagen as an example of a natural biopolymer material, a collagen sheet can be prepared by pouring a collagen solution into a mold so as to form a sheet and freeze-drying. As another method, a sheet-shaped bioabsorbable polymer material is produced by extruding a collagen solution into a coagulating solution to produce fibrous collagen and then producing a non-woven fabric, woven fabric or knitted fabric from the fibrous collagen. be able to. The produced sheet is wound around a core rod according to a desired inner diameter and fixed by heating and cooling to obtain a tubular neuroprotective material having a slit.

[Method of producing from bioabsorbable polymer material molded into a tube shape]
A C-shaped cylindrical neuroprotective material can be obtained by molding a bioabsorbable polymer material into a tubular body by melt extrusion and incising a part of the tubular body in the axial direction. As another method, a tubular body can be produced by melt spinning using a nozzle for hollow fibers, and the tubular body can be produced by making an axial incision.

[Method of producing from fibrous bioabsorbable polymer material]
High bioabsorbability by producing a tubular non-woven fabric, woven fabric or knitted fabric from fibrous polyglycolic acid or fibrous collagen, which are bioabsorbable polymer materials, or by producing a hollow braid using a string making machine. A tubular body made of a molecular material can be produced. By making an axial incision in a part of the tubular body thus produced, a tubular neuroprotective material having a slit can be obtained. As yet another method, a tubular body is produced by winding a fibrous bioabsorbable polymer material around a core rod, a plate-shaped base material, or the like, and a part thereof is incised in the axial direction to obtain the nerve of the present invention. Protective material can be obtained.

The neuroprotective material of the present invention may further have collagen layers on the cylindrical inner surface or outer surface or both sides thereof for reinforcement. The collagen layer can be formed by applying a collagen solution to the lumen surface and / or the outer surface, or by immersing a neuroprotective material in the collagen solution and further drying by freeze-drying or the like. The collagen layer may be a single layer or a multi-layer. In the case of multiple layers, the collagen solution having the same concentration may be applied or immersed multiple times, or the collagen solutions having different concentrations may be applied multiple times or immersed. As another method, a collagen layer can be formed by laminating a non-woven fabric of fibrous collagen in a layer or winding fibrous collagen. In this case, it may be further heated and heat-welded. By providing the collagen layer in this way, the compressive strength and the kink resistance can be further improved.

The neuroprotective material of the present invention can further contain collagen having a sponge structure, linear collagen fibers, or both in its lumen. These collagens can provide a scaffold for tissue repair and nerve regeneration. As an example, collagen having a sponge structure can be filled by filling the lumen of the present material with a collagen solution and freeze-drying it. As another method, the collagen solution is extruded or spun into fibers to prepare linear collagen fibers having the same length as or shorter than that of the present material, and then the linear collagen fibers are used as the lumen of the present material. Can be inserted into one or more fibers.

Examples of collagen used for the collagen layer and the lumen on the inner surface and / or outer surface of the neuroprotective material include type I collagen, type III collagen, type IV collagen, etc., and these may be used alone. , A plurality of them may be mixed and used. Further, as the collagen, those obtained by purifying the sodium chloride content concentration to 2.0% by weight or less, preferably 0.1 to 1.5% by weight in a dry state can be used. By using collagen having a reduced sodium chloride content, improvement in tissue repair, cell adhesion during nerve regeneration, cell proliferation, and ability to induce cell differentiation can be expected.

