Apparatus and method for treating fistulas

Abstract

To provide an improved device and method for promoting fistula closure that has fewer side effects, a reasonable treatment time, and less discomfort for the patient. [Solution] A device for embedding in a fistula tract within a target, wherein the fistula tract has a primary opening in the wall of a body structure and a conduit extending from the primary opening, the device includes a single body configured to fill at least a portion of the fistula tract, the body including an enlarged portion located at a first end of the body and a tubular structure extending from a region adjacent to the enlarged portion and ending at a second end of the body, the enlarged portion having a cross-sectional dimension equal to or greater than the cross-sectional dimension of the tubular structure with respect to the longitudinal axis of the body.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 991,384, filed on March 18, 2020 The entire contents of the application for the above priority claim are incorporated herein by reference .

[0002] Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, the entire contents of which are incorporated herein by reference The above ASCII copy was created on March 18, 2021 and has the name T103022_1250WO_0460_0_SL.txt and a size of 4 ,014 bytes

[0003] The present disclosure relates to an apparatus for embedding into a fistula for promoting healing of the fistula, as well as a method for manufacturing the apparatus and a method for using the apparatus .

Background Art

[0004] Fistulas such as perianal fistulas, rectovaginal fistulas, and enterocutaneous fistulas are common diseases. Generally, a fistula is an abnormal connection between two parts (e.g., tissues or structures) within the body of a subject, e.g., between the intestine and the vagina etc. A fistula usually has a primary opening (usually located inside the body), and a duct or tunnel extending from the primary opening to a secondary opening The duct can be relatively straight or can also be a detour. In some cases, a fistula can have multiple ducts. A general cause of a fistula includes injury, infection, surgical complications, congenital defects, and diseases (e.g., Crohn's disease and ulcerative colitis). Treatment varies depending on the cause, location, or nature of the fistula but fistulas are difficult to treat and may recur frequently

[0005] Treatment usually involves surgery, and may or may not involve the use of antibiotics. For example, setting up a drainage line for drainage, flap treatment, or embolusing part of the fistula (for example) This may include, for example, fibrin glue. However, surgical treatment requires time for recovery. In addition, it can cause many side effects such as incontinence, reinfection, or recurrence of fistulas. Even if a fistula heals naturally, it can take a very long time, which presents further difficulties for the patient. This can occur. Also, so-called plugs are sold commercially, but these "plugs" It typically contains multiple components that need to be sutured together, and includes biodegradable materials. This can lead to a high failure rate, for example, insufficient fistula closure, plug detachment, or infection. It is.

[0006] Therefore, it has fewer side effects, a reasonable treatment time, and causes less discomfort to the patient, and it closes the fistula. Improved devices and methods are needed to accelerate chain formation. [Overview of the project]

[0007] This specification describes a non-biodegradable device for closing fistulas, which promotes faster healing and tissue integration. We disclose a device that facilitates and optionally provides delivery of therapeutic agents. These devices are implantable It is designed to be difficult to detach from the part. Also, the manufacturing method of the device and the use of the device Treatment methods for affected patients, as well as kits including the device, are also disclosed.

[0008] In one embodiment, the present invention relates to a device for implantation in a fistula tract within a subject or patient. The fistula pathway has a primary opening in the wall of a body structure and a tubular passage extending from the primary opening. The device is a fistula tube It includes a single body configured to fill at least a portion of the body. The body has a first end at the body The positioned magnified portion (also referred to as the head in this specification) and the region adjacent to the magnified portion extend It includes a tubular structure that is located and ends at the second end of the main body, and the enlarged portion is relative to the longitudinal axis of the main body. The cross-sectional dimensions are the same as or larger than those of the tubular structure. In one embodiment, the device is positioned between the enlarged portion and the tubular structure and the enlarged portion and It includes a neck with a reduced cross-sectional dimension relative to the cross-sectional dimension of the tubular structure. Generally, The device is designed to be optimally suited to various pipe sizes and shapes, and to improve their handling. It is possible.

[0009] Appropriate fistulas include perianal fistulas, enterocutaneous fistulas, or rectovaginal fistulas, however These are not the only options.

[0010] In various embodiments, at least a portion of the tubular structure is divided into a plurality of elongated members. In other embodiments, the tubular structure is a single solid or substantially hollow structure. The tubular shape can be maintained. If the tubular structure is divided, the main body will be 1 to 20 Elongated members (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1 It can have 4, 15, 16, 17, 18, 19 or 20 elongated members. The size and shape are adapted to specific uses, for example, the size and / or location of the fistula. It can be changed in various ways. In some cases, one or more of the elongated members can be changed to suit the application. , or removed or otherwise modified in order to utilize a specific manufacturing process ( For example, it can be shortened. For example, in some cases, four strips of the same length It may be more efficient to manufacture an apparatus with a long member, while the three elongated members may be preferable for placement within the body. Further, in some cases, an apparatus having elongated members of different lengths obtained through processes after manufacture (or before insertion) may be desirable. In various embodiments, the elongated members may be offset with respect to the longitudinal axis of the apparatus (e.g., the members project outward from a common point). Further, the elongated members may be planar or may have various cross-sectional shapes such as rectangular, trapezoidal, square, hexagonal, arcuate, elliptical, circular, etc. In additional embodiments, at least a portion of the tubular structure may taper toward the second end of the body. The enlarged portion may have a substantially planar outer profile and / or a substantially circular cross-section. The second end of the apparatus may be configured to be inserted into the ostomy, and the first end is configured to fill all or a portion of the fistula tract. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy. In some embodiments, the body may include one or more nanofibrous polymers as described herein. In still other embodiments, at least a portion of the body is made of polyester (e.g., polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT) and combinations thereof) and polyurethane (e.g., polycarbonate, polyether, polyester-based or combinations thereof) and combinations of polyester and polyurethane, etc. It may be possible to obtain an offset with respect to the longitudinal axis of the apparatus (e.g., the members project outward from a common point). Further, the elongated members may be planar or may have various cross-sectional shapes such as rectangular, trapezoidal, square, hexagonal, arcuate, elliptical, circular, etc. In additional embodiments, at least a portion of the tubular structure may taper toward the second end of the body. The enlarged portion may have a substantially planar outer profile and / or a substantially circular cross-section. The second end of the apparatus may be configured to be inserted into the ostomy, and the first end is configured to fill all or a portion of the fistula tract. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy. It may be possible to obtain an offset with respect to the longitudinal axis of the apparatus (e.g., the members project outward from a common point). Further, the elongated members may be planar or may have various cross-sectional shapes such as rectangular, trapezoidal, square, hexagonal, arcuate, elliptical, circular, etc. In additional embodiments, at least a portion of the tubular structure may taper toward the second end of the body. The enlarged portion may have a substantially planar outer profile and / or a substantially circular cross-section. The second end of the apparatus may be configured to be inserted into the ostomy, and the first end is configured to fill all or a portion of the fistula tract. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy.

[0011] In additional embodiments, at least a portion of the tubular structure may taper toward the second end of the body. The enlarged portion may have a substantially planar outer profile and / or a substantially circular cross-section. The second end of the apparatus may be configured to be inserted into the ostomy, and the first end is configured to fill all or a portion of the fistula tract. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy. The enlarged portion may have a substantially planar outer profile and / or a substantially circular cross-section. The second end of the apparatus may be configured to be inserted into the ostomy, and the first end is configured to fill all or a portion of the fistula tract. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy. The second end of the apparatus may be configured to be inserted into the ostomy, and the first end is configured to fill all or a portion of the fistula tract. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy.

[0012] In some embodiments, the body may include one or more nanofibrous polymers as described herein. In additional embodiments, at least a portion of the tubular structure may taper toward the second end of the body. The enlarged portion may have a substantially planar outer profile and / or a substantially circular cross-section. The second end of the apparatus may be configured to be inserted into the ostomy, and the first end is configured to fill all or a portion of the fistula tract. In some cases, the first end of the apparatus (e.g., the enlarged portion or head) is configured to fill the ostomy. In still other embodiments, at least a portion of the body is made of polyester (e.g., polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT) and combinations thereof) and polyurethane (e.g., polycarbonate, polyether, polyester-based or combinations thereof) and combinations of polyester and polyurethane, etc. In still other embodiments, at least a portion of the body is made of polyester (e.g., polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT) and combinations thereof) and polyurethane (e.g., polycarbonate, polyether, polyester-based or combinations thereof) and combinations of polyester and polyurethane, etc. In still other embodiments, at least a portion of the body is made of polyester (e.g., polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT) and combinations thereof) and polyurethane (e.g., polycarbonate, polyether, polyester-based or combinations thereof) and combinations of polyester and polyurethane, etc. In still other embodiments, at least a portion of the body is made of polyester (e.g., polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene terephthalate (PTT) and combinations thereof) and polyurethane (e.g., polycarbonate, polyether, polyester-based or combinations thereof) and combinations of polyester and polyurethane, etc. It contains one or more electrospun polymers such as nanofiber synthetic materials. Generally, electrospun materials Any biocompatible polymer (natural or synthetic) may be used. In this context, the nanofiber polymer has a net charge throughout, internally, or on its surface. In some cases, nanofiber polymers are negatively charged. For example, by treatment with liquid sodium hydroxide (HYD), the material can acquire a negative charge. Polymers modified before or after electrospinning, or negatively charged polyurethanes It may contain polymers. In some cases, the nanofiber polymer is positively charged. This nanofiber polymer is, for example, produced by liquid ethylenediamine (EDA). Polyester modified before or after electrospinning to contain a positive charge through a special process. It may contain polymers.

[0013] Furthermore, the device includes electrospun materials having therapeutic agents incorporated within nanofibers. It is possible. The therapeutic agent may contain small molecules. In some embodiments, the therapeutic agent The medication is an antibacterial agent, such as penicillin (e.g., ampicillin or amoxicillin), ami Bactericidal antibiotics such as noglycoside and ofloxacin; erythromycin, tetracycline Bacteriostatic antibiotics such as phosphorus and chloramphenicol; quinolones such as ciprofloxacin. Antibiotics; or nitroimidazole, or at least one combination thereof There is one more. Additional antibiotics include moxifloxacin, levofloxacin, and linen. Zolid, gentamicin, tobramycin, streptomycin, naphicillin and doxyl Cyclins can be mentioned. Other therapeutic agents include anti-inflammatory drugs, such as NSAIDs and IMS. AIDs, anti-leukotrienes, antihistamines (e.g., diphenhydramine), steroids ( For example, dexamethasone, or immunosuppressants such as azathioprine, tacrolimus, etc. It may also contain lolimus, paclitaxel, everolimus, or biolimus. In embodiments, the therapeutic agent is an NSAID, acetaminophen, bupivacaine, meloxine The device may contain analgesics such as sicam or opioids. In certain embodiments, the apparatus For example, it can also include cells such as allogeneic stem cells, autologous stem cells, and mesenchymal stem cells (MSCs). The device may also include allogeneic adipose tissue-derived stromal stem cells. Additional therapeutic agents include Antifungal agents such as diflucan, fluconazole and itraconazole, paclitaxel, Antiproliferative agents such as everolimus and sodium butyrate, genetic factors such as siRNA, VEGF1 Growth factors such as 65, bFGF, BMP-7, recombinant hirudin / lefludan, argat Anticoagulants such as Roban and Vivalirdan, diatrizoic acid, barium sulfate, and gadodiamide These include contrast agents such as thrombin, triclosan, nanosilver, lactoferrin, and heterobifunctional materials. Sexual crosslinking agent, homobifunctional crosslinking agent, lysozyme, activated protein (activated drolecogin) Alpha), gorse lectin I (UEA-I) and snowdrop lectin (GN Contains various additives such as L).

