Biodegradable hydrogel nerve conduit combined with triboelectric generator for maximizing regeneration of severed nerves

Abstract

The present invention relates to a nerve conduit comprising: a conduit body that connects both sides of a severed nerve within a living body; a triboelectric generator electrically connected to the severed nerve through the conduit body to transmit an electrical signal generated by the application of ultrasound to the severed nerve; and an encapsulation layer covering the triboelectric generator, wherein the conduit body, the triboelectric generator, and the encapsulation layer are made of biodegradable materials. This invention is an output of the research project "SONOSTIM: Ultrasound-Based Triboelectric Generator Applied to Electronic Nerve Stimulation Technology for Pain-Free Peripheral Nerve Stimulation," supported by the Ministry of SMEs and Startups, managed by the Korea Technology and Information Promotion Agency for SMEs, as part of the Entrepreneurship-Oriented University Program (Project ID: 20176104), with Energy Mining as the executing institution. The research period was from 1 May 2023, to 31 December 2023.

Description

Biodegradable hydrogel nerve conduit with triboelectric generator for maximizing severed nerve regeneration

[0001] The present invention relates to a nerve conduit, and more particularly, to a biodegradable hydrogel nerve conduit combined with a triboelectric generator for maximizing regeneration of severed nerves.

[0002] If a nerve is severed due to an accident or surgery, surgery is performed to suture both sides of the severed nerve.

[0003] If the distance between the two sides of the severed nerve is less than 5 mm, it can be easily treated by suturing both sides of the severed nerve or connecting both sides of the severed nerve with a guide catheter.

[0004] However, if the distance between the two sides of the severed nerve is more than 5 mm, treatment by suturing both sides of the severed nerve or connecting both sides of the severed nerve with a guide catheter is not possible.

[0005] Therefore, if the gap between the two sides of the severed nerve is greater than 5 mm, treatment can be achieved using autografts and guide tubes. However, autografts have the disadvantage of causing damage to the nerve harvest site and making multiple applications impossible. For reference, autografts involve harvesting nerves from other parts of the body with little or no use and transplanting them directly to either side of the severed nerve.

[0006] Accordingly, a technology has recently been developed to promote regeneration of severed nerves by connecting both sides of the severed nerve with a conductive hydrogel as an alternative to autograft.

[0007] However, connecting both sides of the severed nerve with a conductive hydrogel had the problem of poor regeneration of the severed nerve compared to autograft and not resolving biostability.

[0008] The present invention has been devised to solve the above-described problems, and the purpose of the present invention is to provide a nerve conduit that can transmit an electric signal to a severed nerve to promote regeneration of the severed nerve.

[0009] The problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0010] A nerve conduit according to one embodiment of the present invention comprises: a conduit body connecting both sides of a severed nerve in a living body; a triboelectric generator electrically connected to the severed nerve through the conduit body to transmit an electric signal generated by application of ultrasound to the severed nerve; and an encapsulation layer covering the triboelectric generator, wherein the conduit body, the triboelectric generator, and the encapsulation layer are made of a biodegradable material.

[0011] In addition, the encapsulation layer comprises one of PLGA [poly(lactic-co-glycolic acid)] and PHBV [poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid)], and the encapsulation layer can be cracked by application of ultrasonic waves having a reference intensity or higher.

[0012] In addition, the frictional electric generator may include a friction layer provided in the conduit body and vibrating by application of the ultrasonic waves; and an electrode layer provided on the inner surface of the encapsulation layer and electrically connected to the conduit body, and generating frictional electricity by friction with the friction layer.

[0013] Additionally, the friction layer may include any one of PLGA [poly(lactic-co-glycolic acid)], PVA (polyvinylalcohol), and PEG (polyehthylene glycol).

[0014] Additionally, the electrode layer may include either Mg or Mo.

[0015] Additionally, a spacer may be further included to separate the friction layer and the electrode layer from each other.

[0016] Additionally, proteinase K, which accelerates biodegradation by body fluids of a living body, can be stored between the conduit body and the encapsulation layer.

[0017] Additionally, the conduit body may contain stem cells for transplantation.

