Gels and related methods for treating fistulas

Abstract

This disclosure includes kits, compositions, and methods useful in medical procedures such as treating a fistula or other target site. In some examples, the kit comprises a dry particle mixture, a first pharmaceutically acceptable buffer solution having a pH in the range of about 3 to about 5, and a second pharmaceutically acceptable buffer solution having a pH in the range of about 9 to about 11. The dry particle mixture may comprise a plurality of polyethylene glycol particles and a plurality of collagen particles.

Description

Technical Field

[0001] The present disclosure generally relates to gel materials useful in medical procedures, including endoscopic procedures.

Background Art

[0002] Gel materials are useful in many medical situations for separating tissues and / or covering wounded tissues. A fistula is an abnormal connection or passageway that connects two organs or blood vessels that do not normally connect. Fistulas can occur, among other places, between the intestine and the skin, between the vagina and the rectum, and within the gastrointestinal tract (e.g., the stomach, intestine, colon, etc.). The ability to adhere to tissues and permanently close fistulas is difficult. Furthermore, it can be difficult to formulate a gel to promote tissue repair at the target site while maintaining the biodegradability of the gel.

Summary of the Invention

[0003] This disclosure includes kits, compositions, and methods useful in medical procedures. For example, this disclosure includes a kit comprising a dry particle mixture, a first pharmaceutically acceptable buffer solution having a pH in the range of about 3 to about 5, and a second pharmaceutically acceptable buffer solution having a pH in the range of about 9 to about 11. The dry particle mixture may comprise a plurality of polyethylene glycol particles and a plurality of collagen particles. The first pharmaceutically acceptable buffer solution may comprise at least one crosslinking agent, optionally comprising trilysine acetate, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, or N-hydroxysuccinimide. The weight ratio of the plurality of polyethylene glycol particles to the plurality of collagen particles in the dry particle mixture may be in the range of about 8:1 to about 6:1. The plurality of collagen particles may have an average particle size in the range of about 300 μm to about 500 μm. The plurality of polyethylene glycol particles may comprise chemically modified polyethylene glycol, such as a polyethylene glycol polymer containing one or more functional groups selected from carboxylic acid groups, ester groups, amine groups, or combinations thereof. Optionally, one or more functional groups may include succinimide groups. The first pharmaceutically acceptable buffer solution and / or the second pharmaceutically acceptable buffer solution may contain radiopaque materials and / or antimicrobial agents. In some examples, the kit may further include instructions for combining the dry particle mixture with the first and second pharmaceutically acceptable buffer solutions to form a gel for application to the fistula. Additionally or alternatively, the kit may further include a double-barrel syringe and instructions for combining the dry particle mixture with the first pharmaceutically acceptable buffer solution to form a slurry, introducing the slurry into the first barrel of the syringe, and introducing the second pharmaceutically acceptable buffer solution into the second barrel of the syringe. The use of the kit for treating the fistula in question is also disclosed herein, and the kit may be described above or elsewhere herein.

[0004] This disclosure also includes a method for preparing the kits described above or elsewhere in this specification. The method may include preparing a collagen scaffold, optionally comprising: preparing a collagen scaffold having an average pore size in the range of about 100 μm to about 200 μm; grinding the collagen scaffold to obtain a plurality of collagen particles; combining the plurality of collagen particles with a plurality of polyethylene glycol particles to obtain a dry particle mixture; and packaging the dry particle mixture with a first pharmaceutically acceptable buffer solution and a second pharmaceutically acceptable buffer solution.

[0005] This disclosure also includes methods for treating a subject. In some examples, the method includes combining a dry particle mixture with a first pharmaceutically acceptable buffer solution having a pH in the range of about 3 to about 5 to form a slurry, and combining the slurry with a second pharmaceutically acceptable buffer solution having a pH in the range of about 9 to about 11 at a target site of the subject to form a gel at the target site. The dry particle mixture may include a plurality of polyethylene glycol particles and a plurality of collagen particles. In some examples, the method includes administering a slurry containing a plurality of polyethylene glycol particles, a plurality of collagen particles, and a first pharmaceutically acceptable buffer solution having a pH in the range of about 3 to about 5 to a target site of the subject, and administering a second pharmaceutically acceptable buffer solution having a pH in the range of about 9 to about 11 to the target site and combining it with the slurry. In some examples, the slurry and the second pharmaceutically acceptable buffer solution may form a gel at the target site, for example, within 30 seconds after being combined at the target site. In some cases, the slurry and the second pharmaceutically acceptable buffer solution may be administered simultaneously to the target site. The slurry and the second pharmaceutically acceptable buffer solution may be administered using a double-barrel syringe, for example, with the first barrel of the syringe containing the slurry and the second barrel of the syringe containing the second pharmaceutically acceptable buffer solution.

[0006] The accompanying drawings, incorporated in this application and constituting part of this specification, illustrate various exemplary embodiments and, together with the description, serve to illustrate the spirit of the disclosed embodiments. [Brief explanation of the drawing]

[0007] [Figure 1] A schematic diagram of a reaction mechanism for synthesizing exemplary chemically modified PEGs according to several aspects of this disclosure is shown. [Figure 2] A schematic diagram of a reaction mechanism for synthesizing another exemplary chemically modified PEG according to several aspects of this disclosure is shown. [Figure 3A] The following are exemplary components of a kit according to several aspects of this disclosure. [Figure 3B] The following are exemplary components of a kit according to several aspects of this disclosure. [Modes for carrying out the invention]

[0008] Specific aspects of this disclosure are described in more detail below. In the event of any conflict between terms and / or definitions incorporated by reference and those provided herein, the terms and definitions provided herein shall prevail. Where used herein, the terms “comprises,” “comprising,” or any other variation thereof are intended to cover non-exclusive inclusion, such that a process, method, composition, article, or apparatus containing a list of elements does not consist solely of those elements, but may also include other elements not expressly enumerated or that are inherent to such process, method, composition, article, or apparatus. The term “exemplary” is used in the sense of “example” rather than “ideal.”

[0009] Where used herein, the singular forms “a,” “an,” and “the” include plural references unless the context should indicate otherwise. The terms “approximately” and “about” refer to something that is approximately the same as the number or value being referenced. Where used herein, the terms “approximately” and “about” should be understood to encompass ±5% of the specified quantity or value. All ranges are understood to include the endpoints; for example, particle sizes in the range of 300 μm to 500 μm include 300 μm, 500 μm, and all values ​​in between.

[0010] This disclosure includes compositions, kits, and methods useful in medical procedures such as treating a target fistula (e.g., a gastrointestinal fistula) or other target site. The compositions, kits, and methods herein may be useful in endoscopic fistula closure and endoscopic fistula ablation procedures.

[0011] In some examples, the compositions and kits herein may be combined and / or administered at a target site (e.g., a fistula) to form a gel at the target site. The gel can adhere to the tissue at the target site (e.g., mucosa and / or submucosa) and can facilitate and / or promote the regeneration of damaged tissue, while simultaneously inhibiting or otherwise preventing the entry of unwanted substances into the target site.

[0012] composition The compositions described herein may be useful in various medical procedures, such as endoscopic procedures, including fistula closure and / or removal of fistula openings.

[0013] The compositions herein (e.g., gels such as hydrogels) may comprise polyethylene glycol (PEG) polymer and collagen. For example, a gel may be prepared from a plurality of PEG particles, a plurality of collagen particles, and one or more pharmaceutically acceptable buffer solutions, e.g., a first pharmaceutically acceptable buffer solution and a second pharmaceutically acceptable buffer solution. The buffer solutions may have different pH values. For example, the PEG particles and collagen particles may first be combined with a buffer having an acidic pH. When combined with a buffer having an basic pH that acts as an accelerator, the PEG particles form a collagen-containing gel, which forms relatively quickly. When the gel is formed in situ at the target site, the gel can maintain the integrity of the area, while the collagen promotes accelerated tissue regrowth and / or tissue angiogenesis at the target site. The characteristics of the PEG polymer and collagen may be selected based on the target site and the type of tissue to be treated.

[0014] For example, PEG polymers useful in this disclosure may have an average molecular weight in the range of about 4,000 Datons (Da) to about 16,500 Da, for example, about 5,000 Da to about 12,000 Da, about 8,500 Da to about 16,500 Da, about 9,000 Da to about 16,000 Da, or about 10,000 Da to about 15,000 Da. The PEG molecular weight may affect the crosslinking density and the viscosity and / or strength of the gel.

[0015] PEG polymers may contain various functional groups that can participate in crosslinking. For example, PEG particles used to prepare gels may contain chemically modified PEG. Exemplary functional groups include, but are not limited to, carboxylic acid groups, ester groups, and amine groups (including, for example, succinimide groups). In some examples, PEG polymers contain one or more functional groups selected from carboxylic acid groups, ester groups, amine groups, or combinations thereof. In at least one example, PEG polymers contain succinimide groups (e.g., N-hydroxysuccinimide). For example, PEG polymers may contain PEG-succinimidyl glutarate (PEG-SG). Optionally, one or more functional groups of PEG particles may be radiopaque. For example, PEG polymers may contain radiopaque functional groups containing iodine (e.g., 3,4,5-triiodobenzoic acid).

[0016] PEG polymers may have branched structures, such as multi-arm structures. For example, a PEG polymer may have 3 to 10 arms, e.g., 5 to 8 arms, or 6 to 9 arms. A multi-arm PEG polymer comprises a central PEG chain and multiple arms attached to the central chain. Each arm may have functional groups that are the same as or different from the functional groups of other arms. In at least one example, PEG particles comprise a multi-arm PEG having at least 3 arms, e.g., 3 to 10 arms, each arm containing a succinimide group. Optionally, one or more arms may contain radiopaque moieties (e.g., radiopaque functional groups containing iodine).

[0017] Figures 1 and 2 show reaction schemes for exemplary PEG polymers useful for the compositions, kits, and methods described herein. For example, Figure 1 shows the synthesis of a PEG polymer containing succinimidyl glutarate groups available for crosslinking to form a gel. Figure 2 shows the synthesis of a branched PEG polymer having succinimidyl glutarate groups available for crosslinking and triiodobenzoate groups for radiopaqueness.

[0018] Collagen particles useful in this disclosure may include any suitable type of collagen, such as type I collagen, type II collagen, type III collagen, type V collagen, and combinations thereof. In some examples, the collagen may be crosslinked. Crosslinking can provide the composition with advantages such as improved bulk mechanical properties (e.g., hardness). Exemplary crosslinking agents include, but are not limited to, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, and combinations thereof.

[0019] As discussed below, collagen particles may be prepared by grinding a scaffold to a desired particle size. For example, collagen particles may have an average particle size in the range of about 200 μm to about 600 μm, e.g., about 250 μm to about 550 μm, or about 300 μm to about 500 μm. The particle size can be measured by a suitable instrument such as a Malvern Morphologi4 instrument using static automated imaging. As used herein, for the purposes of this disclosure, the term “average particle size” refers to the equivalent circle (CE) diameter, defined as the diameter of a circle having the same area as the particle. Collagen particles may be porous, and their porosity is retained in the gel composition. The size of the collagen pores can facilitate tissue repair. For example, the pore size may be on the order of the size of biological components involved in wound healing and / or tissue repair, such as fibroblasts and endothelial cells. The porosity of collagen particles can be controlled during particle production via a porous collagen scaffold, for example, as discussed below.

[0020] Multiple PEG particles and multiple collagen particles may be combined in a mixture, for example, a buffer solution in the form of a dry particle mixture or slurry. The weight ratio of multiple PEG particles to multiple collagen particles in the dry particle mixture or slurry may be in the range of about 10:1 to about 4:1, for example, about 8:1 to about 6:1, or about 7:1 to about 5:1. In at least one example, the dry particle mixture or slurry contains about 2.0 g to about 2.5 g of PEG polymer and about 0.1 g to about 0.5 g of collagen. In at least 0.3 examples, the dry particle mixture or slurry contains about 2.2 g to about 2.4 g of PEG polymer and about 0.3 g to about 0.4 g of collagen.

[0021] Examples of pharmaceutically acceptable buffer solutions useful in this disclosure include phosphate buffer and borate buffer. The kits of this specification may include at least one, two, pharmaceutically acceptable buffer solutions, for example, with different pH values. According to some aspects of this disclosure, the first pharmaceutically acceptable buffer solution may have an acidic pH, and the second buffer solution may have an basic pH. For example, the first pharmaceutically acceptable buffer solution may have a pH in the range of about 3 to about 5, for example, a pH of about 4. The pH of the first pharmaceutically acceptable buffer solution can be adjusted with a suitable acid (e.g., hydrochloric acid).

[0022] The second pharmaceutically acceptable buffer solution may have a basic pH, for example, a pH in the range of about 9 to about 11, for example, a pH of about 10. The second pharmaceutically acceptable buffer solution can be pH-adjusted with a suitable base (e.g., sodium hydroxide).

[0023] The pharmaceutically acceptable buffer may further contain one or more materials and / or agents. As described above, the plurality of PEG particles and the plurality of collagen particles may be combined with a buffer solution to form a slurry. The buffer solution of the slurry may have an acidic pH. Thus, for example, if the composition or kit contains two pharmaceutically acceptable buffer solutions, the first pharmaceutically acceptable buffer solution having an acidic pH may contain PEG particles and collagen particles. The resulting slurry may have a pH in the range of about 3 to about 5, for example, a pH of about 4.

[0024] Exemplary agents that may be included in the pharmaceutically acceptable buffer solution and / or the dry particle mixture (and gel compositions prepared from such buffer solutions) and the particle mixture include, but are not limited to, crosslinking agents, antibacterial agents, anti-inflammatory agents, and radiopaque materials.

[0025] Exemplary crosslinking agents useful in the present disclosure include, but are not limited to, trilisine acetate, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, and combinations thereof. In some examples, the first pharmaceutically acceptable buffer solution may contain at least one crosslinking agent. In some examples, the first pharmaceutically acceptable buffer solution may contain at least one crosslinking agent in combination with the plurality of PEG particles and the plurality of collagen particles, for example, forming a slurry that further contains at least one crosslinking agent.

[0026] Antimicrobial agents may be useful in conferring antimicrobial properties (e.g., antibiotic properties) and / or mechanical properties, among other properties. In some cases, antimicrobial agents can be slowly released from the composition into the surrounding tissue and other anatomical structures during the healing process to minimize the risk of infection recurrence and / or combat residual infection. Exemplary antimicrobial agents useful in this disclosure include, but are not limited to, ciprofloxacin, augmentin, metal ions, metal oxides, and combinations thereof. Metal ions and metal oxides may confer other properties to the gel composition that may be useful for tissue repair (e.g., magnetism, wound healing, and / or electrical conductivity). Metal ions or metal oxides may include, for example, silver, gold, zinc, titanium, magnesium, or copper. In some examples, a dry particle mixture contains at least one antimicrobial agent. In some examples, a slurry containing a particle mixture and a buffer solution (e.g., a first pharmaceutically acceptable buffer solution) contains at least one antimicrobial agent.

[0027] As described above, the PEG particles may contain one or more radiopaque functional groups, for example, iodine-containing compounds such as 3,4,5-triiodobenzoic acid. In addition, or alternatively, the first or second pharmaceutically acceptable buffer solution may contain radiopaque material, for example, a compound having a radiopaque portion. The radiopaqueness of the gel may help medical professionals to visualize and / or confirm the location of the gel at a target site, such as a fistula, during imaging of the object.

[0028] The compositions herein, for example, gels and hydrogels, may be formed by combining a plurality of PEG particles, a plurality of collagen particles, and a pharmaceutically acceptable buffer solution. As described above, the PEG polymer of the PEG particles may contain one or more functional groups available for crosslinking. Although not bound by any particular theory, while in an acidic buffer solution, the PEG polymer may initially remain in slurry form, for example, together with the collagen particles, at least in part due to the pH of the buffer solution. For example, a relatively low pH may inhibit or delay the crosslinking of the PEG polymer. When combined with a basic buffer solution, the change in pH may initiate and / or accelerate the crosslinking of the PEG polymer to form a gel (for example, having collagen particles embedded therein). The gel may be formed relatively quickly, for example, within 1 minute, 45 seconds, 30 seconds, 20 seconds, or 15 seconds after combining a first pharmaceutically acceptable buffer solution (containing PEG particles and collagen particles) at an acidic pH with a second pharmaceutically acceptable buffer solution at a basic pH.

[0029] The first and second pharmaceutically acceptable buffer solutions may be formulated for injection and mixing at a target site such as a fistula. For example, a slurry containing the first pharmaceutically acceptable buffer solution, PEG particles, and collagen particles may be combined with the second pharmaceutically acceptable buffer solution at the target site to form a gel, which may form within 20-30 seconds after combination and / or administration, filling the target site. In some examples, the target site may be a fistula in the gastrointestinal tract of the subject. In some examples, the target site may be a lesion or polyp in the gastrointestinal tract of the subject. For example, the fistula, lesion, or polyp may be located in the esophagus, stomach, small intestine, large intestine, or colon (including, for example, the anus). Once formed, the gel may have a viscosity that allows it to solidify and adhere to the tissue of the target site (e.g., mucosa or submucosa). It will be understood that the gel may be biocompatible, biodegradable, and / or bioabsorbable, for example, to prevent the induction of an immune response from the subject.

[0030] The gel may be formulated to support tissue repair while degrading at a rate that does not require removal of the gel after the formation of new tissue and / or tissue angiogenesis. For example, the gel may be formulated to degrade concurrently with tissue repair at the same or similar rate as the healing timescale of the body in question (e.g., the tissue repair period). In these cases, the gel can facilitate the repair of damaged tissue with reduced fibrous scarring and / or accelerate tissue regeneration and promote angiogenesis of the regenerating tissue. Furthermore, for example, the gel may help to expel infection from the target site, e.g., treat and / or eradicate a fistula, in order to avoid persistent or recurrent disease, while maintaining the functionality of the surrounding biostructure (e.g., maintaining the function of the anal sphincter in the case of a colonic fistula). If the gel contains an antimicrobial agent, the antimicrobial agent can be released into the tissue surrounding the target site during the degradation of the gel to further suppress or prevent infection.

[0031] In addition, in some cases, by forming an impermeable barrier, the gel can at least partially or completely inhibit the entry of unwanted substances into target sites such as fistulas. This barrier can facilitate the closure of fistulas. At the same time, the gel can enable the migration of biological components (e.g., fibroblasts and endothelial cells) involved in wound healing and / or tissue repair. Therefore, collagen present in the gel, for example, can further promote healing and tissue repair assisted by such biological components. The gel can provide a regenerative scaffold for host fibroblasts to migrate to target sites, thereby promoting tissue healing and / or repairing damaged tissue with reduced fibrous scarring.

[0032] kit In some aspects of this disclosure, the compositions herein may be prepared from the components of a kit. For example, a medical professional may use the kit to prepare a gel in situ at a target site of interest.

[0033] The kit may comprise, for example, a particle mixture (e.g., a dry particulate mixture) containing, essentially consisting of, or comprising multiple PEG particles and multiple collagen particles, a first pharmaceutically acceptable buffer solution, and a second pharmaceutically acceptable buffer solution. Any of the dry particle mixture, the first pharmaceutically acceptable buffer solution, and / or the second pharmaceutically acceptable buffer solution may further comprise at least one of a crosslinking agent, an antimicrobial agent, or a radiopaque material. