NERVE SUTURE PATCH HAVING SELF-HEALING PROPERTY AND PRODUCTION METHOD THEREOF

Abstract

The present invention relates to a nerve suture patch having a self-healing property, and a production method thereof, and more specifically, to a self-healing nerve suture patch containing a self-healing polymer and a hydrogel, and a production method thereof. The nerve suture patch may be rapidly attached to epineurium by the adhesiveness of the hydrogel and easily suture a damaged nerve.

Claims

1. A self-healing nerve suture patch comprising a self-healing polymer and a hydrogel patch, wherein the hydrogel patch includes at least one selected from the group consisting of alginate, polyacrylamide, polyetherimide, polyethylene glycol, polyethylene oxide, polyhydroxyethyl methacrylate, polyvinyl alcohol, poly(N-isopropylacrylamide), polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polycaprolactone, gelatin, collagen, carrageenan, hydroxyalkylcellulose, alkylcellulose, silicone, rubber, agar, carboxyvinyl copolymer, polydioxolane, polyacryl acetate, polyvinyl chloride, fibrin, matrigel, gelatin methacrylate, maleic anhydride/vinyl ether, chitosan, and boronic acid.

2. The self-healing nerve suture patch of claim 1, wherein the hydrogel patch includes alginate and boronic acid.

3. The self-healing nerve suture patch of claim 2, wherein the hydrogel patch includes a conjugated polymer in which boronic acid is conjugated to alginate.

4. The self-healing nerve suture patch of claim 1, wherein the hydrogel patch further includes a nerve growth factor.

5. The self-healing nerve suture patch of claim 1, wherein the self-healing polymer includes: a first moiety including a polymer backbone selected from the group consisting of polymethylsiloxane, polyethylene oxide, perfluoropolyether, polybutylene, poly (ethylene-co-1-butylene), poly (butadiene), hydrogenated poly(butadiene), polybutylene and poly(ethylene oxide)-poly(propylene oxide) block copolymer or random copolymer and poly(hydroxyalkanoate) and 4,4′-methylenebis(phenylurea); and a second moiety including isophorone bisurea.

6. The self-healing nerve suture patch of claim 5, wherein the self-healing polymer has a Young's modulus of 1 to 3000 kPa, and an elongation of 1200% to 3000%.

7. A method for preparing a self-healing nerve suture patch, the method comprising steps of: (S1) preparing a self-healing polymer film by applying a self-healing polymer on a substrate and drying the same; (S2) treating a surface of the film with plasma; and (S3) laminating a hydrogel on the surface of the plasma-treated film.

8. The method for preparing a self-healing nerve suture patch of claim 7, wherein the hydrogel includes at least one selected from the group consisting of alginate, to polyacrylamide, polyetherimide, polyethylene glycol, polyethylene oxide, polyhydroxyethyl methacrylate, polyvinyl alcohol, poly(N-isopropylacrylamide), polyvinylpyrrolidone, polylactic acid, polyglycolic acid, polycaprolactone, gelatin, collagen, carrageenan, hydroxyalkylcellulose, alkylcellulose, silicone, rubber, agar, carboxyvinyl copolymer, polydioxolane, polyacryl acetate, polyvinyl chloride, fibrin, matrigel, gelatin methacrylate, maleic anhydride/vinyl ether, chitosan, and boronic acid.

9. The method for preparing a self-healing nerve suture patch of claim 8, wherein the hydrogel patch includes a conjugated polymer in which boronic acid is conjugated to alginate.

10. The method for preparing a self-healing nerve suture patch of claim 7, wherein the hydrogel further includes a nerve growth factor.

