Biomedical implantable microfiber implant and method for manufacturing the same

Abstract

The present invention relates to a bio-insertable microfiber implant and a method for manufacturing the same. A method for manufacturing a bio-insertable microfiber implant according to one embodiment of the present invention includes the steps of: manufacturing a porous nanofiber membrane based on a biocompatible polymer; and forming the porous nanofiber membrane into a twisted structure to manufacture a one-dimensional porous microfiber.

Description

Technical Field

[0001] The present invention relates to a bio-insertable implant, and more specifically, to a bio-insertable microfiber implant that can effectively transmit drugs, cells, etc. into the body using biocompatible microfibers, and a method for manufacturing the same.

Background Art

[0002] The development of materials for drug delivery into the body and tissue regeneration plays a very important role in modern pharmaceuticals and life science fields. Such materials have been studied in the direction of transmitting drugs to target tissues and organs to improve the efficacy of drugs, promoting tissue regeneration, and reducing side effects. Since biodegradable materials have the property of being slowly decomposed over time, when utilized for drug delivery and tissue regeneration, they can improve the effect of drug treatment and reduce side effects. Drug delivery systems using such materials have generally been developed in the form of a solid skeletal material, a scaffold, and a liquid hydrogel.

[0003] After being transplanted to the lesion site by surgery, the scaffold is gradually decomposed and releases drugs over a long period. However, the surface area that can contain drugs is limited, and effective drug delivery is difficult due to insufficient dosage and drug release rate. Due to its inherent rigidity, it causes anatomical inconvenience, and since the mechanical stiffness does not match that of surrounding tissues and organs, as a result, problems such as inflammation and damage to tissues and organs may occur.

[0004] In addition, a biodegradable drug delivery body in the form of a filler such as a hydrogel is injected with a liquid gel filler through a syringe and gradually decomposed to release drugs over a long period. However, it is difficult to ensure the consistency of drug release due to structural instability and low mechanical strength in the liquid form, and it has the instability that the accompanying drugs are easily denatured.

Summary of the Invention

[0005] As mentioned above, among the conventional materials for drug delivery and tissue regeneration in the body, scaffolds have limitations in the surface area that can hold drugs, making effective drug delivery difficult. Furthermore, their inherent rigidity causes anatomical inconveniences and can lead to inflammation and damage of tissues and organs. Hydrogels, on the other hand, have low mechanical strength, making it difficult to guarantee consistent drug release, and drugs are easily denatured.

[0006] One objective of the present invention to solve the aforementioned problems is to provide a bio-implantable microfiber implant that has a large surface area per unit volume, resulting in high drug diffusion efficiency, exhibits high exchangeability with tissue due to its flexible mechanical properties, maintains its shape even after time has passed since insertion into tissue, exhibits uniform drug release characteristics, and exhibits mechanically and chemically stable storage and transport performance during the process of loading and releasing drugs.

[0007] Another object of the present invention to solve the aforementioned problems is to provide a method for manufacturing a bio-insertable microfiber implant that simultaneously achieves a high drug load and a sustained-release drug release mechanism through a microporous structure that facilitates drug absorption and release, and that can deliver drugs in response to diverse environments and stimuli to promote tissue regeneration.

[0008] However, the problems that this invention aims to solve are not limited to these, and can be broadly expanded within the scope of the concept and domain of this invention. [Means for solving the problem]

[0009] A method for manufacturing a bio-insertable microfiber implant according to one embodiment of the present invention for achieving the above-mentioned objective may include the steps of: manufacturing a porous nanofiber membrane based on a biocompatible polymer; and forming the porous nanofiber membrane into a twisted structure to manufacture a one-dimensional porous microfiber.

[0010] According to one aspect, the porous nanofiber film or the microfiber contains parylene (P a It may be coated with rylene.

[0011] A method for manufacturing a bio-insertable microfiber implant according to one embodiment of the present invention may further include the step of depositing a conductive material onto the porous nanofiber membrane to form nanoelectrodes.

[0012] In one aspect, the nanoelectrodes are formed on the surface of the porous nanofiber film in a two-dimensional multi-arrangement structure, and the multiple nanoelectrodes included in the multi-arrangement structure may be arranged to be separated from each other along the longitudinal direction of the microfibers when the porous nanofiber film is manufactured from the microfibers.

[0013] A method for producing a bio-insertable microfiber implant according to one embodiment of the present invention may further include the step of forming a nanofiber bundle from a plurality of the nanofiber films.

[0014] In one aspect, the nanofiber bundle may have a core having a first hardness, and a shell surrounding the core having a second hardness different from the first hardness.

[0015] According to one aspect, the central part of the nanofiber bundle may be formed of PLA (Polylactic Acid), and the outer covering may be formed of PCL (Polycaprolactone).

[0016] In one aspect, the nanofiber bundle may be formed of nail-shaped nanofibers.