[0018] Additionally, the conduit body may further include a bonding layer provided on the inner surface thereof to be bonded to at least one side of the cut nerve.

[0019] Additionally, the above bonding layer may be a mixture of a biodegradable material with a catechol functional group, a gallic functional group, and a plant-derived polyphenol.

[0020] Other specific details of the present invention are included in the detailed description and drawings.

[0021] A nerve conduit according to one embodiment of the present invention has the effect of promoting regeneration of a severed nerve by transmitting an electrical signal to the severed nerve.

[0022] In addition, the nerve conduit according to one embodiment of the present invention can transmit the electrical signal generated from the triboelectric generator to the severed nerve with minimal loss, since the optimal impedance of the electrical signal generated from the triboelectric generator is similar to the impedance of the severed nerve.

[0023] In addition, the nerve conduit according to one embodiment of the present invention has the effect of accelerating biodegradation within a living body by causing cracks to occur upon application of ultrasound of a certain intensity or higher.

[0024] The effects of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below.

[0025] Figure 1 is a perspective view showing a nerve conduit according to one embodiment of the present invention.

[0026] Figure 2 is an exploded perspective view showing a nerve conduit according to one embodiment of the present invention.

[0027] Figure 3 is a cross-sectional view showing a nerve conduit according to one embodiment of the present invention.

[0028] Figure 4 is a cross-sectional view showing a state in which a crack occurs in a nerve conduit due to application of ultrasound of a certain intensity or higher according to one embodiment of the present invention.

[0029] FIG. 5 is a graph showing the RMS power of a triboelectric generator according to the impedance of the main body of a nerve conduit according to one embodiment of the present invention.

[0030] FIG. 6 is a graph showing the impedance of a triboelectric generator according to the size of the electrode layer of a nerve conduit according to one embodiment of the present invention.

[0031] FIG. 7 is a graph showing the impedance of a frictional electric generator according to the operating frequency of the frictional electric generator of a nerve conduit according to one embodiment of the present invention.

[0032] Figure 8 is a perspective view showing a nerve conduit according to another embodiment of the present invention.

[0033] The advantages and features of the present invention, and the methods for achieving them, will become clearer with reference to the embodiments described in detail below together with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below and may be implemented in various different forms. These embodiments are provided solely to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the present invention, and the present invention is defined solely by the scope of the claims.

[0034] The terminology used herein is for the purpose of describing embodiments only and is not intended to limit the present invention. In this specification, the singular also includes the plural unless specifically stated otherwise. As used herein, the terms "comprises" and / or "comprising" do not exclude the presence or addition of one or more other components in addition to the mentioned components. The same reference numerals refer to the same components throughout the specification, and "and / or" includes each and every combination of one or more of the mentioned components.

[0035] Unless otherwise defined, all terms (including technical and scientific terms) used herein may be used in their common sense to those skilled in the art to which the present invention pertains. Furthermore, terms defined in commonly used dictionaries are not to be interpreted ideally or excessively unless explicitly and specifically defined otherwise.

[0036] Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings.

[0037] FIG. 1 is a perspective view showing a nerve conduit according to one embodiment of the present invention, FIG. 2 is an exploded perspective view showing a nerve conduit according to one embodiment of the present invention, FIG. 3 is a cross-sectional view showing a nerve conduit according to one embodiment of the present invention, and FIG. 4 is a cross-sectional view showing a state in which a crack occurs in a nerve conduit according to one embodiment of the present invention by applying ultrasound of a certain intensity or higher.

[0038] As illustrated in FIGS. 1 to 3, a nerve conduit according to one embodiment of the present invention may include a conduit body (100), a triboelectric generator (200), and an encapsulation layer (300). Here, the conduit body (100), the triboelectric generator (200), and the encapsulation layer (300) may be made of a biodegradable material.

[0039] For example, the conduit body (100) and the triboelectric generator (200) may be made of a biodegradable material having a faster biodegradation rate than the encapsulation layer (300).

[0040] The main body of the conduit (100) serves to connect both sides of the severed nerve (10) inside the living body.