[0014] In another aspect, the present invention relates to a primary opening in the wall surface of a body structure and a conduit extending from the primary opening. A device for implantation in internal bodily conduits such as perianal fistulas, enterocutaneous fistulas, or rectovaginal fistulas. The device is configured to fill at least a portion of the fistula pathway, and electrospun polymer It includes a body formed at least partially from the body. The body is positioned at the first end of the body. It includes an enlarged portion and a tubular structure that extends from the enlarged portion and ends at the second end of the main body. The enlarged portion is The cross-section of the tubular structure is the same as or larger than the cross-sectional dimensions of the main body relative to its longitudinal axis. It has dimensions.

[0015] In various embodiments, the electrospun polymer is polyester (e.g., polyethylene). Terephthalate (PET), polybutylene terephthalate (PBT), polytrimethylene Terephthalate (PTT) and combinations thereof) and polyurethane (e.g., polycarbonate) (polycarbonate, polyether, polyester-based or combinations thereof) and polyester It contains one or more nanofiber synthetic materials, such as a combination of sterling silver and polyurethane. In some embodiments, the apparatus uses nanofiber polyethylene terephthalate and Contains a mixture of nanofiber polybutylene terephthalate (nPET-PBT). In embodiments, the device includes nanofiber polyurethane (nPU). Various implementations In this state, the nanofiber polymer has a net charge throughout, internally, or on its surface. In some cases, nanofiber polymers are negatively charged. The polymer is a polymer that has been modified before or after electrospinning to contain a negative charge (HYD). This may include ester polymers or negatively charged polyurethane polymers. In some cases, nanofiber polymers are positively charged. Mer is a polyester that has been modified before or after electrospinning to contain a positive charge (EDA). It may contain telpolymers. The device may be non-biodegradable.

[0016] In an additional embodiment, the device has an electrochemical agent incorporated within a nanofiber. It contains a spun material. The therapeutic agent may contain small molecules. In some embodiments, The treatment involves antibacterial agents, such as penicillin (e.g., ampicillin or amoxicillin), Bactericidal antibiotics such as aminoglycosides and ofloxacin; erythromycin, tetrasaturates Bacteriostatic antibiotics such as Ikurin and chloramphenicol; quinols such as ciprofloxacin A chlorophosphamide antibiotic; or at least one of these nitroimidazoles. It is a combination. Therapeutic agents also include anti-inflammatory agents, such as NSAIDs, IMSAIDs, and anti-inflammatory drugs. Cotrienes, steroids (e.g., dexamethasone), or immunosuppressants (e.g., azathioprine). Purine, tacrolimus, sirolimus, paclitaxel, everolimus, or biolimus It may also contain . In a further embodiment, the therapeutic agent may be an NSAID, acetaminophen It may also contain analgesics such as bupivacaine, meloxicam, or opioids. In the embodiment, the device can use, for example, allogeneic stem cells, autologous stem cells, mesenchymal stem cells (MSCs), Any type of cell can be included. The device may also include allogeneic adipose tissue-derived stromal stem cells. stomach.

[0017] In certain embodiments, the body is a single structure as described herein. The body is also, It includes a neck portion positioned between the enlarged portion and the tubular structure, the neck being the enlarged portion and the tubular structure It has a cross-sectional dimension that is reduced compared to the cross-sectional dimension of the structure. In some embodiments, it is tubular At least a portion of the structure may taper toward the second end of the main body, and / or be tubular. At least a portion of the structure can be divided into a plurality of elongated members as described herein. Example For example, multiple elongated members may be offset with respect to the longitudinal axis, and there may be 1 to 20 elongated members. It may include components. In various embodiments, the enlargement has a substantially planar outer shape or substantially It can have a circular cross-section. The second end of the device fills all or part of the fistula. It may be configured to be inserted into the ostium, along with a first end configured to do so. Therefore, the first end of the device is configured to fill the opening of the nuclear power plant.

[0018] In yet another aspect, the present invention relates to a primary opening in the wall surface of a body structure and a tube extending from the primary opening. Device for implantation in internal ducts such as perianal fistulas, enterocutaneous fistulas, or rectovaginal fistulas, which have a passage. This invention relates to a method for manufacturing a polymer solution. The method involves preparing a polymer solution and electrospinning the solution. The process involves filling the knit and injecting the polymer solution into the injection needle port where a predetermined voltage is applied to the needle. Perfuming at a constant speed and the generated nanofibers ejected from the needle port into the longitudinal grooves The collection is performed by a mandrel-shaped rotating collector having a single tubular electrospinning section with longitudinal grooves. The process involves creating the yarn itself and then performing post-processing such as vacuum heating or solvent extraction to remove any residual solvent. The method includes the steps of removing and removing the electrospinning body from the mandrel. By pulling the end with the vertical groove downwards, the grooved portion is manipulated to the remaining part of the main body. This forms an enlarged portion (the enlarged portion has a cross-sectional dimension that is larger than the cross-sectional dimension of the rest of the main body). (Having the law), flatten the rest of the main body and create a substantially planar structure extending from the elongated portion. To form and divide the planar structure along the longitudinal axis of the main body into multiple elongated members By forming a part of the tubular body adjacent to the enlarged part, the enlarged part and the elongated part are sealed. To form a neck region between the material (the neck region is the enlarged part and the remaining cross-sectional dimensions of the main body) Includes (having smaller cross-sectional dimensions than).

[0019] In various embodiments, the step of preparing the solution involves polyester chips and / or poly Weigh the polyurethane chips and place them into the borosilicate vial, and inside the vial Adding hexafluoroisoproposal (HFIP) to the tip and the prepared solution Seal the vial containing the solution and stir the vial until all the pellets in the solution are dissolved. This includes mixing. In some embodiments, the weighing step is performed using polyethylene. Weighing refractate (PET) chips and polybutylene terephthalate (PBT) chips. This includes the following: In some embodiments, the polymer solution is in the solution before electrospinning. A therapeutic agent such as those disclosed herein can be added to the agent.

[0020] The process of removing the electrospinning body from the mandrel is carried out on a sink or other container, for example, 10 Rinse the main body with 0% ethanol (EtOH) and use a non-pyrogenic serum tube or similar. Fill the device with 100% ethanol and insert the main body and mandrel into the tube. This involves filling a 250 mL graduated cylinder with deionized water (DIH2O) and using a mandrel. Inserting the tube, and placing the cylinder inside the ultrasonic treatment device, and the cylinder The process involves ultrasonic treatment, removing the mandrel from the tube, and using DIH2O. This includes washing with water and drying the main unit.

[0021] In some embodiments, the longitudinal grooves of the mandrel are along the length direction of the mandrel. It is essentially centrally located, which allows for the production of two bodies from a single mandrel. It may be possible to do so. For example, the process of removing the electrospinning body from the mandrel is vertical The body is divided substantially perpendicular to the longitudinal axis of the body in the central region of the groove (for example, (Cut with a razor or similar tool) to create two bodies, each having a longitudinal groove end. It may include. In various embodiments, the size and shape of the mandrel may be used for specific purposes. For example, creating bodies of different lengths and diameters, or using one mandrel to create two or more bodies. It can be modified to suit the creation of the main body above. Furthermore, the main body may have anionic properties Surface modification, such as cationic surface modification, can be applied. Process for forming the neck region. This includes ultrasonic welding a portion of a tubular body adjacent to the enlarged portion.

[0022] In yet another embodiment, the present invention relates to one of the devices for embedding in a pipeline as described herein. The above relates to a kit. In some embodiments, the kit includes dimensions or materials It may include multiple different devices, allowing healthcare professionals to select the optimal device during implantation. The kit also includes non-biodegradable sutures, such as those made from electrospun materials, and / Or it may include, for example, one or more surgical instruments configured to assist in implantation. Cut.

[0023] In yet another aspect of the present invention, the present invention relates to a primary orifice and primary orifice on the wall surface of an intrabody structure. This invention relates to a method for treating a patient having a fistula, the fistula having a fistula pathway extending from [location]. This includes inserting one (or more) of the devices described above. The device passes through the primary port. It can be inserted into the fistula, and the device can fill at least a portion of the fistula.

[0024] In various embodiments, patients have perianal fistulas such as cryptoglandular fistulas. In this embodiment, the patient has a rectovaginal fistula, anal cutaneous fistula, or gastrointestinal fistula. In this case, the patient has Crohn's disease, ulcerative colitis, chronic diarrhea, post-pregnancy tract formation, or rectal cancer. The method may include inserting a device into the fistula. In a particular embodiment of the method, The device is then maintained in the fistula pathway for a sufficient amount of time for the fistula to heal. It can promote or allow internal growth of tissue. For example, the device can promote or allow internal growth of the insertion site. It can alter cell dynamics. Furthermore, the device does not induce fibrosis at the insertion site, and / or it does not induce collagen deposition at the insertion site.

[0025] Further other embodiments, as well as the advantages of these exemplary embodiments, are described below. This will be explained in detail below. Furthermore, both the information above and the detailed explanation below are applicable in various forms and This is merely an example of an embodiment, and the claimed aspects and nature and features of the embodiments are not included. It should be understood that the intention is to provide an overview or framework for understanding. Yes. Therefore, these and other objectives are the advantages and features of the present invention disclosed herein. This will also become clear by referring to the following detailed explanation and attached drawings. Furthermore, the features of the various embodiments described herein are not mutually exclusive, and various combinations are possible. Please understand that this can occur through combination and rearrangement.

[0026] In drawings, the same reference numeral generally refers to the same part across different drawings. The emphasis is not necessarily on strict scales, but rather on explaining the principles of the present invention in general. This is not intended to define any limitations of the present invention. For the sake of clarity, all Not all components may be shown in the drawing. In the following explanation, the following drawing... Various embodiments of the present invention are described with reference to [reference]. [Brief explanation of the drawing]

[0027] [Figure 1A] This is a visual representation of a fistula plug according to one or more embodiments of the present invention. [Figure 1B] This is an enlarged visual representation of the material of a fistula plug according to one or more embodiments of the present invention. [Figure 2] This is a visual representation of an alternative fistula plug according to one or more embodiments of the present invention. [Figure 3] This flowchart shows various steps for manufacturing a fistula plug according to one or more embodiments of the present invention. [Figure 4A] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4B] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4C] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4D] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4E] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4F] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4G] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4H]This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 4I] This is a visual representation of a specific exemplary process step that may be carried out according to one or more embodiments of the present invention. [Figure 5] A to C are visual representations showing surface modification of a fistula plug according to one or more embodiments of the present invention. [Figure 6] A and B are visual representations illustrating the application of the apparatus disclosed herein according to one or more embodiments of the present invention. [Figure 7] This is a graph showing the cell adhesion time of plugs made from different materials according to one or more embodiments of the present invention. [Figure 8A] This is a visual representation of mesenchymal stem cells growing on control, EDA (positive), and HYD (negative) nPET-PBT nanofiber plug materials according to one or more embodiments of the present invention. [Figure 8B] This is a visual representation of mesenchymal stem cells growing on control, EDA (positive), and HYD (negative) nPET-PBT nanofiber plug materials according to one or more embodiments of the present invention. [Figure 8C] This is a visual representation of mesenchymal stem cells growing on control, EDA (positive), and HYD (negative) nPET-PBT nanofiber plug materials according to one or more embodiments of the present invention. [Figure 8D] This is a visual representation of the nanofiber plug material before cell seeding, for reference purposes. [Figure 9] This is a visual representation of a non-drug-carrying plug pair with two drug-carrying plugs, illustrating the effectiveness of drug transport according to one or more embodiments of the present invention. [Figure 10] This is a collection of photographs illustrating the difference in treatment between cases where a plug is implanted and cases where it is not, according to one or more embodiments of the present invention. [Figure 11] This is a collection of photographs showing plugs that have been stained after implantation according to one or more embodiments of the present invention. [Figure 12A] This is a collection of photographs showing the embedding of a plug according to one or more embodiments of the present invention. [Figure 12B] This is a collection of photographs showing the embedded area of ​​the plug in Figure 12A after 30 days according to one or more embodiments of the present invention. [Figure 13] This is a collection of comparative microscopic images showing the implantation of a plug according to one or more embodiments of the present invention into a fistula (bottom panel), the implantation of plugs made from different (non-nanofiber) plug materials into a fistula (upper right panel), and a control path without an implanted plug device (upper left panel). [Figure 14] These are microscopic images of stained embedded plugs according to one or more embodiments of the present invention. [Figure 15] These are microscopic images of stained embedded plugs according to one or more embodiments of the present invention. [Modes for carrying out the invention]

[0028] Here, with reference to the exemplary embodiments shown in the drawings, this specification uses specific terminology. This will be explained. It should be noted that it is not intended to limit the scope of this invention. This will be understood by those familiar with the relevant technology and who have obtained this disclosure. Changes and further modifications to the features of the inventions exemplified herein, and the inventions exemplified herein Further applications of the principle should be considered within the scope of the present invention.

[0029] Figure 1 shows one embodiment of a fistula plug device 10 having an overall club-like shape or configuration. The plug 10 has a body 12 having a first enlarged end 14 and an enlarged part of the body 12. It consists of a tubular structure 16 extending from end 14 to second end 18. You can see this from the diagram. The pipe structure 16 is directed toward the second end 18 to facilitate the embedding of the plug 10. It tapers towards the end. Generally, the plugs disclosed herein are nuclear power plants in the walls of body structures. Inserted through the mouth (for example, through a tapered end), with a small fistula extending from the primary orifice. It is configured so that both exist within a part of it.

[0030] Figure 2 shows a fistula plug device 110 having a "jelly" configuration, which is an alternative embodiment. Similar to plug 10 in Figure 1, plug 110 is an enlarged plug located at the first end of the main body 112. A head 114 and a tubular structure 11 extending from there toward the second end 118 of the main body 112 6 and a plug optionally includes an enlarged head 114 and It may include a "neck" region 120 positioned between tubular structures 116. Region 120 includes a reduced cross-sectional dimension relative to the cross-sectional dimensions of the enlarged head and tubular structure. This is possible. In the embodiment shown in Figure 2, the tubular structure generally has a head 114 and a net Extending from the common point 124 adjacent to the buck 120 and from the longitudinal axis 128 of the device 110 It is divided into several elongated members 122 that protrude outwards. However, the elongated members The common features extending from there include, for example, that part of it is made of a tubular structure and part of it is elongated. The equipment, made from various materials, can be modified to suit specific applications. In this embodiment, the elongated member cuts or slices the tubular structure 116 thinly, for example. It is formed by dividing it into two or more elongated members. Typically, the neck region is In the apparatus including the neck 120, the neck 120 is positioned between the head 114 and the elongated member 122. The neck 120 provides greater strength and / or stability to the entire plug. Other implementations In terms of form, the elongated member 122 extends directly from the head 114. Generally, tubular structure 1 16 (with or without an elongated member) fills all or part of the fistula pathway. It is configured in such a way.

[0031] Four nearly planar, elongated members 122 having substantially equal width and length are roughly shown in Figure 2. This is shown. However, the number of members 122 changes along with the size and shape of each sub-member 122. (For example, the length of the members may differ between members, and the cross-sectional shape may be rectangular, trapezoidal, square, or hexagonal.) (This may include shapes such as square, elliptical, and circular.) In some embodiments, the apparatus is Two or more elongated members, for example, two or more, three or more, four or more, five or more, six or more, seven More than 8, 9 or 10, 11 or 12, 15 or more, It includes 20 or more or 25 or more elongated members. For example, in some embodiments, The apparatus includes 2 to 25 elongated members. In some embodiments, the apparatus includes 2 to 15 It includes elongated members. In some embodiments, the device includes 2 to 10 elongated members. In some embodiments, the apparatus includes 1 to 4 elongated members. In some embodiments, the apparatus includes 4 to 8 elongated members. It includes one elongated member. In some embodiments, the device includes 10 to 20 elongated members. nothing.

[0032] Heads 14 and 114 are substantially circular in shape with a planar outer shape as shown in Figures 1 and 2. Although shown, the shape and size of the head may vary depending on the specific application (e.g., filling the primary opening of a fistula). It can be changed to suit the needs of the device 10, 110. The specific size and shape also depend on the specific application (e.g., the location of the fistula, the size of the fistula, the type of fistula). It can be adapted to different types of fistulas. For example, an anal cutaneous fistula is more closed than a perianal fistula. Since the opening to be closed may be wide, the plug must be wide and long enough to properly close the fistula. It is necessary. In various embodiments, the first end or extended end 14 of the devices 10, 110 ,114 has a diameter of approximately 1 mm to approximately 10 cm (average diameter 2 to 4 mm) (for example, generally the outer dimensions ), approximately 1cm to 30cm in length (average length 3-5cm), approximately 0.050mm to 10cm The wall thickness may be (average wall thickness (0.5 mm to 1 mm)).

[0033] In some embodiments, the enlarged ends 14 and 114 have a cross-sectional area of ​​approximately 1 mm to approximately 10 cm. It may have a diameter. In some embodiments, the enlarged ends 14, 114 are about 10 mm to about 1 It may have a cross-sectional diameter of 5 cm. In some embodiments, the enlarged ends 14, 114 are about 5 cm. It may have a cross-sectional diameter of 0 mm to approximately 2 cm. In some embodiments, the enlarged end 14, 114 may have a cross-sectional diameter of approximately 1 cm to approximately 3 cm. In some embodiments, it can be enlarged. The ends 14 and 114 may have a cross-sectional diameter of approximately 3 cm to approximately 5 cm. In exemplary embodiments... The enlarged ends 14 and 114 are approximately 1 mm, 5 mm, 10 mm, 20 mm, 30 mm, and 40 mm. mm, 50mm, 60mm, 70mm, 80mm, 90mm, 1cm, 1.5cm, 2c m, 2.5cm, 3cm, 3.5cm, 4cm, 4.5cm, 5cm, 5.5cm, 6c m, 6.5cm, 7cm, 7.5cm, 8cm, 8.5cm, 9cm, 9.5cm or It may have a cross-sectional diameter of 10 cm.

[0034] In some embodiments, the fistula plug device may have a length of approximately 1 cm to approximately 30 cm. In some embodiments, the fistula plug device may have a length of approximately 1 cm to approximately 3 cm. In some embodiments, the fistula plug device may have a length of approximately 1 cm to approximately 5 cm. In some embodiments, the fistula plug device may have a length of approximately 3 cm to approximately 8 cm. In some embodiments, the fistula plug device may have a length of approximately 5 cm to approximately 10 cm. In some embodiments, the fistula plug device may have a length of approximately 8 cm to 12 cm. In some embodiments, the fistula plug device has a length of approximately 10 cm to approximately 20 cm. Obtain. In some embodiments, the fistula plug device is approximately 20 cm to approximately 30 cm in length. It may have. In an exemplary embodiment, the fistula plug device is about 1 cm, 2 cm, 3 cm, 4cm, 5cm, 6cm, 7cm, 8cm, 9cm, 10cm, 11cm, 12cm, 1 3cm, 14cm, 15cm, 16cm, 17cm, 18cm, 19cm, 20cm, 2 1cm, 22cm, 23cm, 24cm, 25cm, 26cm, 27cm, 28cm, 2 It may have a length of 9 cm or 30 cm.

[0035] In some embodiments, the fistula plug device may have a wall thickness of approximately 1 mm to approximately 10 cm. In some embodiments, the fistula plug device has a wall thickness of approximately 10 mm to approximately 1 cm. Obtain. In some embodiments, the fistula plug device has a wall thickness of approximately 50 mm to approximately 2 cm. It is possible. In some embodiments, the fistula plug device has a wall thickness of about 1 cm to about 3 cm. It is possible. In some embodiments, the fistula plug device has a wall thickness of about 3 cm to about 5 cm. It is possible. In an exemplary embodiment, the fistula plug device is approximately 1 mm, 5 mm, 10 mm, 20mm, 30mm, 40mm, 50mm, 60mm, 70mm, 80mm, 90mm, 1cm, 1.5cm, 2cm, 2.5cm, 3cm, 3.5cm, 4cm, 4.5cm, 5cm, 5.5cm, 6cm, 6.5cm, 7cm, 7.5cm, 8cm, 8.5cm, The wall thickness may be 9 cm, 9.5 cm, or 10 cm.

[0036] The device can be manufactured as a single piece or formed as a single body. The fistula plug is manufactured as two or more separate pieces that are joined together before application. This is advantageous in that at least two or more parts are desired after being embedded in the object. This is because they can be separated without difficulty. On the other hand, a fistula plug formed as a single entity, It does not have multiple parts that could separate after implantation. An example of the process is described below with respect to Figure 3.

[0037] In some embodiments, the fistula plug apparatus described herein is made of nanofiber poly It is manufactured from mer. In some embodiments, nanofiber polymers are electrospun. Prepared by: Exemplary method for manufacturing a fistula plug device containing electrospun polymer material The process is described in Figure 3.

[0038] As shown in Figure 1B, the electrospun material 26 is normally an extracellular scaffold that can exist in nature. It has a spiderweb-like texture similar to that of a wald. This structure promotes tissue integration. To prevent rejection and / or to promote healing when implanted, the fistula is treated The structure provides a mechanism for introducing therapeutic drugs or cellular materials. The electrospun polymer overlaps The fibers contain spaces or openings between them. In some embodiments, the scaffold The opening of the scaffold (i.e., between the fibers of the scaffold) is approximately 0.1 μm to approximately 1 00 μm, for example, 0.1 μm to approximately 10 μm, 10 μm to approximately 20 μm, 20 μm to approximately 50 μm m, can be in the range of 50 μm to approximately 80 μm or 80 μm to approximately 100 μm. These dimensions The law is merely illustrative; specific sizes and shapes should be adjusted to suit the particular application. It is possible.

[0039] The fistula plug devices described herein can be made from any suitable material. In some embodiments, the fistula plug can be made from a non-biodegradable polymer. Examples of non-biodegradable polymers include polyethylene terephthalate (PET). Polybutylene terephthalate (PBT), polytrimethyl (also known as chloron), polybutylene terephthalate (also known as chloron), polytrimethicone Lenterephthalate (PTT), polyurethane (PU), polytetrafluoroethylene ( Examples include ePTFE, poly(glycolic acid) (PGA), gelatin, or alginic acid. However, it is not limited to these. In some embodiments, the polymer is nanofiber. It is a polymer. In some embodiments, the polymer is an electrospun nanofiber polymer. It is a polymer. In some embodiments, the fistula plug device contains a single type of polymer. In other embodiments, the fistula plug device comprises two or more types of polymers. In one embodiment, the fistula plug device is of two or more types, three or more types, four or more types or It contains a mixture of five or more polymers. In some embodiments, the fistula plug device , including a mixture of 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more types of polymers. In a typical embodiment, the fistula plug device is made of nanofiber polyethylene terephthalate ( Includes nPET. In other exemplary embodiments, the fistula plug device includes nanofibers Contains ribethylene terephthalate (PBT). In other exemplary embodiments, fistula plastic The device uses nanofiber polyethylene terephthalate and nanofiber polybutylene It includes a mixture of terephthalates (nPET-PBT). In other exemplary embodiments, The fistula plug device contains nanofiber polyurethane (nPU). In some embodiments... In this context, the fistula plug device includes one or more nanofiber polymers, and nanofiber At least one of the polymers is derived from nPET, nPBT, nPU, and combinations thereof. Selected from the group. Other polymers are also conceived and considered to be within the scope of the present invention, in particular, electro Polymers suitable for the manufacture of equipment using inter-spinning are conceived and considered.

[0040] In general, any biocompatible polymer suitable for use in electrospinning is used in the application described herein. It can be used in the scaffold layer of the apparatus described herein. Other suitable polymers include polylactic acid (PLA), polyglycolic acid (PGA), and poly Coglycolic acid lactate (PLGA), polycaprolactone (PCL), polypropylene (P P) and polytetrafluoroethylene (PTFE), polyvinyl alcohol (PVA), Polyethylene oxide (PEO), polytrimethylene terephthalate (PTT), poly Ethylene acetate (PEVA), poly-D lactide (PLDA), polylactic acid (PLLA) Other examples include, but are not limited to, polyethylene glycol (PEG). Suitable polymers include collagen, gelatin, alginic acid, fibrinogen, and silk. It includes, but is not limited to, elastin, cellulose, chitin, and chitosan.

[0041] In other embodiments, the fistula plug can be made from a biodegradable polymer. Example Typical biodegradable polymer materials include collagen, cellulose, elastin, and glycosamine. Examples include minoglycans, peptidoglycans, chitin, or fibrin, but are not limited to these. Not specified. Biodegradable materials may optionally include crosslinking agents, aldehydes (e.g., glutaraldehyde). Dehyde, carbodiimide, acrylamide, or diimimate e) can be processed. In some embodiments, the biodegradable material is glutar It contains an aldehyde crosslinked biomembrane. In one embodiment, the fistula plug device includes one or more biomembrane Includes a combination of degradable polymers and one or more non-biodegradable polymers blended / mixed together. In some embodiments, the fistula plug device is made of hydrophilic polyurethane, polycaprol. Polylactic acid (PCL), polylactic acid (PLA), polylactic acid-coglycolic acid (PLGA), Made from liglycolic acid (PGA) or alginic acid, or a combination thereof. obtain.

[0042] In some embodiments, the fistula plug device uses the same polymer throughout the device. or a mixture of polymers. In other embodiments, the fistula plug device has an uneven distribution within the device. It contains multiple polymers dispersed in one place. For example, the apparatus contains a first polymer inside the apparatus - or a mixture of polymers and the external surface of the device (i.e., the surface that comes into contact with the object after embedding) This may include a second polymer or a mixture of polymers on the surface of the apparatus. (Example) In one embodiment, the fistula plug device has an internal polymer containing nPET-PBT and nP It may include an external polymer containing U.

[0043] In various embodiments, all or part of the polymer present in the apparatus is used for a specific application. It can be modified to suit the purpose. For example, nanofiber polymers can be modified within the polymer or within the polymer. The entire polymer, or the surface of the polymer, may have a net positive or negative charge. The substituents that impart a net charge to the polymer are added before processing the polymer into a fistula plug device. It can be added to the polymer during or after production. In certain embodiments, The outer surface of a cell contains either a positive or negative charge. Certain cells adhere to receptors / proteins on their surface. Because they possess an electric charge, they can use their surface charge to attract or repel other cells. This is possible. The charged polymer also has the special ability to promote cell adhesion in the blood and microenvironment surrounding the device. It attracts specific proteins (e.g., glycoproteins, proteins with RGD sequences). It is also possible to improve surface wettability and contact with cells. In an exemplary embodiment, the polymer of the fistula plug device contains a net negative charge. It can be modified in the following way. For example, by treatment with liquid sodium hydroxide (HYD) For example, contact the plug (or its polymer) with a reagent that promotes alkaline hydrolysis. This allows a net negative charge to be imparted to the polymer in the fistula plug. Another example In a typical embodiment, the polymer of the fistula plug device is modified to contain a net positive charge. It is possible to do this. For example, the plug (or its polymer) can be made of ethylenediamine (EDA). , 2-methylpentamethylenediamine, 1,2-diaminocyclohexane or 1,6- By contacting it with diamines such as hexanediamine, the polymer in the fistula plug becomes positively charged. It is possible to impart a positive charge to the taste. Charged surface modification and the creation of charged surface modification. Other examples of the method include, for example, U.S. Patent Nos. 6,743,253B2 and 7,037,52 Further details are provided in Section 7B2, which are incorporated herein by reference in their entirety. .

[0044] In some embodiments, the fistula plug device carries a drug, for example, a therapeutic agent. This process involves weighing a predetermined amount of the activator or therapeutic agent (usually by weight). ), added to the polymer solution before electrospinning. In other embodiments, for example, a drug is included. By immersing the device in a solution or suspension, the drug is loaded into the device after manufacturing. This is possible. In some embodiments, the therapeutic agent is a small molecule. In other embodiments, In other embodiments, the therapeutic agent is a peptide or protein. For example, DNA (expression vector DNA, for example plasmid DNA, viral vector DNA) (including A, etc.) mRNA, miRNA, antisense RNA, siRNA, gRNA In other embodiments, the therapeutic agent is a cell.

[0045] In some embodiments, the fistula plug device includes one or more antimicrobial agents. The presence of antibacterial agents slows down and reduces the growth of microorganisms within the fistula, such as bacteria, and This can be prevented. In some embodiments, the fistula plug device has bactericidal antibiotics. It contains a substance. In some embodiments, the fistula plug device contains a bacteriostatic antibiotic. In one embodiment, the fistula plug device contains a quinolone antibiotic. Exemplary embodiment In this state, the fistula plug contains one or more of the following: penicillin, aminoglycopropyl alcohol D, ofloxacin, erythromycin, tetracycline, chloramphenicol, cyanoacrylate Profloxacin, nitroimidazole, metronidazole, or a combination of these. For example, fistula plug devices use ciprofloxacin, metronidazole, or ciproflo This may include a combination of xacin and metronidazole.

[0046] In some embodiments, the fistula plug device includes one or more anti-inflammatory agents. The presence of anti-inflammatory agents can reduce or prevent inflammation within the fistula tract. For example, in some embodiments, the fistula plug is a nonsteroidal anti-inflammatory drug (NSA ID), immunoselective anti-inflammatory derivatives (IMSAIDs), anti-leukotrienes or steroids This may include drugs such as dexamethasone (for example), or combinations thereof.

[0047] In some embodiments, the fistula plug device includes one or more immunosuppressants. For example In some embodiments, the fistula plug contains azathioprine, tacrolimus, and syruff. Mus, paclitaxel, everolimus, or biolimus, or a combination of these. It may include.

[0048] In some embodiments, the fistula plug device is an NSAID, acetaminophen, Bupivacaine, meloxicam, or an opioid, or a combination thereof. This includes the above-mentioned pain relievers.

[0049] In some embodiments, the fistula plug device can include cells. The cells incorporated can be homogeneous or autologous. In some embodiments, the cells are Stem cells, for example, allogeneic stem cells or autologous stem cells. In some embodiments, The cells are mesenchymal stem cells (MSCs). In other embodiments, the cells are derived from adipose tissue. These are qualitative stem cells (allogeneic or autologous). In such embodiments, the apparatus utilizes known techniques. The device can be used to load cells into a target before implantation. For example, the device can load cells Allow sufficient time for it to adhere to the device, and then in the in vitro cell culture system, together with the cells... It can be incubated.

[0050] In some embodiments, the fistula plug device contains one or more of the above-mentioned drugs (e.g. For example, combinations of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more items can be included. For example, in some embodiments, the fistula plug device contains antibacterial agents, anti-inflammatory agents, and immune agents. It may contain one or more of the following: inhibitors, analgesics, or cells.

[0051] Figure 3 shows an exemplary method for producing a fistula plug according to one or more embodiments of the present invention. This is flowchart 200 showing various processes that may be used. Generally, the method is manual It is described from the perspective of small-scale batch processes. However, this process is a production engineering part. As any ordinary engineer in the field knows, it is scaled up to be suitable for large-scale production. And it is automated (for example, via robotics) and executed as a continuous process. It is possible.

[0052] The first step 202 includes preparing a solution for manufacturing the main body. Generally, poly The solution contains polymer chips (e.g., polyester chips and / or polyurethane chips). This involves weighing the ingredients (e.g., borosilicate vials) and placing them into a vial. It is prepared by the following. In some embodiments, (0.5%~30% w:v) Polyethylene terephthalate (PET) chips and (0.5%~30% w:v) polybutylene Lenterephthalate (PBT) tips are used. Next, the solvent is added to the tips in the vial. (For example, add hexafluoroisoproposal (HFIP)) and, for example, put it in a vial. Screw in the top, for example, Bemis C, headquartered in Neenah, Wisconsin. Flexible film such as Parafilm (registered trademark) available from company, Inc. It is sealed by sealing it with a cap. Next, the sealed vial is placed so that the tip in the solution is completely sealed. Stir until dissolved (approximately 5-7 days or more) (for example, at an appropriate speed, e.g., 45 RPM). (By placing it on the configured rotating device.)

[0053] In step 203, the polymer solution can be introduced into the electrospinning unit. In some embodiments, the unit may be loaded via a syringe. Specifically, a plunger Remove the connector and connect the tip of the syringe to the needle port to use the 10mL syringe. This can be done. After introducing the solution into the syringe, the syringe is then fed into the pump of the electrospinning unit. It can be connected.

[0054] When the process moves to step 204, the solution is delivered onto a rotating collector 250 such as a mandrel. The solution is delivered by injecting the polymer solution into the injection needle port through which a predetermined voltage is applied to the needle. The process involves perfusing the system at a predetermined rate and using the generated nanofibers ejected from the needle port. The material is collected by a rotating mandrel-shaped collector with longitudinal grooves, and then collected in a single tubular shape with longitudinal grooves. This includes the process of fabricating the electrospinning unit. See Figure 4A. Operation of the electrospinning unit. The parameters can be determined to suit specific applications, such as the number and size of the devices to be manufactured. In one embodiment, the e-spinning range is approximately 10-20 cm, and the rotation speed is approximately 50 The RPM is set to ~150 RPM and the voltage to approximately 20~23kV. The mandrel used is... The size and rotation time depend on the size and type of device being created (club or jelly). Table 1 below shows two examples of mandrel size and rotation time. Mandrels are typically made of Teflon. A ron-coated steel mandrel is used, but other types are available to suit specific applications. You may choose the following materials. Furthermore, the overall shape of the mandrel can be adapted to suit a specific application. It can be changed. In certain embodiments, each is connected in the center of the collector. Two jelly-type devices are manufactured using two mandrels equipped with longitudinal grooves. In this embodiment, the mandrel tapers along its length. Furthermore, the mandrel The diameter can range from approximately 1 mm to 30 mm, and the length can range from approximately 5 cm to 60 cm. [Table 1]

[0055] After rotation is complete, any excess material can be removed by cutting it with, for example, a razor blade. In the application configuration, the razor blade is held against the mandrel, and the mandrel is rotated to remove To create clean cut pieces of material that can be removed and discarded. Furthermore, to the electrospinning body In contrast, residual solvents can be removed by post-treatment such as vacuum heating or solvent extraction. .

[0056] In some embodiments, when the device is implanted, therapeutic agents (e.g., antibacterial agents) are delivered. The therapeutic agents disclosed herein can be delivered to the patient (anti-inflammatory agents). The therapeutic agent can be added to the polymer solution before the electrospinning process. Furthermore, the polymer solution This is to create a electrospinned body having a net charge (i.e., negative or positive charge). Furthermore, it can be further modified before electrospinning.

[0057] The process of removing the electrospinning body 252 from the collector 250 (step 205) is performed at a predetermined position The process begins by removing the collector held in the device and moving it to the ultrasonic processor. It can be done. The main body 252 is 100% ethanol (EtOH) and is used as a sink or other It can be rinsed on a type of recovery tank. Next, non-pyrogenic serum tubes (or as specified by the lab). (Similar substances that may be used) 100% ethanol (for example, a collector placed inside a tube) - It can be filled with enough to cover the upper body. Insert a collector inside. Place the tube into a container filled with deionized water (DI-H2O) (for example, a 250 mL measuring tube). It can be placed inside the (Linder). The container can then be placed inside the ultrasonic processor. Otherwise, do not touch the electrospinning machine itself. Run the ultrasonic treatment device for approximately 30 minutes. Obtain. After sonication in ethanol for 30 minutes, remove the collector 250 from the serum tube. It can be removed and rinsed with DI-H2O. EtOH can be removed from the tube, and the tube... DI-H2O can be filled into it. Return the collector to the tube and put both into the container. It can be returned to its original position. Return the container to the ultrasonic device and perform ultrasonic treatment for approximately 2 minutes. This can be done. After the 2-minute ultrasonic treatment is complete, remove the collector from the tube and dry it. It can be placed on the surface and dried at room temperature for about 24 hours. In some embodiments The dry surface may include paper-based substrates such as cardboard, paperboard, or fiberboard. In the embodiment, for example, a tunnel dryer, infrared heating, or the body is exposed to an airflow. Mechanical means such as [specific method] may be used to dry the main body.

[0058] After the material has dried, remove the main body 252 from the collector 250 and the two fistula plastics A cutting device can be formed. Using a cutting tool (for example, a sharp razor blade), Around the axis that is close to the midpoint of the ctor and generally corresponds to the longitudinal groove or the center of the bead 254 The main body 252 can be cut. See Figure 4B. The beads can be completely cut, and the main body can be cut. Cut it in two. Gently twist the material with gloved hands to separate the main body 252 on the mandrel. It can be loosened. In the case of a mandrel with two parts, hold one and twist the other body. Then, repeat the same process for the other side. The body is completely loose and rotates around the mandrel. Once you can do it, you can slide it off the mandrel (for example, mand (Avoid the longitudinal groove of the reel). See Figures 4C to 4E.

[0059] Steps 206 to 209 mainly relate to forming a jelly-type apparatus as shown in Figure 2. Before forming the final device, the main body is made of either anionic or cationic surface. Surface treatments such as modification can be exposed to various surface treatments. Generally, surface modification treatments are tailored to specific applications. To achieve this, it can be implemented at virtually any stage of the manufacturing process.

[0060] Surface modification is performed before, during, or after the manufacture of the plug using methods approved in the art. It can be added to the polymer according to the following. For example, to perform anionic surface modification, The main body can be inserted into a 4mm Teflon-coated mandrel. Next, The mandrel containing the main body contains NaOH, for example, 0.5% by weight / volume of NaOH. It can be placed in a 1000 mL beaker containing boiling water for about 30 minutes. Several methods In terms of form, at least approximately 6 cm of the main body can be in contact with the solution. For approximately 30 minutes. After boiling, remove the mandrel and main body from the solution and rinse with DI-H2O for about 30 seconds. It can be air-dried at room temperature.

[0061] In another embodiment, the following exemplary procedure is followed to perform cationic surface modification. It is possible to insert the main body into a 4mm Teflon-coated mandrel. It can be done. The mandrel containing the main body contains approximately 250 mL of 50% ethylenediamine (EDA). It can be placed in a 600mL beaker. The main body can be immersed in the solution for approximately 4 hours. After processing is complete, remove the mandrel and main body from the solution, rinse with DI-H2O, It can be completely immersed in DI-H2O for 24 hours. After 24 hours, DI-H2O The main unit can be removed and dried at room temperature.

[0062] Step 206 relates to forming an enlarged portion of the main body, which generally involves the longitudinal groove of the main body 252. This includes manipulating part 254. See Figure 4F. The process involves taking material from the longitudinal groove and shaping the conical region. The area needs to be slightly lowered to form the head. A substantially circular, flat head 256 To form it, there is no need to stretch the material; simply pull it. Other head shapes and It should be noted that the configuration is conceived and deemed to be within the scope of the present invention. Also, head 25 The tubular structure 258 extending from 6 may be tapered, and the body formed at this point may be club-shaped Please also note that it can be used as a device.

[0063] Next, the main body 252 is placed on a solid surface (for example, a cutting board or robot platform) By placing it on the foam, the tubular structure 258 extending from the enlarged head portion 256 is flattened. It is possible (step 207). The main body here consists of the magnifying head and the comparison extending from the magnifying head. It consists of a flat, planar body. See Figure 4G.

[0064] Process 208 generally involves forming a planar body along its longitudinal axis 260 into multiple elongated members 2 This concerns dividing it into 62 parts. See Figure 4H. The number of elongated members can be changed to suit the specific application. To transform. Using a cutting tool, cut along the longitudinal axis, starting from the distal end of the body, and expand. The pipe is cut near the center, extending approximately 4-5 mm from the large head section. This yields two elongated members 262. Further cutting is performed to form additional elongated members. For example, using surgical scissors, select a point approximately 4-5 mm away from the magnifying head. Cut the elongated piece in the middle. Repeat this process on the other elongated pieces to create four elongated pieces. It can be manufactured. Furthermore, it can be cut in the longitudinal direction to form additional elongated members.

[0065] Once the enlarged head and the elongated member are formed, between the enlarged head 256 and the elongated member 262 The neck portion 264 can be formed (step 209). In various embodiments, the neck The section can be formed via ultrasonic welding (for example, via a handheld welding torch). See Figure 4I.

[0066] Those skilled in the art can easily determine the conditions and parameters suitable for ultrasonic welding. In an exemplary embodiment, in the case of a body that is not surface modified, the ultrasonic handheld welding machine The settings can be applied as follows: 4 amplitudes and a welding time of approximately 0.25 seconds. (To head 256) Grasp the adjacent neck portion 264 (either with a gloved hand or a gripping tool such as tweezers). Then, the main body is introduced into the welding machine 266. After the creation of the elongated member 262, the tubular structure 258 Bring the welding torch head close to the opening inside the main body. Start the welding torch and the neck of the main body. Apply amplitude to seal area 264. With minimal damage to head 256 or damage Repeat this process without giving any liquid until the neck area is completely sealed. The arrangement consists of a main body 252 having an enlarged head portion 256, and a reduced cross-sectional area relative to the head 256. A neck portion 264 having a neck portion 264 and a plurality of elongated members 262 extending outward from the neck portion 264 , including. If the main body 252 is excessively damaged (for example, if the head 256 can be easily detached) If too many holes are hit or the welding torch is applied, the device can be discarded and pulled. It is neither used for testing nor for implantation.

[0067] Surface modification (e.g., exposure to EDA, hydrolysis, or loading of therapeutic agents) For the main body that has undergone welding, the welding parameters can be appropriately adjusted, for example, several implementations In terms of form, the welding time is 5 amplitudes and approximately 1.0 second. The remaining steps are performed on the unmodified body. The same applies to the above. The process is to cause minimal damage to the head 256 or damage Repeat without further processing until the neck area is completely sealed.

[0068] Once the device is complete, measure it against the template to obtain the desired measurement values ​​(e.g., ). Head diameter, head thickness, length of the elongated member from the neck / weld, and starting point for cutting the elongated member. The position, the thickness of each elongated member, the width of the base of each elongated member, and the weight of each device were obtained. The device can perform specific quality control processes, such as verification. Additional testing may be required as needed. Subjected to testing (e.g., tensile strength), and further modified or prepared for embedding. obtain.

[0069] In some embodiments, the fistula plug device described herein is used to have a fistula A method for treating a patient is provided herein. When used herein, a patient having a fistula To "treat" someone means, for example, to close, fill, block, heal, or reduce a patient's fistula. By causing, reducing the size of, or alleviating symptoms associated with the fistula in the patient This includes stabilizing or improving one or more conditions related to the patient's fistula pathway. It can be done.

[0070] The diameter and length of the fistula plug are sized to approximate the diameter and length of the patient's fistula pathway. It can be determined. In an exemplary embodiment, the fistula plug is used after the plug is applied to the patient, To fill in all or part of a road.

[0071] Substantially all types of fistulas can be filled using the fistula plugging device described herein. For example, the fistula plug device described herein can be used for perianal fistulas, cryptogland fistulas, etc. It can be used to treat patients with anal fistulas, rectovaginal fistulas, anal cutaneous fistulas, or gastrointestinal fistulas. In some cases, fistulas are associated with inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. It can occur secondary to enteritis or atypical colitis. In some cases, the fistula may be associated with chronic diarrhea or pregnancy. Later complications may be associated with colitis or rectal cancer. The fistula plug device described herein It can also be used to treat gastrointestinal fistulas, enterobastostomies, and complex fistulas. Some fistulas are It has a single primary opening from which fistula pathways or tunnels extend. Furthermore, it has one or more secondary openings connected to the fistula pathway. Some fistulas are It may have multiple ducts. Patients receiving treatment for ulcerative colitis or atypical colitis, You can undergo ileal pouch-anal anastomosis (IPAA) to create an internal pouch. Patients undergoing this procedure are at high risk of postoperative fistula formation. Such fistulas are also described herein. It can be filled using the fistula plug device described.

[0072] Therefore, in some embodiments, the subject matter described herein requires it. Treatment, healing, or closing of the fistula in question, including the application of a fistula plug device. A method for doing so is provided herein. In some embodiments, the subject is a perianal fistula, Having a cryptogland fistula, rectovaginal fistula, anal cutaneous fistula, gastrointestinal fistula, gastrointestinal fistula, enterobasculostosal fistula, or complex fistula. In some embodiments, the subjects are the rectum and vagina, the large intestine and the skin surface, and the stomach and the skin surface. , the uterus and peritoneal cavity, arteries and veins, bile ducts and skin surface, cervix and vagina, between the neck and throat and / or It has a fistula located in the paranasal sinuses. The fistula plug device treats, heals the fistula. Alternatively, it may be kept within the fistula for a sufficient period of time to close.

[0073] In some embodiments, the subject is a disorder in which the fistula is secondary, such as inflammatory bowel disease. (IBD), for example, combination therapy for Crohn's disease, ulcerative colitis or atypical colitis. It is being received. For example, in some embodiments, the subject is α4β7 integrin. Combination therapy using antibodies that bind heterologously or their antigen-binding portions is available. In one embodiment, the antibody or its antigen-binding portion is CDR1 of SEQ ID NO: 2, sequence Heavy chain variable region including CDR2 of number 3 and CDR3 of sequence number 4, and / or sequence number Includes a light chain variable region including CDR1 of sequence 6, CDR2 of sequence number 7, and CDR3 of sequence number 8. In some embodiments, the antibody or its antigen-binding moiety is a heavy weight containing SEQ ID NO: 1. Includes a chain variable region and / or a light chain variable region including SEQ ID NO: 5. In some embodiments, In this context, the antibody that specifically binds to α4β7 integrin is vedolizumab or its antigen. This is the binding portion. Vedolizumab is sold under the trade name ENTYVIO (registered trademark) (Millenn Also known as ium Pharmaceuticals, Inc. Mab specifically binds to α4β7 integrins, such as the α4β7 complex, and α4β7-in Tegrin, mucosal adresin cell adhesion molecule-1 (MAdCAM-1), and fibronectin It inhibits interaction with lymphocytes, such as CD4, CD8, or memory T lymphocytes, and It is a humanized monoclonal antibody that inhibits migration from the skin to the inflammatory gastrointestinal parenchymal tissue. The use of vedolizumab in patients with perianal fistula-forming Crohn's disease is, for example, covered by a US patent. It is described in publication no. 2017 / 0327584A1, and the full content can be found by referring to this document. It will be included in the specifications.

[0074] The fistula plug device can be applied to the patient using standard surgical techniques. To the target fistula pathway. Any method that results in the implantation of the fistula plug may be used to apply the device.

[0075] In some embodiments, the fistula plug may be inserted into the fistula pathway through the primary opening. In other embodiments, the fistula plug may be inserted into the fistula pathway through a secondary opening. In one embodiment, an opening to the fistula pathway is surgically created for the insertion of a fistula plug.

[0076] Either end of the fistula plug device can be inserted first. In some embodiments, The fistula plug is inserted into the fistula tract by applying gentle force. In other embodiments, The fistula plug may be attached to a surgical suture or cord, in a designated position within the fistula pathway. It can be pulled. Generally, fistula plug devices are designed so that the widest part of the device is at the widest part of the fistula pathway. It is positioned to be placed in the section.

[0077] Before applying the fistula plug device, the fistula pathway may be cleaned and / or wiped.

[0078] In some embodiments, the fistula plug device is immersed in sterile saline solution before application. obtain.

[0079] After insertion, the fistula plug is held in place using surgical sutures or stitches. Obtain. In embodiments in which the fistula plug contains a non-biodegradable polymer, a non-biodegradable suture is used. In some embodiments, it is desirable to hold the fistula plug in place. In this context, the fistula plug is made of nanofiber polymer, the same as that found in the fistula plug. It is held in place using non-biodegradable sutures containing various polymers.

[0080] The device can be maintained within the fistula tract of the subject for any period of time, for example, a time sufficient for the healing or partial healing of the fistula. For example, the fistula plug can be maintained in the fistula tract for a time sufficient for closing one or more openings to the fistula tract, reducing inflammation of the fistula tract, reducing infection of the fistula tract, reducing the size of the fistula tract, and / or promoting internal growth of tissue into the fistula tract. In some embodiments, the fistula plug is not removed from the subject. In some embodiments, the fistula plug is maintained within the subject for one week or more, for example, 1, 2, 3, 4, 5 weeks. In some embodiments, the fistula plug is maintained within the subject for one month or more, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. In some embodiments, the fistula plug is maintained within the subject for one year or more, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years or more. In some embodiments, the fistula plug is maintained within the subject indefinitely. In some embodiments, the fistula plug is permanently implanted within the subject. Preferably, the fistula plug device does not induce fibrosis at the insertion site and / or does not induce collagen deposition at the insertion site. The fistula plug device can promote healing of the fistula tract by allowing internal growth of tissue into the device and / or by changing the cellular dynamics at the insertion site. In embodiments where the device carries a therapeutic agent, the device can also deliver the therapeutic agent to the fistula tract, providing additional benefit to the patient. Also provided is a kit comprising the fistula plug device disclosed herein. In some embodiments, the kit can include instructions for use of the device for treating a fistula. For example, the instructions can include instructions for surgical implantation of the device and / or for loading a therapeutic agent onto the device.

[0081] Instructions for use may be included. In some embodiments, the kit may be fitted to the patient. It may contain non-biological sutures for use in implanting implants. In embodiments, the nonbiological suture may contain an electrospun nanofiber polymer. Yes, it is possible. In some embodiments, the kit provides one or more devices for inserting the device into the patient. This may further include surgical instruments. [Examples]

[0082] The following examples illustrate how the apparatus and methods described herein are used and manufactured. And an explanation of how it can be evaluated is presented to those skilled in the art. The examples are pure This is intended to be illustrative in a refined way and does not limit the scope of the invention in any sense. That was not the intention.

[0083] Example 1: Surface modification of the device Figure 5 shows three fistula plugs 210a, 210b, and 210c, and two plugs 210 b, 210c has undergone surface modification, and the third plug is the control plug 210a. 210b is modified using sodium hydroxide to have a negative charge, and a positively charged dye ( This represents an HYD plug combined with ethylene blue. [ka] As shown, plug 210c is modified with liquid ethylenediamine to have a positive charge. This represents an EDA plug bound to a negatively charged dye (Acid Red 1), [ka] As shown in the figure, neither dye bound to the control plug 210a. , The surface modification was effective based on the substantial and consistent coloring (shown as patterned in the figure) of the plugs 210b, 210c. It was shown to be effective based on the substantial and consistent coloring (shown as patterned in the figure) of the plugs 210b, 210c.

[0084] Example 2: Device Arrangement Figures 6A and 6B generally show two possible applications for the device (generally 310) described herein. Figure 6A shows a rectovaginal fistula 330, while Figure 6B shows an anorectal skin fistula 332. The rectovaginal fistula 330 can result from Crohn's disease and benefit from the implantation of a device 310a capable of delivering cell material to that site. The anorectal skin fistula 332 can result from complications of abdominal surgery and can also benefit from implanting a device 310b carrying biological material to strengthen the boundary between the intestine and the skin. The rectovaginal fistula 330 can result from Crohn's disease and benefit from the implantation of a device 310a capable of delivering cell material to that site. The anorectal skin fistula 332 can result from complications of abdominal surgery and can also benefit from implanting a device 310b carrying biological material to strengthen the boundary between the intestine and the skin. The anorectal skin fistula 332 can result from complications of abdominal surgery and can also benefit from implanting a device 310b carrying biological material to strengthen the boundary between the intestine and the skin. The anorectal skin fistula 332 can result from complications of abdominal surgery and can also benefit from implanting a device 310b carrying biological material to strengthen the boundary between the intestine and the skin. The specific device 310 used is configured to fit a specific fistula site and can directly deliver a sustained level of therapeutic agent to that site, for example, to alter the cell dynamics at the wound site.

[0085] In various embodiments, the device can contain therapeutic agents such as small molecules that can be incorporated into, for example, electrospun fibers or captured by the scaffold-like structure of the device body, or antibiotics. In some embodiments, the device can be soaked in a therapeutic agent before implantation or incorporated as part of the manufacturing process. The therapeutic agent can include, for example, antibacterial agents, immunosuppressive agents, anti-inflammatory agents, analgesics or cells as disclosed herein. In various embodiments, the device can contain therapeutic agents such as small molecules that can be incorporated into, for example, electrospun fibers or captured by the scaffold-like structure of the device body, or antibiotics, or the device can be soaked in a therapeutic agent before implantation or incorporated as part of the manufacturing process. The therapeutic agent can include, for example, antibacterial agents, immunosuppressive agents, anti-inflammatory agents, analgesics or cells as disclosed herein. or cells as disclosed herein. or cells as disclosed herein. or cells as disclosed herein.

[0086] Example 3: Cell loading In general, in some embodiments, the therapeutic agent includes adipose tissue-derived mesenchymal stem cells. Homogeneous fatty acids can be incorporated into the device by immersing them in a solution for approximately 30-60 minutes. Contains tissue-derived stromal stem cells. The incubation time for cell attachment is used. It varies depending on the cells and materials. Generally, MSCs are time-dependent on the surface of all electrospun materials. nPET-PBD(HYD), which adheres rapidly and is negatively charged, is a tissue culture plastic. It showed similar adhesion, but positively charged nPET-PBD(EDA) showed MSC binding level It decreased.

[0087] Human adipose-derived mesenchymal stem cells (MSCs) (passage 4) are placed in a 16mm diameter disk-shaped electric field. Spinned polymer materials: nPET-PBT, nPET-PBT(EDA) and nPET-PB T(HYD), and as a control, 40,000 cells in a standard 24-well tissue culture plate. Cells were seeded at a density of cells / well. The cells were placed in adipose-derived mesenchymal stem cell basal medium (2% saturates). Fetal serum (FBS), 5 ng / mL basic rhFGF, 5 ng / mL acidic rhFGF F, 5 ng / mL of ehEGF, and 2.4 mM L-alanyl-L-glutamine were added. Incubate in an incubator at 37°C under 5% CO2 conditions in ATCC (registered trademark) The discs were then placed in fresh culture solution at 15, 30, and 60 minutes after sowing. Transfer to a 4-well plate and use the cell counting kit 8 ("CCK-8", Dojindo Mol). (Available from ecular Technologies, Inc.) For an additional 90 minutes Intermittent incubation was performed. As a reference, 20,000, 10, 000, 5,000, 2,500, 1,250, 625, 313, 156 and 78 cells / MSCs, serially diluted at a known density in the wells, were seeded and subjected to the same treatment as the cells on the material described above. The number of cells was calculated based on the absorbance at 450 nm obtained from each well. See Figure 7. The graph shows the attachment time of MSCs to various electrospun materials.

[0088] Figures 8A and 8C show the control (Figure 8A), positive charge (EDA) (Figure 8B), and negative charge (HYD). (Figure 8C) shows MSCs grown on nPET-PBT electrospun polymer material 426. The image shows cells 470 attached to the electrospun polymer 426 after seeding. Cell 470 is generally shown as white. The protocol for seeding and staining the material is as follows: This will be explained. Human adipose-derived MSCs (passage 4) are processed in ink at 37°C under 5% CO2 conditions. Celltracker Green (trademark) was used in a tube at a concentration of 5 μM for 30 minutes. Stained with phosphoric acid (available from Thermo Fisher Scientific). After washing with buffered saline (PBS), the cells were treated with trypsin, and the culture medium was converted to adipose-derived MSCs. Mesenchymal stem cell basal medium (2% FBS, 5 ng / mL basic rhFGF, 5 ng / mL Acidic rhFGF, 5 ng / mL ehEGF, 2.4 mM L-alanyl-L-glutamyl Cells 470 were collected in ATCC (registered trademark) with added mine. mm disc-shaped electrospun nanofiber polymer material 426: nPET-PBT, nPE 30,000 cells / well on T-PBT(EDA) and nPET-PBT(HYD) Seeds were seeded at a density and cultured in a culture medium under 5% CO2 conditions in an incubator at 37°C. 60 minutes after inoculation, the culture medium was replaced with fresh medium and the cells were incubated overnight. 1 mL of P After washing twice with BS, the membrane containing cells was treated with 3.7% formaldehyde (SIGMA). The samples were treated for 15 minutes. 1 mL of 0.1% TritonX100 / PBS solution was added to each of the materials. It was added and incubated for 15 minutes. Image-iT(registered trademark) FX Signal E Enhancer (available from Thermo Fisher Scientific) Each was applied, washed with PBS, and incubated at room temperature for an additional 30 minutes. 0.1 The material was examined using a 5 μg / mL phalloidin PBS solution containing % bovine serum albumin (BSA). By incubating the mixture for 60 minutes, Invitrogen (trademark) Alexa Fluor(trademark) 594 phalloidin (Thermo Fisher Scient Staining (available from iFi) was performed, followed by observation with a confocal laser scanning microscope. Figure 8D shows, for general reference, the electrospun polymer material 426 before sowing.

[0089] Example 4: Drug loading Figure 9 shows an electric field prepared as described herein and supporting a low-molecular-weight antibiotic agent. This shows a spun polymer material. Bacterial growth inhibition zone 582 is non-drug-supported nPET-PBT. Plug 510 (white dot in the upper well) and metronidazole-ciprofloxacin The plug 510 (white dots in the two lower wells) is shown around the pre-selected plug. Weigh the amounts of metronidazole and ciprofloxacin, and before electrospinning, use PET-PBT It was added to the polymer solution. As seen in lower well 580, the agent was absorbed by the nanofibers. It was supported within the rimer material and inhibited the growth of bacteria in the vicinity of the plug (inhibition zone 582). (Shown as the "transparent" area of ​​plug 510). The protocol for preparing the material is as follows. Let me explain. Generally, the protocol involves smearing blood agar plates in strips. This includes creating a microbial community and embedding segments of the device.

[0090] B. Fraglis KWIK-STIK™ pouch and an appropriate number of blood agar plates The plate was allowed to return to room temperature. Starting from the center, the blood agar plate was evenly covered with blood. The sea urchin was smeared in stripes from one end to the other.

[0091] Next, a fragment of the fistula plug material 510 was placed on a plate coated with B. fragilis in a striped pattern. Embedded in the 580. Non-drug-carrying nPET-PBT plug segment (upper plate) ), metronidazole-supported nPET-PBT plug (lower left plate), and ciproflo We tested a xacin-metronidazole-supported nPET-PBT plug (lower right plate). .

[0092] Anaerobe container system sachet for generating an anaerobic atmosphere (Becton BD GasPak® EZ Incubation Container with Dickinson Plate 580 was incubated with (Becton Dickinson) for 48 hours. After a while, check whether there is a clear ring around the sample (i.e., inhibition zone 582). The rates were examined. No zones were observed in plate A, and the fistula plug alone did not provide bactericidal activity. It was shown that this does not occur. In plates B and C, the inhibition zone 582 was clearly defined. Yes, a fistula plug 510 carrying metronidazole-ciprofloxacin is located near the plug. It has been shown to inhibit bacterial growth.

[0093] Example 5: Implantation of the device into a rat model A electrospun nanofiber fistula plug 610 prepared according to the method described herein The treatment was applied to the subcutaneous tract of a rat model (684 cells) and maintained for 30 days.

[0094] In short, the goal is to prevent rats from coming into contact with the implanted fistula plug 610. Subcutaneous tracts 684 were created in the dorsal region of rats. After allowing the tracts to form for 30 days (2 per rat) (1 conduit), (i) no device (conduit only), (ii) unmodified nPET-PBT jelly composition Plugging device, (iii) nPET- negatively charged by sodium hydroxide (HYD) treatment PBT jelly-based plug device, (iv) positively charged by ethylenediamine (EDA) treatment nPET-PBT jelly-based plug device, (v) nPE carrying metronidazole T-PBT jelly-based plug device, (vi) nPU club-based plug device, or (vii ) Biodegradable plug device (control) (Gore Bio-A, Cook Medical) The implants were then left in rats for another 30 days.

[0095] Thirty days later, the device was removed, and all implanted fragments were determined by visual inspection to be intact. It remained in the pipeline. The results of the nPET-PBT plug are shown in Figure 10 (hematoxylin and eosin). (Syn (H&E) staining) and Figure 11 (More detailed analysis of jelly-forming plug apparatus from rats) (For immunohistochemistry) Trichrome and immunostaining are shown. Specifically, upper 2 in Figure 10. One photo shows the duct 684 30 days after suture removal, and the bottom four photos show the 3 days after suture removal. The image shows plug 610 after 0 days. The photograph in Figure 11 shows CD-31 purplish-red, collagen I Trichrome (Masson's) and immunohistochemical staining were applied using Type II green and DAPI blue. The interface between tissue 634 and plug 610, which is visible afterwards, is highlighted in the right photograph. .

[0096] Histologically, the HYD-jelly composition shows superior tissue internal growth, which is characteristic of the porcine model. It appeared to be similar to the internal growth observed in these devices embedded (described later). The metronidazole-supported jelly composition allows for cell penetration to the external surface of the device, unlike unmodified jelly. —The configuration showed similar healing. The nPU club configuration was finer than the nPET-PBT jelly configuration. Cellular osmosis was minimal, but some cell osmosis appeared. (Control (Cook) apparatus) In some of the devices tested, there was limited cell healing within the device.

[0097] Example 6: Embedding the device into a pig model A electrospun nanofiber fistula plug 710 prepared according to the method described herein Next, the experiment was conducted using a pig fistula model. In the pig experiment, a 10-French silicone drain was used. By inserting the 786 as far as possible into the sphincter with a trocar for 30 days, three An independent pipeline 784 was created. This resulted in a slightly longer pipeline 784. 30 days later Remove drain 786 and connect to conduit 784, (i) without equipment (conduit only), (ii) unmodified. (iii) Sodium hydroxide (HYD) treatment of a PET-PBT jelly-based plug device. (iv) Ethylenediamine (EDA) Positively charged nPET-PBT jelly-based plug device, (v) Meth (vi)nPU club-shaped plug device, (vii) Biodegradable plug device 713 (control, Cook Medical) is further 3 It was implanted for 0 days. In all cases, the skin was passed between the exit site on the skin and the mucous membrane. A small incision was made. A plug 710 was inserted, and Mersilene® sutures were used. (Available from J&J Medical Devices) is used to fix the incision through the site. The mucosal side was sutured with 3-0PDS(registered trademark)II suture (J&J Medical De It was secured using (available from Vices). Figure 12A shows the plug during insertion. .

[0098] Figure 12B shows intracutaneous vascular pathways in a pig fistula model 30 days after plug implantation. This is a collection of photographs. The exit part 736 of the jelly-forming device, indicated by the dashed line (upper left photograph), is excellent. The images show healing and integration. The upper right and lower photos show the pig fistula 30 days after plug implantation. The entrance duct of the mucosal portion in the pore model is shown, and the entrance of the jelly-forming device 736 is indicated by a dashed line. The mouth area indicates that the head of device 710 is fully integrated into the mucosal tissue.

[0099] After 30 days, the device was removed. Histological evaluation of the nPET-PBT jelly structure over 30 days The apparatus has internal tissue growth within the slender, jelly-like members, and larger internal growth is in the apparatus It was shown that the cells were concentrated on the external surface. Furthermore, cells had also infiltrated the inner parts of the device. However, they were not at the same level. These results were compared to the rat dorsal subcutaneous implantation described in the previous example. The results were similar to those observed with the addition of trichrome staining, which was achieved by dark collagen staining. The presence of the piping was shown. As generally shown in the photograph in Figure 13, around the jelly structure. Alternatively, there was minimal collagen deposition nearby. Specifically, the upper left photo shows the device embedded. The upper right shows control channel 784, which was not filled and showed collagen deposition after 30 days. The photograph shows the implantation of control device 713 in which no tissue invasion occurred and the plug was lost. The photo below shows the formation of tissue that has penetrated into the conduit area between the elongated member 722 of the device and the conduit wall. This indicates length and represents deep cell penetration similar to that obtained in rat experiments.

[0100] The composition of one anionic and one cationic nPET-PBT jelly was found to be bubbling on day 16. Extracted from the model. Histological evaluation showed that both devices had internal tissue growth. This indicates that it occurs at a faster rate than the nPET-PBT control jelly composition on day 30. I could see it. The cells also appeared to have penetrated deeply into the elongated material. Trichrome staining showed that The fact that the tubing was intact and there was minimal collagen staining around the device indicates that the 30th The results were similar to those of the excised tissue (see Figures 14 and 15).

[0101] Although several exemplary embodiments of the present invention have been described here, the foregoing is merely illustrative. It will be obvious to those skilled in the art that this is a description and not an exhaustive one. Numerous changes Other embodiments are within the scope of the art and are conceived as being within the scope of the present invention. In particular, many of the embodiments presented herein are specific to method actions or system elements. This includes combinations, but those actions and their elements are not related to each other in order to achieve the same purpose. It should be understood that these methods can be combined.

[0102] Furthermore, as those skilled in the art will know, the parameters and configurations described herein are illustrative and practical. The parameters and / or configurations used in the present invention are specific to the application in which the system and technology of the present invention are used. It should be understood that this depends on the particular embodiment of the present invention. Equivalents can be recognized or confirmed without using anything beyond routine experiments. Therefore, the embodiments described herein are presented only as examples. Within the scope of the attached claims and equivalents, the present invention relates to the invention as described in addition to the above. It will be understood that this can be done by the method.

[0103] Furthermore, the terminology and grammar used herein are for illustrative purposes only and should not be considered restrictions. It should not be. As used herein, the term "multiple" means two or more items or This refers to the constituent elements. "comprising" or "including." "carrying," "having," "containing" The terms "involving)" and "involving" are defined herein or in particular. Regardless of the scope of the claim, it is a non-restrictive term, meaning "includes, but not limited to." It means "cannot be included but not limited to". Therefore, the use of such terms is inappropriate for the items listed after them and their It means to include equivalents and additional items. Transitional phrases: "consisting of" and "or The only thing that essentially becomes limited or semi-limited with respect to any claim is a transition It is a phrase. In the claims, to modify the claim elements, "first", "second", Using ordinal terms such as "the third" itself refers to one element of a claim element relative to another element. It does not mean priority, precedence, or order, or the temporal order in which the actions of a method are performed. in which one claim element has the same name (but using an ordinal word) as one claim element having a specific name It is merely used as a label to distinguish other elements. Table 2

Claims

1. A device for implantation within a fistula tract within a target, wherein the fistula tract is the primary opening in the wall of a body structure. and has a pipeline extending from the nuclear power plant port, and the device is The device includes a single body configured to fill at least a portion of the fistula pathway, the body being 、 An enlarged portion located at the first end of the main body, A tubular structure extending from the region adjacent to the enlarged portion and ending at the second end of the main body Including the enlarged portion, the cross-sectional dimensions of the tubular structure are the same as those of the longitudinal axis of the main body. The apparatus having or having a larger cross-sectional dimension.

2. At least a portion of the tubular structure tapers toward the second end of the main body, claim The apparatus described in item 1.

3. At least a portion of the tubular structure is divided into a plurality of elongated members, as described in claim 1. Device.

4. The apparatus according to claim 3, wherein the elongated member is offset with respect to the longitudinal axis. 。

5. The apparatus according to claim 3 or 4, wherein the main body includes 1 to 20 of the elongated members.

6. The apparatus according to any one of the prior claims, wherein the enlarged portion has a substantially planar outer shape. 。

7. The apparatus according to any one of the prior claims, wherein the enlarged portion has a substantially circular cross-section.

8. The second end is configured to be inserted into the primary opening, and the first end is configured to pass through the fistula pathway. The apparatus according to any one of the prior claims, configured to fill in or partially.

9. The first end is configured to fill the nuclear port, as described in any one of the prior claims. The device.

10. The fistula pathway is a perianal fistula, an enterocutaneous fistula, or a rectovaginal fistula, as per any of the prior claims. The apparatus described in item 1.

11. The main body comprises one or more nanofiber synthetic materials as described in any one of the prior claims. A mounted device.

12. The main body comprises one or more nanofiber polymers, according to any of the prior claims. The apparatus described in item 1.

13. Prior claim, at least a portion of the main body comprises one or more electrospun polymers. The apparatus described in any one of the items.

14. The polymer is a nanofiber polyester, a nanofiber polyurethane, or Claims comprising a combination of nanofiber polyester and nanofiber polyurethane. The apparatus described in 12 or 13.

15. The aforementioned nanofiber polyester is nanofiber polyethylene terephthalate (P ET), nanofiber polybutylene terephthalate (PBT), nanofiber poly Claim 14 includes limethylene terephthalate (PTT) or a combination thereof. A mounted device.

16. The apparatus according to claim 12 or 13, wherein the polymer is nPET-PBT.

17. Claim 12 or 13, the polymer is nanofiber polyurethane (nPU). The device described above.

18. The aforementioned nanofiber polyurethane is polycarbonate, polyether or these The apparatus according to claim 17, including combinations.

19. The nanofiber polymer has a net charge in its whole, internally, or on its surface, claim The apparatus described in any one of items 12 to 18.

20. The apparatus according to claim 19, wherein the nanofiber polymer is negatively charged.

21. The nanofiber polymer is negatively charged nPET-PBT, as described in claim 20. A mounted device.

22. The apparatus according to claim 19, wherein the nanofiber polymer is positively charged.

23. The nanofiber polymer is positively charged nPET-PBT, as described in claim 22. A mounted device.

24. The apparatus according to any one of the prior claims, wherein the apparatus is non-biodegradable.

25. The apparatus includes an electrospun material having a therapeutic agent incorporated within the nanofiber. The apparatus according to any one of the prior claims.

26. The apparatus according to claim 25, wherein the therapeutic agent is a small molecule.

27. The apparatus according to claim 25, wherein the therapeutic agent is an antibacterial agent.

28. The aforementioned antibacterial agent is one of the following: a bactericidal antibiotic, a bacteriostatic antibiotic, or a quinolone antibiotic. The apparatus according to claim 27, comprising at least one of the following:

29. The aforementioned bactericidal antibiotics are a group consisting of penicillin, aminoglycosides, and ofloxacin. The bacteriostatic antibiotics selected are erythromycin, tetracycline, and chloramfen. Selected from the group consisting of phenicol, the quinolone antibiotic is ciprofloxacin and The apparatus according to claim 28, selected from the group consisting of nitroimidazole.

30. The apparatus according to claim 25, wherein the therapeutic agent is an anti-inflammatory agent.

31. The aforementioned anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), immunoselective anti-inflammatory derivatives ( These are IMSAIDs, anti-leukotrienes, or steroids (e.g., dexamethasone). The apparatus according to claim 30.

32. The apparatus according to claim 25, wherein the therapeutic agent is an immunosuppressant.

33. The aforementioned immunosuppressants include azathioprine, tacrolimus, sirolimus, paclitaxel, and The apparatus according to claim 32, wherein the apparatus is verolimus or biolimus.

34. The apparatus according to claim 25, wherein the therapeutic agent is an analgesic.

35. The analgesic is an NSAID, acetaminophen, bupivacaine, meloxicam or The apparatus according to claim 34, wherein the device is an opioid.

36. The apparatus according to any one of the prior claims, further comprising cells.

37. The apparatus includes allogeneic stem cells, autologous stem cells, mesenchymal stem cells, or a combination thereof. The apparatus according to claim 36.

38. The apparatus according to claim 36, wherein the apparatus includes allogeneic adipose tissue-derived stromal stem cells.

39. The single body further includes a neck positioned between the enlarged portion and the tubular structure. Furthermore, the neck has a cross-sectional dimension that is reduced compared to the cross-sectional dimensions of the enlarged portion and the tubular structure. The apparatus according to any one of the prior claims, including the apparatus described in any one of the prior claims.

40. A device for implantation within a fistula tract within a target, wherein the fistula tract is the primary opening in the wall of a body structure. and has a pipeline extending from the nuclear power plant port, and the device is The electrospun nanofiber polymer is configured to fill at least a portion of the fistula pathway. - Includes a body formed at least partially from, the body is An enlarged portion located at the first end of the main body, It includes a tubular structure that extends from the enlarged portion and ends at the second end of the main body, The cross-sectional dimensions of the tubular structure are the same as or different from the cross-sectional dimensions of the main body with respect to the longitudinal axis of the main body. The device has a larger cross-sectional dimension.

41. The fistula pathway is a perianal fistula, an enterocutaneous fistula, or a rectovaginal fistula, as described in claim 40. Device.

42. The aforementioned nanofiber polymer is polyester, polyurethane, or polyester and poly The apparatus according to claim 40, including a combination of polyurethanes.

43. The aforementioned nanofiber polymer is polyethylene terephthalate (PET), polybutylene Polyterephthalate (PBT), polytrimethylene terephthalate (PTT), and these Polyester and / or polycarbonate, polyether selected from combinations The apparatus according to claim 42, comprising polyurethane selected from a combination thereof.

44. The apparatus according to claim 43, wherein the nanofiber polymer comprises nPET-PBT.

45. The nanofiber polymer is nanofiber polyurethane (nPU), claim The apparatus described in 43.

46. The nanofiber polymer has a net charge in its whole, internally, or on its surface, claim The apparatus described in any one of paragraphs 40 to 45.

47. The apparatus according to claim 46, wherein the nanofiber polymer is negatively charged.

48. The nanofiber polymer is negatively charged nPET-PBT, as described in claim 47. A mounted device.

49. The apparatus according to claim 46, wherein the nanofiber polymer is positively charged.

50. The nanofiber polymer is positively charged nPET-PBT, as described in claim 49. A mounted device.

51. The apparatus further includes a therapeutic agent incorporated within the nanofibers of the electrospun material. The apparatus according to any one of claims 40 to 50.

52. The apparatus according to claim 51, wherein the therapeutic agent is a small molecule.

53. The apparatus according to claim 51, wherein the therapeutic agent is an antibacterial agent.

54. The aforementioned antibacterial agent is one of the following: a bactericidal antibiotic, a bacteriostatic antibiotic, or a quinolone antibiotic. The apparatus according to claim 53, including at least one of the following:

55. The aforementioned bactericidal antibiotics are a group consisting of penicillin, aminoglycosides, and ofloxacin. The bacteriostatic antibiotics selected are erythromycin, tetracycline, and chloramfen. Selected from the group consisting of phenicol, the quinolone antibiotic is ciprofloxacin and The apparatus according to claim 54, selected from the group consisting of nitroimidazole.

56. The apparatus according to claim 51, wherein the therapeutic agent is an anti-inflammatory agent.

57. The aforementioned anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), immunoselective anti-inflammatory derivatives ( These are IMSAIDs, anti-leukotrienes, or steroids (e.g., dexamethasone). The apparatus according to claim 56.

58. The apparatus according to claim 51, wherein the therapeutic agent is an immunosuppressant.

59. The aforementioned immunosuppressants include azathioprine, tacrolimus, sirolimus, paclitaxel, and The apparatus according to claim 58, wherein the apparatus is berolimus or biolimus.

60. The apparatus according to claim 51, wherein the therapeutic agent is an analgesic.

61. The analgesic is an NSAID, acetaminophen, bupivacaine, meloxicam or The apparatus according to claim 60, wherein the opioid is used.

62. The apparatus according to any one of claims 40 to 61, further comprising cells.

63. The apparatus includes allogeneic stem cells, autologous stem cells, mesenchymal stem cells, or a combination thereof. The apparatus according to claim 62.

64. The apparatus according to claim 62, wherein the apparatus includes allogeneic adipose tissue-derived stromal stem cells.

65. The apparatus according to any one of claims 40 to 64, wherein the main body is a single structure.

66. The main body further includes a neck positioned between the enlarged portion and the tubular structure, The neck includes a cross-sectional dimension that is reduced compared to the cross-sectional dimensions of the enlarged portion and the tubular structure. The apparatus according to any one of claims 40 to 65.

67. At least a portion of the tubular structure tapers toward the second end of the main body, claim The apparatus described in any one of paragraphs 40 to 66.

68. Claims 40 to 67, wherein at least a portion of the tubular structure is divided into a plurality of elongated members. The device described above.

69. The slender member is offset with respect to the longitudinal axis, as described in claim 68. Place.

70. The apparatus according to claim 68, wherein the main body includes 1 to 20 of the elongated members.

71. The enlarged portion has a substantially planar outer shape, as described in any one of claims 40 to 70. The device.

72. The enlarged portion has a substantially circular cross-section, as described in any one of claims 40 to 71. Device.

73. The second end is configured to be inserted into the primary opening, and the first end is configured to pass through the fistula pathway. The apparatus according to any one of claims 40 to 72, configured to fill in or partially. 。

74. The first end is configured to fill the nuclear outlet, any one of claims 40 to 73. The device described above.

75. A tube within a body structure, such as a fistula, which has a primary opening in the wall of the body structure and a conduit extending from the primary opening. A method for manufacturing a device to be embedded in a road, wherein the method is Preparing a polymer solution, The solution is filled into the electrospinning unit, The polymer solution is injected into the injection needle port having a predetermined voltage applied to the injection needle. Perfusing at a certain speed, The generated nanofibers ejected from the aforementioned needle port are formed into a mandrel shape having longitudinal grooves. The material is collected by a rotary collector and used to produce a single tubular electrospinning body with longitudinal grooves. and, Post-treatment such as vacuum heating or solvent extraction is performed to remove residual solvent, To remove the electrospinning body from the mandrel, To form an enlarged portion relative to the rest of the main body, the end with the longitudinal groove is pulled downward. The vertical groove is operated by stretching, and the enlarged portion is the remaining part of the main body. Operate the longitudinal groove portion having a cross-sectional dimension larger than the cross-sectional dimension of the portion, The remaining part of the main body is flattened to form a substantially planar structure extending from the elongated portion. To do, The planar structure is divided along the longitudinal axis of the main body to form a plurality of elongated members. To do, By sealing a part of the tubular body adjacent to the enlarged portion, the enlarged portion and the elongated portion The method involves forming a neck region between the material and the enlarged portion and the main To form the neck region having a cross-sectional dimension smaller than the remaining cross-sectional dimension of the body, The method, including the method described above.

76. The step of preparing the aforementioned solution is: Weigh the polyester chips and / or polyurethane chips and place them in the vial. Putting it in, Add hexafluoroisoproposal (HFIP) to the tip inside the vial. and, The vial containing the prepared solution is sealed, This includes stirring the vial until all the pellets in the solution are dissolved, The method according to claim 75.

77. The weighing process described above involves polyethylene terephthalate (PET) chips and polybutylene The method according to claim 76, comprising weighing terephthalate (PBT) chips.

78. The step of removing the electrospinning body from the mandrel is as follows: Rinse the main body with 100% ethanol (EtOH), Filling non-pyrogenic serum tubes with 100% ethanol, Inserting the main body and the mandrel into the tube, The mandrel-containing tube is placed in a container filled with deionized water, Placing the container inside the ultrasonic treatment device, The container is subjected to ultrasonic treatment, To remove the mandrel from the tube, Washing with deionized water, The method according to claim 75, comprising drying the main body.

79. The longitudinal groove of the mandrel is positioned substantially in the center along the length of the mandrel. The method according to claim 75.

80. The step of removing the electrospinning body from the mandrel is performed in the central region of the longitudinal groove. The main body is divided substantially perpendicular to its longitudinal axis, and each division has a longitudinal groove end. The method according to claim 75, comprising manufacturing two bodies.

81. The polymer solution contains at least one therapeutic agent to be added to the solution before electrospinning. The method according to any one of claims 75 to 80.

82. The method according to claim 81, wherein the therapeutic agent is a small molecule.

83. The method according to claim 81, wherein the therapeutic agent is an antibacterial agent.

84. The aforementioned antibacterial agent is one of the following: a bactericidal antibiotic, a bacteriostatic antibiotic, or a quinolone antibiotic. The method according to claim 83, comprising at least one of the following:

85. The aforementioned bactericidal antibiotics are a group consisting of penicillin, aminoglycosides, and ofloxacin. The bacteriostatic antibiotics selected are erythromycin, tetracycline, and chloramfen. Selected from the group consisting of phenicol, the quinolone antibiotic is ciprofloxacin and The method according to claim 84, selected from the group consisting of nitroimidazoles.

86. The method according to claim 81, wherein the therapeutic agent is an anti-inflammatory agent.

87. The aforementioned anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (NSAIDs), immunoselective anti-inflammatory derivatives ( These are IMSAIDs, anti-leukotrienes, or steroids (e.g., dexamethasone). The method according to claim 86.

88. The method according to claim 81, wherein the therapeutic agent is an immunosuppressant.

89. The aforementioned immunosuppressants include azathioprine, tacrolimus, sirolimus, paclitaxel, and The method according to claim 88, wherein the material is berolimus or biolimus.

90. The method according to claim 81, wherein the therapeutic agent is an analgesic.

91. The analgesic is an NSAID, acetaminophen, bupivacaine, meloxicam or The method according to claim 90, wherein the method is an opioid.

92. Perform surface modification of the main body, such as anionic surface modification or cationic surface modification. The method according to any one of claims 75 to 91, further comprising:

93. The process of forming the neck region involves ultrasonically welding a portion of the tubular body adjacent to the enlarged portion. The method according to any one of claims 75 to 92, including wearing.

94. A kit comprising a device for implantation in a fistula according to any one of claims 1 to 74.

95. The kit according to claim 94, further comprising non-biodegradable sutures.

96. The kit according to claim 95, wherein the non-degradable suture includes an electrospun material.

97. The following is a surgical instrument according to any one of claims 94 to 96, further comprising at least one surgical instrument. .

98. Patients having a fistula that has a primary opening on the wall of an internal body structure and a fistula pathway extending from the primary opening. A method for treating a person, wherein the method is the apparatus described in any one of claims 1 to 74. The method comprising inserting the device into the fistula through the primary orifice.

99. The method according to claim 98, wherein the apparatus fills at least a portion of the fistula.

100. The method according to claim 98 or 99, wherein the patient has a perianal fistula.

101. The method according to claim 98 or 99, wherein the patient has a cryptogland fistula.

102. The patient has Crohn's disease or ulcerative colitis, any one of claims 98 to 101. The method described in section [section number].

103. The patient has colitis, chronic diarrhea, post-pregnancy tract formation, or rectal cancer, claims 98-1 The method described in any one of item 01.

104. The method according to claim 98 or 99, wherein the patient has a rectovaginal fistula.

105. The method according to claim 98 or 99, wherein the patient has an intestinal cutaneous fistula.

106. The method according to claim 98 or 99, wherein the patient has a gastrointestinal fistula.

107. The device does not induce fibrosis at the insertion site, according to any one of claims 98 to 106. Method of description.

108. The device does not induce collagen deposition at the insertion site, any one of claims 98 to 107. The method described in item 1.

109. The apparatus allows internal growth of tissue within the apparatus, any one of claims 98 to 108. The method described in item 1.

110. The device alters the cell dynamics at the insertion site, any one of claims 98 to 109. Methods used.

111. The further includes maintaining the device in the fistula pathway for a sufficient amount of time for the fistula to heal. The method according to any one of claims 98 to 110.

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