[0017] In one aspect, the nanofiber bundle may include a main fiber and fine fibers connected thereto.

[0018] In one aspect, the nanofiber bundle may be formed by mixing multilayered nanofiber films in a wound or twisted form.

[0019] According to one aspect, the nanofiber membrane is manufactured from a nanofiber membrane having an area equal to or greater than a predetermined critical surface area through a multi-nozzle, and the microfibers may have a length equal to or greater than a predetermined critical length.

[0020] The method for manufacturing a bio-insertable microfiber implant according to an embodiment of the present invention may further include a step of mounting a stimulus-responsive hydrogel on the nanoelectrode.

[0021] According to one aspect, drugs may be included inside the stimulus-responsive hydrogel.

[0022] According to one aspect, the stimulus-responsive hydrogel may release drugs in response to pH.

[0023] According to one aspect, the stimulus-responsive hydrogel may release drugs in response to ion concentration.

[0024] According to one aspect, the stimulus-responsive hydrogel may release drugs in response to glucose concentration.

[0025] According to one aspect, the stimulus-responsive hydrogel may release drugs in response to antigen concentration.

[0026] The method for manufacturing a bio-insertable microfiber implant according to an embodiment of the present invention may further include a step of mounting functional stem cells on the porous nanofiber membrane.

[0027] According to one aspect, the cross-section of the microfiber formed on the porous nanofiber membrane on which the functional stem cells are mounted may be formed such that the density and strength gradually change from one side to the other side.

[0028] According to one aspect, a hydrogel based on a decellularized extracellular matrix (ECM) of a target organ may be mounted on at least a part of the surface of the microfiber.

[0029] The bioinsertable microfiber implant according to an embodiment of the present invention may include a one-dimensional microfiber manufactured by forming a porous nanofiber membrane based on a biocompatible polymer into nanofiber bundles and then shaping them into a twisted structure.

Advantages of the Invention

[0030] The disclosed technology can have the following advantages. However, it should not be understood that the scope of the rights of the disclosed technology is limited thereby, as it does not mean that a specific embodiment must include all of the following advantages or only the following advantages.

[0031] According to the bioinsertable microfiber implant and its manufacturing method according to the above-described embodiment of the present invention, by forming a nanofiber membrane into a twisted structure to manufacture microfibers, it is possible to provide a bioinsertable microfiber implant that has excellent mechanical strength, is flexible, has a large surface area per unit volume, and has excellent drug release characteristics.

[0032] In addition, by polarizing a porous nanofiber membrane having a large surface area per unit volume, which has an excellent sensing rate of an electrode, and mounting a stimulus-responsive hydrogel that can respond to various stimuli, various drugs can be effectively released without changing the structure of the microfiber implant.

[0033] Moreover, the bioinsertable microfiber implant mimics body tissues, and by mounting stem cells on the porous nanofiber membrane, cells can be effectively cultured to optimize tissue regeneration, and by mounting a decellularized extracellular matrix-based hydrogel, target tissues and organs can be effectively regenerated without causing immune reaction problems.

Brief Description of the Drawings

[0034] [Figure 1] It is a schematic diagram showing the manufacturing process of the bioinsertable microfiber implant according to an embodiment of the present invention.

[0035] [Figure 2] This diagram illustrates the thickness and twist structure of microfibers.

[0036] [Figure 3] This is a schematic diagram showing the manufacturing process of a large-area nanofiber film according to one embodiment of the present invention.

[0037] [Figure 4] This is a photograph showing the coating of parylene on microfibers.

[0038] [Figure 5] This figure illustrates the implantation process of a bio-insertable microfiber implant according to one embodiment of the present invention.

[0039] [Figure 6] This is a photograph showing the results of transplantation of bio-insertable microfiber implants.

[0040] [Figure 7] This figure illustrates the process of forming nanoelectrodes from a nanofiber film according to one embodiment of the present invention.

[0041] [Figure 8] This is a schematic diagram of a two-dimensional multi-arranged electrode formed on a nanofiber film.

[0042] [Figure 9] This figure illustrates the mounting of a reactive hydrogel on a nanoelectrode according to one embodiment of the present invention.

[0043] [Figure 10] Figure 9 is a schematic diagram illustrating the reaction of the reactive hydrogel.

[0044] [Figure 11] This figure illustrates a nanofiber film in response to a change in density.

[0045] [Figure 12] This is a schematic diagram illustrating the voltage characteristics in response to density changes in a nanofiber film on which nanoelectrodes are formed.

[0046] [Figure 13] This figure illustrates, in part, stem cell culture and material diffusion onto a nanofiber membrane according to one embodiment of the present invention.

[0047] [Figure 14] This is a schematic diagram illustrating the multilayered structure of a bio-insertable microfiber implant.