[0041] For example, the conduit body (100) may have a ring shape and an inner diameter corresponding to the outer diameter of the severed nerve (10). Accordingly, both sides of the severed nerve (10) may be inserted into each side of the conduit body (100).

[0042] The conductive hydrogel included in the conduit body (100) can play a role in electrically connecting both sides of the severed nerve (10). In addition, the conductive hydrogel included in the conduit body (100) has mechanical properties similar to those of a nerve, so it can minimize nerve fatigue, and has permeability, so that nerve regeneration promoting substances such as ionic cells can easily penetrate. In addition, when both sides of the severed nerve (10) are electrically connected through the conductive hydrogel included in the conduit body (100), the regeneration of the severed nerve (10) can be activated by the minute electromotive force (e.g., 100 mV or less) of the severed nerve (10) itself. However, when the regeneration of the severed nerve (10) is activated by the minute electromotive force of the severed nerve (10) itself, the regeneration of the severed nerve (10) is not promoted.

[0043] For example, the conductive hydrogel included in the conduit body (100) may be any one of GelMa, Chitosan, Collagen, and PVA, and salt may be added to improve conductivity.

[0044] For example, the conduit body (100) may further include PLGA [poly(lactic-co-glycolic acid)]. Therefore, the conduit body (100) may be cracked by application of ultrasound having a reference intensity or higher. At this time, biodegradation of the conduit body (100) may proceed as the body fluid of the living body infiltrates into the inside of the conduit body (100) through the crack that occurs in the conduit body (100). Therefore, by setting the time point at which ultrasound having a reference intensity or higher is applied to the friction layer (210), the time point at which biodegradation of the friction layer (210) proceeds may be determined. Here, the reference intensity of the ultrasound is 3 W / cm 2 It could be.

[0045] Furthermore, proteinase K may be stored between the conduit body (100) and the encapsulation layer (300). In this way, when proteinase K is stored between the conduit body (100) and the encapsulation layer (300), proteinase K is dissolved by the body fluid of the living body that has penetrated into the inside of the conduit body (100) through the crack that has occurred in the conduit body (100), and the dissolved proteinase K may act as an enzyme that accelerates the biodegradation of the nerve conduit.

[0046] For example, the conduit body (100) may include stem cells for transplantation. In this way, when stem cells for transplantation are transplanted into the conduit body (100), an electric signal is transmitted from the triboelectric generator (200) to the severed nerve (10) through the conduit body (100), and when the regeneration of the severed nerve (10) is promoted, the therapeutic effect of the stem cells is added, so that the regeneration of the severed nerve (10) can be further promoted. Such stem cells for transplantation may be transplanted into the inner surface of the conduit body (100).

[0047] The frictional electric generator (200) is electrically connected to the severed nerve (10) through the main body (100) of the conduit, and can transmit an electric signal generated by the application of ultrasound to the severed nerve (10). As a result, the electric signal transmitted from the frictional electric generator (200) to the severed nerve (10) can promote the regeneration of the severed nerve (10). For reference, the frictional electric generator (200) can transmit frictional electricity generated based on friction by the application of ultrasound to the severed nerve (10), and this frictional electricity can be an electric signal.

[0048] For example, the ultrasonic waves applied to the friction electric power generator (200) may be generated from the ultrasonic wave generator (20). The ultrasonic wave generator (20) may set the intensity of the ultrasonic waves applied to the friction electric power generator (200), and may set the time at which the ultrasonic waves are applied to the friction electric power generator (200).

[0049] As another example, the frictional electric generator (200) may have a curved plate shape with a radius corresponding to the radius of the conduit body (100).

[0050] As another example, the frictional electric generator (200) may have a ring shape corresponding to the circumference of the conduit body (100).

[0051] The triboelectric generator (200) may include a friction layer (210), an electrode layer (220), and a spacer (230).

[0052] The friction layer (210) is provided on the main body of the conduit (100) and can vibrate by application of ultrasonic waves.

[0053] For example, the friction layer (210) may include any one of PLGA [poly(lactic-co-glycolic acid)], PVA (polyvinylalcohol), and PEG (polyehthylene glycol).

[0054] The electrode layer (220) is provided on the inner surface of the encapsulation layer (300) and can generate frictional electricity through friction with the friction layer (210). This frictional electricity can be identical to an electric signal.

[0055] For example, the electrode layer (220) may include either Mg or Mo.

[0056] As another example, the electrode layer (220) is connected to the conduit body (100) through the electrode lead line (221), so that frictional electricity generated in the electrode layer (220) can be transmitted to the conduit body (100) through the electrode lead line (221).

[0057] The electrode lead line (221) can extend from the electrode layer (220) to the conduit body (100) and be connected to the conduit body (100). Therefore, since the electrode layer (220) is connected to the conduit body (100) through the electrode lead line (221), a separate wire is not required.

[0058] The spacer (230) serves to separate the friction layer (210) and the electrode layer (220) from each other. The reason why the spacer (230) separates the friction layer (210) and the electrode layer (220) is to prevent the friction layer (210) and the electrode layer (220) from being separated after being attached due to friction between the friction layer (210) and the electrode layer (220).

[0059] For example, the spacer (230) is provided around the friction layer (210) and has a thickness thicker than the friction layer (210), so that it can serve to mutually separate the friction layer (210) and the electrode layer (220).

[0060] For example, the optimal impedance of the triboelectric generator (200) varies depending on the ultrasonic frequency applied to the triboelectric generator (200) and the size of the electrode layer (220), but is generally 30 to 300 kΩ. This optimal impedance of the triboelectric generator (200) is similar to the impedance of the nerve, and by forming the optimal impedance of the triboelectric generator (200) to be similar to the impedance of the conduit body (100), the loss of the electric signal transmitted from the triboelectric generator (200) to the severed nerve (10) through the conduit body (100) can be minimized, and the optimal electric signal can be transmitted from the triboelectric generator (200) to the conduit body (100). Therefore, the nerve conduit according to one embodiment of the present invention can transmit the electric signal generated from the frictional electric generator (200) to the severed nerve (10) with minimal loss, since the optimal impedance of the electric signal generated from the frictional electric generator (200) is similar to the impedance of the severed nerve (10).

[0061] The encapsulation layer (300) serves to cover the triboelectric generator (200).

[0062] As illustrated in FIG. 4, the encapsulation layer (300) includes either PLGA [poly(lactic-co-glycolic acid)] or PHBV [poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid)], and may be cracked by application of ultrasonic waves having a reference intensity or higher. At this time, when a crack occurs in the encapsulation layer (300), the electrode layer (220) coupled to the encapsulation layer (300) is also mechanically cracked, and as body fluids of a living body penetrate into the encapsulation layer (300) and the electrode layer (220), biodegradation of the encapsulation layer (300) and the electrode layer (220) may proceed. Therefore, by setting a time point at which ultrasonic waves having a reference intensity or higher are applied to the encapsulation layer (300), the time point at which biodegradation of the encapsulation layer (300) proceeds can be determined. Here, the reference intensity of ultrasound is 3W / cm 2 may be, and the encapsulation layer (300) is 3W / cm 2 Cracks may occur due to the application of the above ultrasonic waves. For reference, until ultrasonic waves exceeding the reference intensity are applied to the encapsulation layer (300), the encapsulation layer (300) may serve to protect the triboelectric generator (200) from the body fluids inside the living body.

[0063] Furthermore, proteinase K may be stored between the conduit body (100) and the encapsulation layer (300). In this way, when proteinase K is stored between the conduit body (100) and the encapsulation layer (300), the proteinase K is dissolved by the body fluid of the living body that has penetrated into the encapsulation layer (300) through the cracks that occur in the encapsulation layer (300) and the electrode layer (220), and the dissolved proteinase K may act as an enzyme that accelerates the biodegradation of the nerve conduit.

[0064] For example, in a severed nerve (10), the cell membrane acts as a dielectric, so that the severed nerve (10) can be modeled as an electric circuit in which multiple capacitors and resistors are connected. Accordingly, as the frequency of the ultrasonic wave applied to the severed nerve (10) increases, the reactance of the capacitor decreases, so that the electric signal can be better transmitted to the severed nerve (10). Furthermore, the ultrasonic wave applied to the triboelectric generator (200) may be in a high-frequency range of 20 kHz or more. When such high-frequency ultrasonic wave is applied to the triboelectric generator (200), the efficiency of the triboelectric generator (200) transmitting an electric signal to the severed nerve (10) can be improved compared to when a low-frequency ultrasonic wave is applied.