When a collagen layer is provided on the inner surface and / or outer surface of the neuroprotective material, and when the inner cavity is filled with collagen or contains linear collagen fibers, it is preferable to carry out a cross-linking treatment to cross-link the collagen. Examples of the cross-linking method include γ-ray cross-linking, ultraviolet cross-linking, electron beam cross-linking, thermal dehydration cross-linking, glutaaldehyde cross-linking, epoxy cross-linking, and water-soluble carbodiimide cross-linking. However, thermal dehydration cross-linking that does not affect the living body is preferable. The thermal dehydration cross-linking treatment is carried out under vacuum at a temperature of, for example, about 105 to 150 ° C., more preferably about 120 to 150 ° C., still more preferably about 140 ° C., for example, about 6 to 24 hours, more preferably about 6 to 12 hours. , More preferably for about 12 hours. If the cross-linking temperature is too high, the strength of the biodegradable and absorbent material may decrease. Further, if the crosslinking temperature is too low, a sufficient crosslinking reaction may not occur.

The neuroprotective material of the present invention has a compressive strength in the radial direction of 50 Pa or more and 5000 Pa or less. The compression strength is more preferably 100 Pa or more, and even more preferably 150 Pa or more. The upper limit is more preferably 3000 Pa or less, and further preferably 1000 Pa or less. If the compression strength is less than 50 Pa, it is likely to be crushed by the tissues surrounding the nerve, and the effect of neuroprotection may be reduced.

The compression strength is measured as follows. First, a neuroprotective material is cut to a length of 5 mm to prepare a sample, and the test force (N) when the sample is compressed to a diameter halved by a compression tester is measured. At this time, the sample is placed so that the C-shaped cylindrical opening is in the horizontal direction. Next, the compression strength (Pa) is calculated from the following equation (2).
Equation (2) Compression strength (Pa) = test force (N) / (sample outer diameter (mm) x sample length (5 mm) x 1000 x 1000)

The neuroprotective material of the present invention preferably has a curvature of 10% or more and 80% or less. More preferably, it is 20% or more and 70% or less. The curvature rate is measured as follows. The sample is cut to a length of 5 cm and immersed in saline for 30 minutes. Next, a force is gradually applied from both ends of the sample to bend it in a U shape, and the distance W (cm) between both ends of the sample when it is completely bent (buckling) is measured. The curvature rate (%) is calculated from the following formula (3).
Equation (3) Curvature (%) = (1-W / 5) x 100
It can be said that the higher the curvature rate, the less likely it is to buckle and the higher the kink resistance. When the thickness is non-uniform, stress is concentrated on the thin portion, and buckling is likely to occur. Since the present invention has a uniform thickness, it has high kink resistance.

The neuroprotective material of the present invention is preferably immersed in a physiological saline solution before use. By immersing in a physiological saline solution, the neuroprotective material can be swollen in advance to give flexibility. Further, the neuroprotective material can be cut to an appropriate length and used according to the size of the damaged part of the nerve to be protected. The neuroprotective material according to the present invention covers the sutured portion and its surroundings, the transplanted nerve and the periphery of the sutured portion when the nerve stumps are directly sutured, in addition to the partially damaged or partially defective part of the unruptured nerve. It can be attached so as to cover it. In the attached neuroprotective material, the cylindrical gap can be sutured with at least one needle, and both ends of the material and the surface layer of the nerve tissue can be moored with sutures. Since the present invention maintains a cylindrical shape, it is also one of the features that the number of sutures in the gap is reduced. The number of sutures in the gap depends on the length of the neuroprotective material used, but for example, if the length is 10 mm, 1 or 2 stitches may be used, and if the length is 30 mm, 2 to 4 stitches may be used. It's fine.

The collagen used in this example was prepared by the following method.
[Collagen preparation]
Pig skin-derived type I / III collagen (manufactured by Nippon Ham Co., Ltd.) is dissolved in distilled water (water for injection by Nippon Pharmacy, manufactured by Otsuka Pharmaceutical Factory, Ltd.), and this collagen solution is concentrated at an isoelectric point of pH 8 or more and less than 9. And freeze-dried to prepare collagen having a sodium chloride content of 2.0% by weight or less in a dry state.
[Preparation of collagen solution]
Put 396 g of 0.001 mol / l hydrochloric acid (pH 3) in a plastic bottle, put 4 g of the collagen prepared above in it, and stir well at 4 ° C. to dissolve it, and the final concentration of collagen becomes 1.0% by weight. The solution was prepared. Further, this collagen solution was diluted with the above-mentioned hydrochloric acid to prepare a collagen solution so that the final concentrations of collagen were 0.2 and 0.5% by weight, respectively.

The neuroprotective material was prepared by the following method.
[Manufacturing Example 1]
A cylindrical tubular body having an inner diameter of 3 mm and a length of 50 mm was prepared by alternately knitting a fiber bundle of 28 ultrafine fibers (diameter of about 15 μm) made of polyglycolic acid as warp and weft. Using a Teflon (registered trademark) brush on the outer surface of the tubular body, a 0.2 wt% collagen solution was applied twice, and a 0.5 wt% collagen solution was applied once, 1.0 wt%. The concentrated collagen solution was uniformly applied 17 times. In the application, after applying once, the mixture was air-dried to confirm that it was completely dried, and then the next application was performed in order. The cavity of the tubular body for which application was completed was filled with the 1.0 wt% collagen solution. After filling, freeze-drying and freeze-drying treatments were performed to sponge collagen molecules. After freeze-drying, the collagen molecules were crosslinked by thermal cross-linking at 140 ° C. for 24 hours under a reduced pressure of 1 Pa or less.

One part of this tubular body was cut over the entire length in the axial direction to obtain a tubular body having slits. At this time, the gap in the circumferential direction of the cylindrical shape was 5% with respect to the length of the outer surface in the circumferential direction. The minimum thickness of the tubular body was 340 μm, and the maximum thickness was 433 μm. The maximum thickness at this time was 1.27 times the minimum thickness.

[Manufacturing Example 2]
A cylindrical tubular body having an inner diameter of 2 mm and a length of 10 mm was prepared by alternately knitting a fiber bundle of 28 ultrafine fibers (diameter of about 15 μm) made of polyglycolic acid as warp threads and weft threads. One part of this tubular body was cut over the entire length in the axial direction to obtain a tubular body having slits. At this time, the minimum thickness was 253 μm and the maximum thickness was 285 μm. The maximum thickness at this time was 1.13 times the minimum thickness.

[Manufacturing Example 3]
A cylindrical tubular body having an inner diameter of 2 mm and a length of 10 mm was prepared by alternately knitting a fiber bundle of 28 ultrafine fibers (diameter of about 15 μm) made of polyglycolic acid as warp threads and weft threads. Using a Teflon (registered trademark) brush on the outer surface of the tubular body, a 0.2 wt% collagen solution was applied twice, and a 0.5 wt% collagen solution was applied once, 1.0 wt%. The concentrated collagen solution was uniformly applied 17 times. In the application, after applying once, the mixture was air-dried to confirm that it was completely dried, and then the next application was performed in order. The cavity of the tubular body for which application was completed was filled with the 1.0 wt% collagen solution. After filling, freeze-drying and freeze-drying treatments were performed to sponge collagen molecules. After freeze-drying, the collagen molecules were crosslinked by thermal cross-linking at 140 ° C. for 24 hours under a reduced pressure of 1 Pa or less.

One part of this tubular body was cut over the entire length in the axial direction to obtain a tubular body having slits. At this time, the minimum thickness was 253 μm and the maximum thickness was 285 μm. The maximum thickness at this time was 1.13 times the minimum thickness.

[Manufacturing Example 4]
A non-woven fabric sheet was prepared from fibrous collagen, wound around a core rod and molded into a roll shape to obtain a roll-shaped cylindrical neuroprotective material having an inner diameter of 3 mm and a length of 50 mm. The obtained neuroprotective material was involved in a length of about 60% with respect to the length of the outer circumference of the cylinder. Simply put, the material rolls about one and a half laps. At this time, the minimum thickness was 84 μm and the maximum thickness was 210 μm. The maximum thickness at this time was 2.5 times the minimum thickness. Further, the maximum thickness at the overlapping portion was 378 μm excluding the gap portion between the overlapping layers from the measurement.

(Measurement of compression strength)
Each neuroprotective material is cut to a length of 5 mm to prepare a sample, and the sample is halved in diameter by a compression tester (Autograph AGS-J, manufactured by Shimadzu Corporation, load cell capacity: 1 kN). The test force (N) when compressed to was measured. At this time, the sample was placed so that the slit of the tubular body was located in the middle of the upper and lower compression jigs when viewed from the measurer. Next, the compression strength (Pa) was calculated from the following equation (2).
Equation (2) Compression strength (Pa) = Test force (N) / Sample outer diameter (mm) x Sample length (5 mm) x 1000

(Measurement of curvature rate)
The 5 cm long material was immersed in saline for 30 minutes. Next, a force was gradually applied from both ends of the sample by hand to bend it into a U shape, and the distance W (cm) between both ends of the sample when completely bent (buckling) was measured. The curvature rate (%) was calculated from the following formula (3).
Equation (3) Curvature (%) = (1-W / 5) x 100

[Example 1]
Using the neuroprotective material prepared in Production Example 1, the compression strength and the curvature rate were measured. As a result of the measurement of the compressive strength, the test force of the neuroprotective material of Production Example 1 was 9.34 N, and the compressive strength was 533.4 Pa. As a result of measuring the curvature rate, the curvature rate of the neuroprotective material of Production Example 1 was 50%.

[Comparative Example 1]
Using the neuroprotective material produced in Production Example 4, the compression strength and the curvature rate were measured in the same manner as in Example 1. The test force of the neuroprotective material of Production Example 4 was 0.57 N, and the compressive strength was 32.6 Pa. The neuroprotective material of Production Example 4 had buckling immediately after the start of the test and was unmeasurable (curvature rate 0%).

[Example 2]
Using the neuroprotective materials prepared in Production Example 2 and Production Example 3, the effect of suppressing pain and numbness by protecting the nerve-damaged site was confirmed by animal experiments.
Male, 7-week-old CD (SD) rats were used as test animals in the experiment.
The neuroprotective materials prepared in Production Example 2 and Production Example 3 were immersed in a physiological saline solution for 20 minutes before use.
Animals were anesthetized with isoflurane and fixed in the prone position. An incision was made in the skin on the lateral side of the femur of the left hind limb, and the fascia was peeled off to expose the sciatic nerve. The sciatic nerve was detached from the surrounding tissue so as not to damage it, and the sciatic nerve was crushed by pressing with a width of 5 mm for 5 seconds using Mr. Pean's non-hooked hemostat to prepare a partial nerve injury site. The neuroprotective material prepared in Production Example 2 or Production Example 3 was wrapped so as to cover the entire site, and the entire circumference of the nerve was covered. A 9-0 nylon thread was used to secure the material perimeter and both ends to the sciatic nerve. After completion of the procedure, the muscles and skin were sutured with 4-0 nylon thread to awaken the animal. After the operation was completed, ampicillin sodium (1 g for injection of Bixillin (registered trademark), Meiji Seika Pharma Co., Ltd.) (dose: 50 mg / 0.25 mL / body) was administered subcutaneously to the back. Rats in the control group were treated in the same manner after the site of partial nerve injury was prepared, except that no neuroprotective material was used.

[Walking evaluation (motor function test)]
Walking ability was evaluated using a treadmill before and after 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks and 12 weeks after the operation. That is, start the treadmill speed at 10 m / min, increase it by 5 m / min every 3 minutes, and measure the time until the animal becomes unable to continue walking (when it falls off the walking belt 3 times). The total walking distance was calculated. If walking was not impossible until 60 minutes after the start of walking, the measurement was completed in 60 minutes.

[Result of walking evaluation]
FIG. 1 shows the total walking distance before, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, and 12 weeks after the operation. FIG. 2 shows the rate of change in total walking distance before, 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, and 12 weeks after surgery. In the control group of rats, the total walking distance and the rate of change were not significantly changed as compared with those before the operation. Even in the rats to which the neuroprotective material of Production Example 2 was applied, the total walking distance and the rate of change did not change significantly as compared with those before the operation. On the other hand, in the rats to which the neuroprotective material of Production Example 3 was applied, the total walking distance and the rate of change tended to increase from 4 weeks after the operation to 12 weeks after the operation as compared with those before the operation.

[Measurement method of Autotomy Score]
Twelve weeks after surgery, the method of Wall et al. Was used to evaluate autotomy. One of the toes of the left hind limb of the test animal had a defect in one of the toes due to a bite, and one of the five toes had peripheral joint damage (that is, the tip of the first toe was bitten off). If there was a symptom), one point was added for each according to the number of injured toes. If there was damage to the central joint of each toe (that is, a symptom of being bitten off from the base of the toe), one additional point was added according to the number of damaged toes. That is, if all the toes are damaged or deleted from the root, the score is 11 points. Self-harm behavior is thought to correspond to human neuropathic pain in response to pain or abnormal perception of the affected limb.

[Result of Autotomy Score]
FIG. 3 shows the results of the Autotomy Score evaluation. In the rats to which the neuroprotective material of Production Example 2 was applied, an average of 3.5 points of self-harm was observed. On the other hand, in the rat to which the neuroprotective material prepared in Production Example 3 was applied, the score was 0 and no self-harm was observed. It was suggested that the use of the neuroprotective material of Production Example 3 may suppress sensory abnormalities due to nerve damage.

The nerve protective material according to the present invention protects a partially damaged or partially defective part of an unruptured nerve, protects the sutured part and its surroundings when the nerve stumps are directly sutured to each other, and protects an autologous nerve or an allogeneic nerve. Can be used to protect transplanted nerves, including sutures, in nerve reconstruction surgery.

Claims (11)

It is a tubular body made of a bioabsorbable polymer material and having slits over the entire length along the axial direction, and the gap between the slits is 0% or more and 25% with respect to the length of the outer surface in the circumferential direction of the tubular body. A neuroprotective material having an inner diameter of 0.1 mm or more and 20 mm or less, a length of 1 mm or more and 100 mm or less, and a thickness of 150 μm or more and 1000 μm or less. The neuroprotective material according to claim 1, wherein the bioabsorbable polymer material contains collagen and / or polyglycolic acid. The neuroprotective material according to claim 1 or 2, wherein the bioabsorbable polymer material contains fibrous collagen and / or fibrous polyglycolic acid. The neuroprotective material according to any one of claims 1 to 3, further comprising a collagen layer on the inner surface and / or outer surface of the tubular body. The neuroprotective material according to any one of claims 1 to 4, which contains collagen having a sponge structure and / or linear collagen fibers in the lumen of the tubular body. The neuroprotective material according to claim 1, wherein the tubular body is made of a braided fibrous polyglycolic acid. The neuroprotective material according to claim 6, further comprising a collagen layer on the inner surface and / or outer surface of the tubular body. The neuroprotective material according to any one of claims 1 to 7, wherein the maximum thickness of the tubular body is 1.5 times or less the minimum thickness. The neuroprotective material according to any one of claims 1 to 8, wherein the compression strength in the radial direction is 50 Pa or more and 5000 Pa or less. A method for producing a neuroprotective material, which comprises alternately knitting fibers made of a bioabsorbable polymer material to produce a tubular body, cutting the tubular body over the entire length along the axial direction, and providing a slit. .. After alternately knitting fibers made of a bioabsorbable polymer material to prepare a tubular body, a collagen solution is applied or impregnated on the outer surface of the tubular body, and then the tubular body has a total length along the axial direction. The method for producing a neuroprotective material according to claim 10, further comprising cutting over and providing a slit.