[0048] [Figure 15] This figure illustrates the action of a bio-insertable microfiber implant according to one embodiment of the present invention. [Modes for carrying out the invention]

[0049] The present invention can be modified in various ways and may have a variety of embodiments. A specific embodiment will be illustrated and described in detail in the drawings.

[0050] However, this should be understood not as an attempt to limit the present invention to any particular embodiment, but rather as including all modifications, equivalents, or substitutions that fall within the spirit and technical scope of the present invention.

[0051] While terms such as "first," "second," etc., may be used to describe a variety of components, the components should not be limited by such terms. The terms are used solely for the purpose of distinguishing one component from another. For example, without excluding the scope of the present invention, the first component may be named the second component, and similarly, the second component may be named the first component. The terms "and" and / or include combinations of multiple described items or any of the multiple described items.

[0052] When one component is described as being "linked" or "connected" to another component, it should be understood that it may be directly linked or connected to the other component, but other components may also exist between them. On the other hand, when one component is described as being "directly linked" or "directly connected" to another component, it should be understood that no other components exist between them.

[0053] The terms used in this application are used solely to describe specific embodiments and are not intended to limit the invention. Singular expressions include plural expressions unless the context clearly indicates otherwise. In this application, terms such as “includes” or “having” are intended to specify the existence of features, figures, steps, actions, components, parts, or combinations thereof described in the specification, and should be understood not to preclude the existence or possibility of adding one or more other features, figures, steps, actions, components, parts, or combinations thereof.

[0054] Unless otherwise specified, all terms used herein, including technical or scientific terms, have the same meaning as those generally understood by a person of ordinary skill in the art to which this invention pertains. Terms as defined in commonly used dictionaries should be interpreted as having the meaning consistent with their meaning in the context of the relevant art, and not as to be interpreted in an ideal or overly formal sense unless explicitly defined herein.

[0055] The following describes preferred embodiments of the present invention in more detail with reference to the accompanying drawings. In describing the present invention, the same reference numerals are used for identical components in the drawings, and redundant descriptions of identical components are omitted to facilitate overall understanding.

[0056] As discussed above, conventional drug delivery and tissue regeneration systems using solid or liquid materials for tissue regeneration and drug delivery into the body have problems such as difficulty in effective drug delivery, causing anatomical inconveniences, and resulting in problems such as inflammation and damage to tissues and organs because the mechanical rigidity does not match that of surrounding tissues and organs. It is also difficult to guarantee consistency in drug release, and the accompanying drugs are easily degraded due to instability.

[0057] The bio-implantable microfiber implant according to one embodiment described herein is intended to solve the aforementioned problems. By manufacturing a porous nanofiber membrane with one-dimensional microfibers, it is possible to provide a bio-implantable microfiber implant that has excellent mechanical strength and flexibility, and a large surface area per unit volume, thereby providing excellent drug release characteristics. This allows the bio-implantable microfiber implant to be used as a surgical suture. Furthermore, by attaching electrodes, stimulus-reactive hydrogels, decellularized extracellular matrix-based hydrogels, and stem cells to the bio-implantable microfiber implant, drugs can be effectively released, enabling effective cell culture and tissue regeneration without problems of immune reactions to tissues and organs.

[0058] In the following, with reference to the drawings, a bio-insertable microfiber implant according to one embodiment of the present invention and its manufacturing will be described in more detail.

[0059] In this document, "biomechanically insertable microfibers" can refer to any fibrous structure, generally having a diameter ranging from nanometers to micrometers, that can be inserted into body tissue to perform various functions. However, it should be understood that the units of microfibers are not limited to these.

[0060] Figure 1 is a schematic diagram showing the manufacturing process of a bio-insertable microfiber implant according to one embodiment of the present invention. The manufacturing method of a bio-insertable microfiber implant according to one embodiment of the present invention first allows for the production of a porous nanofiber membrane based on a biocompatible polymer, as shown in Figure 1(a). As a non-limiting example, a porous nanofiber membrane can be produced by electrospinning a biocompatible polymer, but it should be noted that this is not the only way. Therefore, a biocompatible polymer is dissolved in a solvent to prepare a biocompatible polymer solution of the desired viscosity and concentration, and this is supplied to a needle-shaped nozzle. After positioning the needle toward a current collector plate, a high voltage is applied between the needle and the current collector plate using a high voltage source, generating an electric field, and the resulting electric force draws out the polymer solution in the form of fine fibers. As the solvent inside these fibers evaporates, they form nanofibers, and the nanofibers released from the needle accumulate on the current collector plate, thereby producing a porous nanofiber membrane. Such porous nanofiber films can be modified to obtain the optimal final product structure by controlling the concentration and viscosity of the polymer solution, as well as the electrospinning environment (voltage, temperature, humidity).