[0065] FIG. 5 is a graph showing the RMS power of the triboelectric generator (200) according to the impedance of the conduit body (100) of the nerve conduit according to one embodiment of the present invention, FIG. 6 is a graph showing the impedance of the triboelectric generator (200) according to the size of the electrode layer (220) of the nerve conduit according to one embodiment of the present invention, and FIG. 7 is a graph showing the impedance of the triboelectric generator (200) according to the operating frequency of the triboelectric generator (200) of the nerve conduit according to one embodiment of the present invention. For reference, FIGS. 5 to 7 show that the size of the electrode layer (220) of the triboelectric generator (200) is 0.5 X 1.0 cm. 2 , and was measured at an operating frequency of 20 kHz.

[0066] Referring to FIG. 5, it can be confirmed that when the impedance of the conduit body (100) is 10,000 ohm corresponding to the nerve impedance, the RMS power of the frictional electric generator (200) is 20 μW.

[0067] Referring to FIGS. 6 and 7, it can be confirmed that the impedance of the triboelectric generator (200) is inversely proportional to the size of the electrode layer (220) and the intensity of the operating frequency. Therefore, by adjusting the size of the electrode layer (220) of the triboelectric generator (200) and the intensity of the operating frequency so that the impedance of the triboelectric generator (200) corresponds to the impedance of the severed nerve (10), the impedance of the triboelectric generator (200) can be designed and applied to a customized manner for the severed nerve (10).

[0068] Hereinafter, the operation of a nerve conduit according to one embodiment of the present invention will be described. The following process can be performed by a user or a robotic arm. Furthermore, the operation of a nerve conduit according to one embodiment of the present invention can be applied to the operation of a nerve conduit according to another embodiment of the present invention.

[0069] First, the main body of the conduit (100) is connected to both sides of the severed nerve (10) inside the living body.

[0070] Next, ultrasonic waves are applied to the frictional electric generator (200). At this time, the frictional electric generator (200) can transmit an electric signal generated by the application of the ultrasonic waves to the severed nerve (10). As a result, the electric signal is transmitted to the severed nerve (10), thereby promoting the regeneration of the severed nerve (10). Here, the ultrasonic waves applied to the frictional electric generator (200) may be generated from the ultrasonic generator (20).

[0071] Next, when rapid biodegradation of the nerve conduit is required, ultrasonic waves having a standard intensity or higher are applied to the triboelectric generator (200). As a result, cracks occur in the encapsulation layer (300), and the electrode layer (220) coupled to the encapsulation layer (300) is also mechanically cracked, so that the body fluid of the living body penetrates into the inside of the encapsulation layer (300) and the electrode layer (220), thereby allowing biodegradation of the encapsulation layer (300) and the electrode layer (220). Furthermore, proteinase K stored between the conduit body (100) and the encapsulation layer (300) is dissolved by the body fluid of the living body that has penetrated into the inside of the encapsulation layer (300) through the cracks that occur in the encapsulation layer (300), and can act as an enzyme that accelerates the biodegradation of the nerve conduit.

[0072] Hereinafter, a process for manufacturing a nerve conduit according to one embodiment of the present invention will be described.

[0073] First, a conduit body (100) having an inner diameter corresponding to the outer diameter of the severed nerve (10) is manufactured.

[0074] Next, a friction layer (210) is attached to the outer surface of the conduit body (100). Here, the friction layer (210) may be dip coated or brush coated and may have a film form.

[0075] Next, a spacer (230) is attached around the friction layer (210). At this time, a bonding agent may be applied to the spacer (230).

[0076] Afterwards, an electrode layer (220) is coated or deposited on the inner surface of the encapsulation layer (300).

[0077] Finally, the encapsulation layer (300) is attached to the conduit body (100).

[0078] Figure 8 is a perspective view showing a nerve conduit according to another embodiment of the present invention.