11. The method for preparing a self-healing nerve suture patch of claim 7, wherein the self-healing polymer includes: a first moiety including a polymer backbone selected from the group consisting of polymethylsiloxane, polyethylene oxide, perfluoropolyether, polybutylene, poly (ethylene-co-1-butylene), poly(butadiene), hydrogenated poly(butadiene), polybutylene and poly(ethylene oxide)-poly(propylene oxide) block copolymer or random copolymer and poly(hydroxyalkanoate) and 4,4′-methylenebis(phenylurea); and a second moiety including isophorone bisurea.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0026] FIG. 1 is a view schematically showing when the hydrogel patch and the self-healing polymer film in the present invention are applied to peripheral nerves.

[0027] FIG. 2 is a view showing the results of confirming the adhesive strength and physical properties of the nerve suture patch having self-healing ability according to an example embodiment of the present invention.

[0028] FIG. 3 is a view showing the results of confirming that the nerve is sutured by introducing a nerve suture patch having self-healing ability according to an example embodiment of the present invention into a cut nerve.

BEST MODE FOR CARRYING OUT THE INVENTION

[0029] The present invention can have various changes and can have various example embodiments, so specific example embodiments are illustrated in the drawings and described in detail in the detailed description.

[0030] However, this is not intended to limit the present invention to specific embodiments, it should be understood to include all modifications, equivalents and substitutes included in the spirit and technical scope of the present invention. In describing the present invention, if it is determined that a detailed description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be excluded.

[0031] The terms used in the present application are only used to describe specific example embodiments and are not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly dictates otherwise.

[0032] In the present invention, it is to be understood that terms such as “comprising” or “having” are intended to designate that the features, numbers, steps, operations, components, parts, or combinations thereof described in the specification exist, and this does not preclude the presence or addition possibility of one or more other features, numbers, steps, operations, components, parts, or combinations thereof.

[0033] The present invention relates to a nerve suture patch having self-healing ability, and more particularly, to a nerve suture patch having self-healing ability capable of chemical bonding with an epineurium.

[0034] In one example embodiment of the present invention, there is provided the self-healing nerve suture patch which is characterized in that it includes a self-healing polymer and a hydrogel patch, and the hydrogel patch includes at least one selected from the group consisting of alginate, polyacrylamide (PAA), polyetherimide (PEI), polyethylene glycol (PEG), polyethylene oxide (PEO), polyhydroxyethyl methacrylate (PHEMA), polyvinyl alcohol (PVA), poly(N-isopropylacrylamide) (PNIPAM), polyvinylpyrrolidone (PVP), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), gelatin, collagen, carrageenan, hydroxyalkylcellulose, alkylcellulose, silicone, rubber, agar, carboxyvinyl copolymer, polydioxolane, polyacryl acetate, polyvinyl chloride, fibrin, matrigel, gelatin methacrylate (GelMA), maleic anhydride/vinyl ether, chitosan, and boronic acid.

[0035] Prior to the description, among the terms used in the present invention, the term “self-healing polymer” may refer to a polymer that recognizes a damaged or scratched area by itself and restores it to a previous state. In particular, in one example embodiment of the present invention, the combination of the dynamic stress relaxation characteristics of the self-healing polymer and the low modulus of the hydrogel has advantages in preventing nerve necrosis due to nerve compression and facilitating nerve regeneration.

[0036] FIG. 1 is a view schematically showing a process of i applying a self-healing nerve suture patch of the present invention into peripheral nerves.

[0037] Referring to FIG. 1, the self-healing nerve suture patch according to an example embodiment of the present invention includes a self-healing polymer and a hydrogel patch. Specifically, a hydrogel patch may be included on one side of the self-healing polymer film, and when the self-healing nerve suture patch is applied to the epineurium, the hydrogel patch may be attached to the epineurium.

[0038] In a specific embodiment, the hydrogel patch may include at least one selected from the group consisting of alginate, polyacrylamide (PAA), polyetherimide (PEI), polyethylene glycol (PEG), polyethylene oxide (PEO), polyhydroxyethyl methacrylate (PHEMA), polyvinyl alcohol (PVA), poly(N-isopropylacrylamide) (PNIPAM), polyvinylpyrrolidone (PVP), polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL), gelatin, collagen, carrageenan, hydroxyalkylcellulose, alkylcellulose, silicone, rubber, agar, carboxyvinyl copolymer, polydioxolane, polyacryl acetate, polyvinyl chloride, fibrin, matrigel, gelatin methacrylate (GelMA), maleic anhydride/vinyl ether, chitosan, and boronic acid. For example, the hydrogel patch includes alginate and boronic acid and may include a conjugated polymer in which boronic acid is conjugated to alginate.

[0039] In addition, the hydrogel patch according to an example embodiment of the present invention may further include a nerve growth factor (NGF, neurotrophic factor), and the nerve growth factor may facilitate nerve regeneration during nerve suturing.

[0040] The hydrogel patch is manufactured by combining a gel-forming agent and a crosslinking agent, and a transdermally absorbable formulation having a patch form is designed to fundamentally solve the problem of conventional skin irritation, the toxicity due to residual solvent and/or unreacted monomer, and crosslinking for a long time.

[0041] Moreover, the self-healing polymer may include: a first moiety including a polymer backbone selected from the group consisting of polydimethylsiloxane (PDMS), polyethylene oxide (PEO), perfluoropolyether (PFPE), polybutylene (PB), poly(ethylene-co-1-butylene), poly(butadiene), hydrogenated poly(butadiene), polybutylene and poly(ethylene oxide)-poly(propylene oxide) block copolymer or random copolymer and poly(hydroxyalkanoate) and 4,4′-methylenebis(phenylurea) (MPU); and a second moiety including isophorone bisurea (IU). Thus, the self-healing polymer may have a Young's modulus of 1 to 3000 kPa, and an elongation of 1200% to 3000%. The self-healing polymer of the present invention has the same Young's modulus and elongation as described above, so it has a modulus similar to that of a peripheral nerve. Accordingly, when wrapped around and in contact with a damaged nerve, shear force and compression can be minimized

[0042] More specifically, the self-healing polymer may be a PDMS-MPU.sub.x-IU.sub.1-x polymer represented by Chemical Formula 1 below. Meanwhile, x may be in the range of 0.3 to 0.6.

##STR00001##

[0043] Furthermore, the alginate-boronic acid conjugate polymer is applied to the polymer film made of the self-healing polymer to prepare a self-healing nerve suture patch. 10% of the total polymer chain of the alginate may be substituted with boronic acid, and through this, it has adhesiveness and can be easily attached to the nerve.

[0044] As described above, the nerve suture patch includes a self-healing polymer and an adhesive polymer film, and the adhesive polymer film includes a polysaccharide material such as alginate.

[0045] As described above, the patch in which the polysaccharide material is thinly coated on the self-healing polymer can be applied to the nerve part. Through this, the patch of the present invention can easily suture the severed nerve.

[0046] In addition, the nerve suture patch may further include nerve growth factor (NGF) in the alginate-boronic acid conjugated polymer.

[0047] As described above, unlike the conventional nerve conduit having a different modulus from that of a peripheral nerve to generate nerve compression, the present invention uses a patch containing a self-healing polymer having excellent stress relaxation characteristics to relieve nerve compression and grafts a hydrogel having a mechanical modulus of 10 to 99 kPa to the self-healing polymer to provide a nerve suture patch kit having a similar modulus to that of the peripheral nerve, thereby removing the nerve compression.

[0048] Accordingly, the present invention can provide a method for nerve splice using the above-described kit for nerve suturing, and the method for nerve splicing surgery may include the following steps:

[0049] (1) covering both cuts of the cut nerve with the self-healing nerve suture patch and contacting them;

[0050] (2) leaving them after the contact; and

[0051] (3) removing the nerve suture patch.

[0052] In addition, the present invention may provide a method for preparing a self-healing nerve suture patch, the method including steps of:

[0053] (S1) preparing a self-healing polymer film by applying a self-healing polymer on a substrate and drying the same;

[0054] (S2) treating the surface of the film with plasma; and

[0055] (S3) laminating a hydrogel on the surface of the plasma-treated film.

[0056] The plasma treatment is oxygen plasma treatment. By treatment with plasma, the surface of the self-healing polymer is modified to be hydrophilic so that the hydrogel can be easily laminated.

[0057] Hereinafter, the present invention will be described with reference to the following examples. However, the examples are for describing the present invention in detail, and the scope of the present invention is not limited to the following examples.

EXAMPLE

Example 1. Preparation of Nerve Suture Patch Having Self-Healing Ability

[0058] 1-1. Preparation of Polymer Films

[0059] A self-healing polymer film was prepared by using a polymer of PDMS-MPU.sub.x-IU.sub.1-x of the following formula (1).

##STR00002##

[0060] A PDMS-MPU.sub.0.4-IU.sub.0.6 film was prepared. Specifically, 4 g of PDMS-MPU.sub.0.4-IU.sub.0.6 in CHCl.sub.3 was stirred at 50° C. for 3 hours and then cooled at room temperature. Then, the solution was poured onto an OTS-treated silicon substrate (e.g., 4 inches), dried at room temperature for 6 hours, and then dried at about 80° C. under reduced pressure (about 100 torrs) for 3 hours.

[0061] Accordingly, a self-healing polymer film was prepared. The polymer film had a thickness of 0.5 mm. Then, the film was cut to a size of 1 cm×1 cm.

[0062] The surface of the prepared self-healing polymer film was treated with oxygen plasma to modify the surface of the self-healing polymer film to be hydrophilic. Then, an adhesive polymer was synthesized for lamination on the surface of the self-healing polymer film.

[0063] 1-2. Alginate-Boronic Acid Production Method

[0064] 1 g of alginate polymer was dissolved in 250 mL of 0.1 M MES buffer (pH 4.5). 700 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 100 mg of N-hydroxysuccinimide were dissolved in 10 mL of tertiary distilled water, and the mixture was added to the alginate solution. Thereafter, 3-aminophenylboronic acid hydrochloride (300 mg) was dissolved in 10 mL of tertiary distilled water, and the mixture was added to the above solution. After 12 hours of reaction, dialysis was performed for 3 days. A dried polymer was obtained through freeze-drying. In addition, a nerve growth factor was added to the solution and mixed.

[0065] 1-3. Preparation of Nerve Suture Patches

[0066] The alginate-boronic acid conjugate was thinly coated on the self-healing polymer film prepared above in the same manner.

Example 2. Adhesion and Physical Properties of Nerve Suture Patch

[0067] 2-1. Measurement of Adhesion of Nerve Suture Patches

[0068] Nerves have strong flexibility and elasticity, so physical activity causes stress, requiring a modulus that distributes the force applied to the surgical site. Since the self-healing polymer of this nerve suture patch has flexible properties similar to that of nerve tissue, it can show the effect of improving adhesion by dispersing the stress applied to the tissue and the attached part. In order to prove the contents, through a universal test machine, a self-healing polymer-based nerve suture patch and a general silicone (PDMS)-based suture patch were prepared in the same manner as in Example 1, and they were prepared in a size of 0.5 cm in width and 1 cm in length. A polyethylene terephthalate (PET) film (backing film) was attached to the back side of the film and the tissue without the adhesive polymer. Then, the tissue and the adhesive patch were attached, and the sample was measured while stretched upwards at a rate of 20 mm per minute using a 10 N load cell. All experiments were measured three or more times, and the suture patch using a self-healing polymer improved the adhesive force more than 10 times than the silicone-based suture patch as shown in FIG. 2A.

[0069] 2-2. Measurement of Physical Properties of Nerve Suture Patches

[0070] This nerve suture patch wraps around nerves to help nerve regeneration. Therefore, elasticity of the patch generated by nerve contraction and tension is required, and additional compression should not adversely affect nerve regeneration. Conventional polymers such as PDMS have the potential to cause nerve damage due to these properties, but the self-healing polymer used in this patch dramatically reduces this compression over time. In order to measure the corresponding physical properties, the self-healing polymer of this patch was installed with a width of 5 mm and a length of 10 mm in a universal test machine and tensioned at a rate of 20 mm/min. As the polymer stretched, the force applied to the equipment increased. When the force reached 0.3 N, the tension of the polymer was stopped. Then, the stress of the polymer was analyzed over time. As shown in FIG. 2B, it was confirmed that the polymer stress was 7 kPa.

[0071] The stress relaxation effect of the polymer over time was confirmed by dividing the stress over time by the stress (0.3 N) applied to the initial polymer. As shown in FIG. 2C, it was confirmed that the force applied to the initial polymer was reduced to half compared to the initial within 1 minute and continued to decrease thereafter. These properties minimize nerve compression when applied to nerves, thereby preventing nerve necrosis and helping regeneration.

EXPERIMENTAL EXAMPLE

Experimental Example 1. Animal Preparation and Implantation of Nerve Suture Patch

[0072] All animal experiments were performed and processed in accordance with the regulations of the Korea Institute of Science and Technology Institutional Animal Care and Use Committee (Approval No. 2018-067). Experimental procedures were performed according to the Guide for the Care and Use of Laboratory Animals. For implantation of the nerve suture patch, Sprague-Dawley rats (male, 300 g) were anesthetized using Zoletil and Xylize cocktail (3:1 mg/kg) by intraperitoneal injection. After a deep level of anesthesia was carried out, a skin incision was extended to the dorsal side of the paw in order to expose the hind paw muscles. The femoral-biceps and semitendinosus muscles were identified, and the sciatic nerve was exposed from the muscle, and then the nerve was cut (FIG. 3A).

[0073] As shown in FIGS. 3B and 3C, surgery was operated in which both cut nerves were placed in the middle of the film and then were winded with the nerve suture patch prepared in Example 1. Comparing the time required at this time, as shown in FIG. 3F, it was about 70 seconds, which can save more than 10 times compared to the operation time using the existing suture thread.

[0074] As shown in FIGS. 3D and 3E, when the patch was opened 10 days after nerve surgery, it was observed that fibrosis did not progress around the nerve and the cut nerve was recovered. To determine the degree of recovery after surgery, the sciatic functional index (SFI) evaluation method and the myelin sheath thickness (g-ratio, axon diameter/total fiber diameter, normal range: 0.6-0.8) measurement method were used.

[0075] FIG. 3G shows the experimental design for measuring the sciatic nerve index. The front and back paws of the mouse were stained with black ink, and the mouse was lured into a black box. The sciatic nerve index level was measured based on the footprints taken. The sciatic nerve index could be obtained by substituting the total plantar length (PL), the distance between the first to fifth toes (TS), and the distance between the second and fourth toes and the middle toes (IT) into the formula. It was expressed on a scale from −100 without neural function to 0 with normal function. As shown in FIG. 3H, it was confirmed that the functional recovery of the nerve was further improved by the nerve suture patch compared to the suture thread. In addition, the recovery rate according to nerve conductance could be measured by obtaining the ratio of the total outer diameter to the inner axon diameter during nerve recovery through the thickness of myelin (G-ratio). As shown in FIG. 3I, the normal range was 0.6 to 0.8, and the same recovery rate was observed as the suture thread after 12 weeks.

[0076] The above results confirmed that the nerve suture patch of the present invention has an excellent recovery effect on a cut nerve.

[0077] In the above, a specific portion of the present invention has been described in detail, and it is clear for those of ordinary skill in the art that this specific description is only a preferred example embodiment, and the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention is defined by the appended claims and their equivalents.