[0061] Subsequently, as shown in Figure 1(b), one-dimensional porous microfibers can be manufactured by forming the porous nanofiber membrane into a twisted structure. Nanofiber membranes composed of very fine nanofibers can sometimes have very weak mechanical strength due to their structure. However, two-dimensional nanofiber membranes composed of one-dimensional nanofibers have a porous structure from a microscopic perspective and are well known as materials that mimic the extracellular matrix of biological tissues. Therefore, in order to increase the mechanical strength of such porous nanofiber membranes and increase the surface area of ​​the nanofiber membrane due to its porous structure so that it can be transplanted into biological tissues, the porous nanofiber membrane can be formed into a twisted structure and converted into one-dimensional porous microfibers, as shown in Figure 1(b).

[0062] Figure 2 illustrates the thickness and twist structure of microfibers as an example. The twist structure required to enable the nanofiber membrane to withstand even greater tensile forces can be varied by various design approaches that optimize the mechanical strength and flexibility of the microfibers. Generally, as the degree of twist increases, the strength of the fiber increases, but the flexibility decreases. Therefore, experiments were conducted to determine the limit of the maximum twist structure of the nanofiber membrane that can maintain the flexibility of the microfibers, in order to optimize the design of the twist structure according to the thickness adjustment of the electrospun nanofibers.

[0063] Figure 2(a) shows nanofibers with a diameter of 300 nm formed by adjusting the concentration of the polymer solution for manufacturing the nanofiber film to 20 wt%, Figure 2(b) shows nanofibers with a diameter of 220 nm formed by adjusting the concentration of the polymer solution to 15 wt%, and Figure 2(c) shows nanofibers with a diameter of 90 nm formed by adjusting the concentration of the polymer solution to 10 wt%. When nanofibers are twisted together, when a load is applied, the stress is distributed among the twisted fibers, allowing each fiber to withstand a certain load, and the load is uniformly distributed, improving the tensile strength of the entire twisted fiber. In addition, the nanofibers support each other while transmitting force in opposite directions in their twisted form, and friction is generated when the twisted fibers cross and come into contact with each other, which can contribute to withstanding tensile force.

[0064] As mentioned above, fibers with increased tensile strength and durability due to their twisted structure can be formed with thinner individual fibers due to the increased tensile strength and durability, and the ratio of surface area per unit volume can be maximized by the bundle of finely twisted fiber structures. Because such nanofibers have a significantly increased surface area per unit volume, the passive diffusion behavior of particles inside the fiber is greatly improved, and reaction efficiency can be increased. Such passive diffusion behavior of particles is schematically shown in Figure 2. On one hand, microfibers made from such nanofiber films can function as drug delivery platforms by converting the release of particles such as drugs into time-series data, and can also be used to monitor precise particle diffusion behavior by incorporating fluorescent particles into the drug.

[0065] Although not shown in the figures, a method for manufacturing a bio-insertable microfiber implant according to one embodiment of the present invention can form a nanofiber bundle from multiple nanofiber films. In one aspect, the nanofiber bundle can be adjusted so that the diameter, arrangement, and convergence of the nanofibers are in the form of a nanofiber bundle by changing the polymer solution and electrospinning conditions, for example, nanofiber films formed in multiple layers may be mixed and formed in a wound or twisted form.

[0066] In one aspect, a nanofiber bundle may have a core with a first hardness and a shell surrounding the core with a second hardness different from the first hardness. As a non-limiting example, the second hardness may be lower than the first hardness, but is not limited to this. In one aspect, for example, the core of the nanofiber bundle may be formed of PLA (Polylactic Acid), and the shell may be formed of PCL (Polycaprolactone). PLA and PCL are typical biodegradable nanofiber materials. The PLA core is relatively more biodegradable than the PCL shell, with a faster biodegradation rate, higher hardness, and lower elongation. The PCL shell, on the other hand, is relatively less biodegradable than the PLA core, with a slower biodegradation rate, higher flexibility, and better elongation, but with lower hardness. In other words, the core of the nanofiber bundle is made of a rigid material to maintain strength, while the outer layer is made of a flexible material to facilitate the formation of a twisted structure. Such a structure can be effective in optimizing the flexibility and mechanical strength of the microfibers. On the other hand, the nanofiber bundle may be composed of heterogeneous materials other than PLA and PCL for the core and outer layer, and any heterogeneous material that is bio-implantable is acceptable, so there are no restrictions on the type of material.

[0067] In one respect, the nanofiber bundle may be formed of claw-shaped nanofibers. Such claw-shaped nanofibers can increase their surface area by forming claw-like ends, providing a mechanical interlocking effect. Therefore, during bioinvasion, the improved adhesion and friction can significantly enhance cell adhesion and proliferation. In another respect, the nanofiber bundle may include main fibers and fine fibers connected thereto. In such a composite nanofiber bundle, the thicker fibers forming the main structure have high strength and thus act as a structural support, while the fine fibers connected to the main fibers increase the surface area and can improve functionality such as drug release or flexibility. In another respect, the nanofiber bundle can also be manufactured in a wound or twisted form by mixing multi-layered nanofiber films without distinguishing between a core and an outer layer.

[0068] In one aspect, a bio-implantable microfiber implant according to one embodiment of the present invention may include one-dimensional microfibers manufactured by forming a porous nanofiber membrane, which is formed by electrospinning a biocompatible polymer as described above, into a nanofiber bundle, and then forming it into a twisted structure. Since such one-dimensional microfibers have high strength and specific surface area after being formed into a nanofiber bundle from a porous nanofiber membrane and then formed into a twisted structure, they can have sufficient strength and functionality for implantation into the body, and the microfibers themselves can be used as surgical sutures.

[0069] Figure 3 is a schematic diagram showing the manufacturing process of a large-area nanofiber film according to one embodiment of the present invention. From one perspective, the nanofiber film is manufactured via a multi-nozzle to have an area greater than or equal to a predetermined critical area, and the microfibers can have a length greater than or equal to a predetermined critical length. As mentioned above with respect to Figure 2, in order to use the microfibers according to the present invention as surgical sutures, microfibers of a critical length or longer that can be used as surgical sutures are required. Therefore, as shown in Figure 3, by controlling the electric field of the multi-nozzle using an electrospinning technique based on a needle-shaped multi-nozzle, a large-area nanofiber film having an area greater than or equal to the critical area and ensuring uniformity can be manufactured. The large-area nanofiber film can be converted into a microfiber film with a length of, for example, 30 cm or more by forming it as a nanofiber bundle and twisted structure as described above, thereby making it possible to use the microfiber film as surgical sutures.

[0070] Figure 4 shows parylene (P) against microfibers. a This is a photograph showing a coating of parylene (P). According to one aspect of the present invention, a porous nanofiber film or microfiber is coated with parylene (P). aParylene may be used as a coating. Parylene is a well-known bioinactive material that is very stable chemically and biologically, exhibiting excellent biocompatibility and low tissue reactivity, while also showing excellent electrical insulation properties and being mechanically flexible and strong. Nanofiber films without such parylene coating may have areas where the nanofibers are not bonded to each other, as shown in Figure 4(a). If gaps occur between the nanofibers that are not bonded to each other, the distance between the nanofibers may increase during subsequent metal deposition for electrode formation, potentially causing the electrodes to break. Therefore, to integrate the nanofiber joints, parylene may be used as shown in Figure 4(b). Figure 4(b) shows the initial PU nanofiber film, the PU nanofiber film with primary parylene coating, and the PU nanofiber film with secondary parylene coating. Comparing Figures 4(a) and (b), it can be seen that the nanofiber joints have been integrated. Figure 4 illustrates parylene coating on a PU nanofiber film, but it should be understood that the material and thickness are no longer limited, and parylene coating can be applied to nanofiber films, nanofiber bundles, or microfiber states, respectively, to integrate the junctions with the nanofibers.

[0071] Figure 5 illustrates the transplantation process of a bioinsertable microfiber graft according to one embodiment of the present invention, and Figure 6 is a photograph showing the transplantation result of the bioinsertable microfiber graft. As shown in Figure 5, the bioinsertable microfiber graft according to the present invention has a structure similar to a surgical suture and can be transplanted into living tissue by connecting with a surgical needle. For example, as shown in Figure 5, the microfibers can be flexibly transplanted into living tissue like a suture by three or more reciprocating movements at the expected lesion site of an organ. Because such flexibility is highly compatible with the flexibility of the organ, a more effective cell engraftment effect can be obtained when cells are subsequently placed on it. The results of such cell engraftment are shown in Figure 6. Referring to Figure 6, the results of transplanting microfibers formed on a nanofiber membrane as a surgical suture can be seen. Compared to the control group on the left, it can be seen that the size of the lesion site has decreased in the microfiber graft on the right, and the cellular components have recovered their original orientation and are showing anisotropic cell alignment, so it can be seen that tissue regeneration is being carried out effectively.

[0072] Figure 7 illustrates the process of forming nanoelectrodes from a nanofiber film according to one embodiment of the present invention. The method for manufacturing a bio-insertable microfiber implant according to one embodiment of the present invention, formed as described above, may further include the step of depositing a conductive material onto a porous nanofiber film to form nanoelectrodes. As an example, the conductive material may include metals or conductive polymers. For example, conductive metals may include, but are not limited to, gold, silver, copper, platinum deposition, silver nanowires, or gold nanoparticles. Conductive polymers may include, but are not limited to, PEDOT:PSS. As described above with respect to Figure 4, after loading parylene, a bioinactive material, onto the surface of the nanofiber film, nanoelectrodes can be formed by depositing a conductive material onto the surface of such a nanofiber film, as shown in Figure 7. Such conductive materials exhibit excellent biocompatibility and can be any electrochemically stable metal, such as gold (Au), platinum (Pt), titanium (Ti), iridium (Ir), silver (Ag), aluminum (Al), iron (Fe), and carbon, which can be selected from the group. Such conductive metals can be deposited onto nanofiber films using known techniques capable of depositing metals onto polymer fibers, such as inorganic vacuum deposition, sputter deposition, evaporation deposition, electron beam physical vapor deposition, pulsed laser deposition, chemical vapor deposition, and wet coating.

[0073] Figure 8 is a schematic diagram of a two-dimensional multiple-arranged electrode formed on a nanofiber film. As shown in Figure 8, the nanoelectrode on one side may be formed in a two-dimensional multiple-arranged structure on the surface of a porous nanofiber film. When the porous nanofiber film is manufactured from microfibers, the multiple nanoelectrodes included in the multiple-arranged structure may be arranged spaced apart from each other along the length direction of the microfibers. More specifically, when the nanoelectrode has a multiple-arranged structure and is made of one-dimensional microfibers, multiple nanoelectrodes can be arranged along the length direction of the fiber, so that it may be possible to quantify changes at a specific location (e.g., physical deformation, defects on the surface of the nanofiber film, and changes in the strength of the charge exhibited by the surrounding environment) by sensing an electrical signal at that specific location. Furthermore, the multiple-arranged structure of the nanoelectrodes can increase spatial resolution, allowing for selective monitoring of signals in a specific region, and since a large number of nanoelectrodes can be integrated, a high channel density can be ensured, making it possible to sense more information simultaneously.

[0074] Figure 9 illustrates the mounting of a reactive hydrogel on a nanoelectrode according to one embodiment of the present invention, and Figure 10 is a schematic diagram illustrating the reaction of the reactive hydrogel in Figure 9. The method for manufacturing a bio-insertable microfiber implant according to one embodiment of the present invention may further include the step of mounting a stimulating reactive hydrogel on a nanoelectrode. A drug may be contained within such a stimulating reactive hydrogel.

[0075] More specifically, the hydrogel is a hydrophilic polymer material with a high water content. In order to allow the stimuli-reactive polymer to flow into the hydrogel, the stimuli-reactive polymer monomers are crosslinked in a three-dimensional structure using light or heat and synthesized with the hydrogel. Subsequently, as shown in Figure 9, the stimuli-reactive hydrogel can be mounted on nanoelectrodes formed on the surface of a nanofiber film. In one aspect, such a stimuli-reactive hydrogel can be integrated with the nanoelectrodes, for example, by dip coating or by an electrical method, thereby allowing the expansion and contraction of the stimuli-reactive hydrogel to be quantified in real time through the nanoelectrodes.

[0076] More specifically, referring to Figure 10, in one aspect, the stimulus-reactive hydrogel is synthesized by incorporating monomers that induce expansion or contraction of the hydrogel by having different surface charges in response to changes in the external environment, and may also contain crosslinking agents, reactive functional groups, and drugs. When a bio-implantable microfiber implant equipped with the external stimulus-reactive hydrogel according to the present invention is inserted into the body, if the concentration of, for example, pH, glucose, ions, or antigens in the internal environment increases, the reactive functional groups bind to these target particles and the hydrogel expands; conversely, if the concentration increases, the hydrogel contracts. When the hydrogel expands, drugs inside the stimulus-reactive hydrogel may be released, causing a response to the stimulus.

[0077] In one aspect, when a reactive functional group binds to a pH target particle, the stimulating reactive hydrogel can react to the pH concentration and release a drug when the pH increases. In another aspect, when a reactive functional group binds to an ion target particle, the stimulating reactive hydrogel reacts to the ion concentration and can release a drug when the target ion concentration increases. In another aspect, when a reactive functional group binds to a glucose target particle, the stimulating reactive hydrogel reacts to the glucose concentration and can release a drug (e.g., insulin) when the glucose concentration increases. In another aspect, when a reactive functional group binds to an antigen target particle, the stimulating reactive hydrogel reacts to the antigen concentration and can release a drug (e.g., antibody) when the antigen concentration increases.

[0078] Figure 11 illustrates a nanofiber film with varying density, and Figure 12 is a schematic diagram illustrating the voltage characteristics of a nanofiber film with nanoelectrodes formed on it, with varying density. In one embodiment of the present invention, the density of nanofibers in a nanofiber film can be adjusted by adjusting the electrospinning properties. Such density adjustment is intended to increase the surface area per unit volume. For example, if the same volume of nanofiber film is produced using even thinner fibers, the surface area per unit volume becomes much larger. Therefore, if a drug is contained within the nanofiber film, the drug release rate becomes much faster, and if there are electrodes on the surface of the nanofiber film, the sensing rate or sensitivity of the electrodes can become much higher. Consequently, the high-density nanofiber film shown in Figure 11(b) may have even better drug release characteristics and electrode characteristics than the low-density nanofiber film shown in Figure 11(a).

[0079] Referring to Figure 12, it can be seen that the sensing rate of the electrode increases as the density of the nanofiber film increases. The single-layer nanofiber film shown in Figure 12(a) has a relatively high turn-on voltage, the multilayer nanofiber film in Figure 12(b) has a lower turn-on voltage, and the high-density multilayer nanofiber film in Figure 12(c) has the lowest turn-on voltage. As described above, the bio-insertable microfiber implant according to one embodiment of the present invention can effectively enhance the drug release characteristics and nanoelectrode characteristics of the microfiber implant by forming very thin nanofibers in a high-density multilayer structure, multi-bundle structure, or twisted structure.

[0080] Figure 13 illustrates the stem cell culture and material diffusion onto a nanofiber membrane according to one embodiment of the present invention, and Figure 14 is a schematic diagram illustrating the multilayer structure of a bioinsertable microfiber implant. A method for producing a bioinsertable microfiber implant according to one embodiment of the present invention may further include the step of loading functional stem cells onto a porous nanofiber membrane. In one aspect, the stem cell culture medium can be loaded onto the bioinsertable microfiber implant according to the present invention by various methods such as electrospinning, self-spinning assembly, surface modification, or compounding. When microfibers loaded with stem cells are implanted in the body, the stem cells take up healing factors released at the lesion site, further stimulating the cells at the lesion site and releasing environmentally reactive regenerative factors (paracrine effect), thereby further promoting the recovery of the lesion site.

[0081] Referring to Figure 14, in one aspect, the bio-insertable microfiber implant may be formed as a multilayered structure having different properties from one another, and the multilayered structure may consist of a porous nanofiber membrane carrying functional stem cells. Such multilayers of microfibers can have different densities and strengths from one another, and the cross-section of the microfibers may be formed so that the density and strength gradually change from one side to the other. For example, when microfibers are implanted in a part such as a ligament, since ligaments are connective tissue fibers that connect bone and muscle, they are structurally arranged anisotropically, so generally the part connected to bone has high strength, and the part connected to muscle has flexible properties. Therefore, the bio-insertable microfiber implant according to the present invention can mimic such a structure and be formed as a multilayered structure of nanofiber membranes with different properties from one another so that the density and strength of the microfibers gradually change.

[0082] According to one aspect of the present invention, a hydrogel based on the decellularized extracellular matrix of a target organ can be mounted on at least a portion of the surface of the microfiber. To mount the decellularized extracellular matrix-based hydrogel, first, cells containing DNA are removed while retaining the extracellular matrix of the organ through a decellularization process, and all components that could trigger an immune response are removed. Then, the decellularized extracellular matrix is ​​processed into a powder. Subsequently, the powdered decellularized extracellular matrix can be manufactured as a hydrogel by adding a crosslinking agent, a bioactive substance, etc., to a hydrogel precursor solution, and then mounted on the surface of the microfiber. In one aspect, since the decellularized extracellular matrix-based hydrogel is derived from tissue cells that do not trigger an immune response, it can also be mounted only in the area that comes into contact with the transplanted tissue.

[0083] Figure 15 illustrates the action of a bio-insertable microfiber implant according to one embodiment of the present invention. As described above, by forming a porous nanofiber membrane, which is formed by electrospinning nanofibers, into a twisted structure to produce one-dimensional microfibers, it is possible to provide a bio-insertable microfiber implant that is excellent in mechanical strength and flexibility, and has a large surface area per unit volume, thus exhibiting excellent drug release properties. If such microfibers are implanted into the lesion site of tissue as surgical sutures, as shown in Figure 15(a), the microfiber implant can be inserted into the body minimally invasively, while simultaneously providing a flexible and highly strong scaffold. Furthermore, the porosity and multilayer structure of the porous nanofiber membrane according to the present invention naturally result in excellent drug release effects. On the other hand, by mounting functional stem cells and a decellularized extracellular matrix-based hydrogel onto the microfibers, environmentally reactive regenerative factors can be released without rejection of the microfiber implant, thereby enabling effective culture of tissue cells at the lesion site. Furthermore, by mounting nanoelectrodes and a stimulus-reactive hydrogel on the nanofiber membrane, as shown in Figure 15(b), it becomes possible to release drugs in response to pH, ion concentration, glucose concentration, and antigen concentration. Such drug release can be stimulated by the nanoelectrodes and simultaneously monitored. In one embodiment of the present invention, other bio-implantable microfiber implants undergo a combination of the aforementioned effects, enabling the restoration of organ defects and the regeneration of cells and tissues, as shown in Figure 15(c).

[0084] Although the invention has been described above with reference to the drawings and embodiments, this does not mean that the scope of protection of the present invention is limited by the drawings or embodiments. A person skilled in the art will understand that the invention can be modified and altered in various ways, as long as it does not deviate from the spirit and scope of the invention as described in the following claims.

[0085] Although the present invention described above is based on a series of functional blocks, it is not limited by the embodiments and accompanying drawings, and it will be obvious to those with ordinary skill in the art to which the present invention pertains that various substitutions, modifications, and changes are possible without departing from the technical spirit of the present invention.

[0086] The combinations of the embodiments described above are not limited to those described above, and various combinations other than those described above can be provided as needed and / or to embody them.

[0087] In the embodiments described above, the method is explained based on a sequence diagram as a series of steps or blocks, but the present invention is not limited to the order of the steps, and some steps may occur in a different order or simultaneously with other steps than those described above. Furthermore, a person with ordinary skill in the art will understand that the steps shown in the sequence diagram are not exclusive, and other steps may be included, or one or more steps in the sequence diagram may be omitted without affecting the scope of the present invention.

[0088] The embodiments described above include examples of various modes. It is not possible to describe all possible combinations for demonstrating various modes, but a person with ordinary skill in the art should be able to recognize that other combinations are possible. Therefore, the present invention can be said to include all other substitutions, modifications, and changes that fall within the scope of the following claims.

Claims

1. A step of manufacturing a porous nanofiber film based on a biocompatible polymer, A method for producing a bio-insertable microfiber implant, comprising the step of forming the porous nanofiber membrane into a twisted structure to produce a one-dimensional porous microfiber.

2. A method for producing a bio-insertable microfiber implant according to claim 1, wherein the porous nanofiber membrane or the microfiber is coated with parylene.

3. A method for producing a bio-insertable microfiber implant according to claim 1, further comprising the step of depositing a conductive material onto the porous nanofiber film to form a nanoelectrode.

4. The nanoelectrode is formed on the surface of the porous nanofiber film in a two-dimensional multi-arrangement structure. The method for manufacturing a bio-insertable microfiber implant according to claim 3, wherein the plurality of nanoelectrodes included in the multi-arranged structure are arranged to be separated from each other along the longitudinal direction of the microfibers when the porous nanofiber membrane is manufactured from the microfibers.

5. A method for producing a bio-insertable microfiber implant according to claim 1, further comprising the step of forming a plurality of the nanofiber films into a nanofiber bundle.

6. The aforementioned nanofiber bundle is A method for manufacturing a bio-insertable microfiber implant according to claim 5, wherein the core has a first hardness, and the shell surrounding the core has a second hardness different from the first hardness.

7. A method for manufacturing a bio-insertable microfiber implant according to claim 6, wherein the central part of the nanofiber bundle is formed of PLA (Polylactic Acid) and the outer covering is formed of PCL (Polycaprolactone).

8. The method for producing a bio-insertable microfiber implant according to claim 5, wherein the nanofiber bundle is formed of nail-shaped nanofibers.

9. The method for producing a bio-insertable microfiber implant according to claim 5, wherein the nanofiber bundle includes a main fiber and fine fibers connected thereto.

10. The method for producing a bio-insertable microfiber implant according to claim 5, wherein the nanofiber bundle is formed in a wound or twisted form by mixing a multilayer nanofiber film.

11. The method for manufacturing a bio-insertable microfiber implant according to claim 1, wherein the nanofiber membrane is manufactured via a multi-nozzle using a nanofiber membrane having an area greater than or equal to a predetermined critical area, and the microfibers have a length greater than or equal to a predetermined critical length.

12. The method further includes the step of mounting a stimuli-reactive hydrogel on the nanoelectrode, A method for producing a bio-insertable microfiber implant according to claim 3, wherein the inside of the stimulus-reactive hydrogel contains a drug.

13. The method for producing a bio-insertable microfiber implant according to claim 12, wherein the stimulant-reactive hydrogel releases a drug in response to pH.

14. The method for producing a bio-insertable microfiber implant according to claim 12, wherein the stimulant-reactive hydrogel releases a drug in response to ion concentration.

15. The method for producing a bio-insertable microfiber implant according to claim 12, wherein the stimulus-reactive hydrogel releases a drug in response to glucose concentration.

16. The method for producing a bio-insertable microfiber implant according to claim 12, wherein the stimulus-reactive hydrogel releases a drug in response to the antigen concentration.

17. A method for producing a bio-insertable microfiber implant according to claim 1, further comprising the step of mounting functional stem cells on the porous nanofiber membrane.

18. A method for producing a bio-insertable transplantable agent according to claim 17, wherein the cross-section of the microfibers formed on the porous nanofiber membrane on which the functional stem cells are mounted is formed such that the density and strength gradually change from one side to the other.

19. A method for producing a bio-insertable microfiber implant according to any one of claims 1 to 18, wherein at least a portion of the surface of the microfiber is loaded with a hydrogel based on the decellularized extracellular matrix of a target organ.

20. A bio-insertable microfiber implant comprising a one-dimensional microfiber manufactured by forming a porous nanofiber membrane based on a biocompatible polymer into a nanofiber bundle, and then shaping it into a twisted structure.

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