[0079] As illustrated in FIG. 8, a nerve conduit according to another embodiment of the present invention may further include a bonding layer (400), unlike the first embodiment.

[0080] The bonding layer (400) is provided on the inner surface of the conduit body (100) and can be bonded to at least one side of the severed nerve (10). Therefore, in the present embodiment, since the conduit body (100) and the severed nerve (10) are bonded, the procedure of suturing the conduit body (100) and the severed nerve (10) with a suture can be omitted.

[0081]

[0082] *For example, the bonding layer (400) may be a mixture of a biodegradable material with a catechol functional group, a gallic functional group, and a plant-derived polyphenol. Here, the biodegradable material may be a naturally derived biodegradable material such as Chitosan or collagen, or a synthetic biodegradable material such as GelMa, PVA, or PEG. Additionally, the plant-derived polyphenol may be tannic acid.

[0083] According to the present invention, a nerve conduit according to one embodiment of the present invention has the effect of promoting regeneration of a severed nerve (10) by transmitting an electric signal to the severed nerve (10).

[0084] In addition, since the optimal impedance of the electric signal generated from the triboelectric generator (200) according to one embodiment of the present invention is similar to the impedance of the severed nerve (10), the nerve conduit can transmit the electric signal generated from the triboelectric generator (200) to the severed nerve (10) with minimal loss.

[0085] In addition, the nerve conduit according to one embodiment of the present invention has the effect of accelerating biodegradation within a living body by causing cracks to occur upon application of ultrasound of a certain intensity or higher.

[0086] While the embodiments of the present invention have been described with reference to the attached drawings, those skilled in the art will appreciate that the present invention can be implemented in other specific forms without altering the technical concept or essential features thereof. Therefore, the embodiments described above should be understood to be illustrative in all respects and not restrictive.

Claims

1. The main body of the conduit that connects both sides of the severed nerve inside the body; A frictional electric generator electrically connected to the severed nerve through the main body of the conduit and transmitting an electric signal generated by the application of ultrasound to the severed nerve; An encapsulation layer covering the above triboelectric generator; and Provided on the inner surface of the above conduit body, it includes a bonding layer that is bonded to at least one side of the cut nerve, The above conduit body, the frictional electric generator and the encapsulation layer are made of biodegradable materials, The impedance of the above triboelectric generator is 30 kΩ to 300 kΩ, which is similar to the impedance of a nerve. The impedance of the above frictional electric generator and the impedance of the above conduit body are similar to each other, The above bonding layer is a mixture of a catechol functional group, a gallic functional group, and a plant-derived polyphenol in a biodegradable material. The above biodegradable material is a naturally derived biodegradable material or a synthetic biodegradable material, The above natural biodegradable material is Chitosan or collagen. The above synthetic biodegradable material is a nerve conduit, which is any one of GelMa, PVA and PEG.

2. In paragraph 1, The above encapsulation layer comprises one of PLGA [poly(lactic-co-glycolic acid)] and PHBV [poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid)], The above encapsulation layer is a nerve conduit that is cracked by application of ultrasound of a standard intensity or higher.

3. In paragraph 1, The above frictional electric power generator is, A friction layer provided in the above conduit body and vibrating by application of the ultrasonic waves; and A nerve conduit comprising an electrode layer provided on the inner surface of the encapsulation layer and electrically connected to the conduit body, the electrode layer generating frictional electricity by friction with the friction layer.

4. In paragraph 3, The above friction layer is a nerve conduit comprising any one of PLGA [poly(lactic-co-glycolic acid)], PVA (polyvinylalcohol), and PEG (polyehthylene glycol).

5. In paragraph 3, The above electrode layer is a nerve conduit comprising either Mg or Mo.

6. In paragraph 3, A nerve conduit further comprising a spacer that mutually separates the friction layer and the electrode layer.

7. In paragraph 3, A nerve conduit, wherein proteinase K, which accelerates biodegradation by body fluids of a living body, is stored between the above conduit body and the above encapsulation layer.

8. In paragraph 1, The above conduit body is a nerve conduit containing stem cells for transplantation.

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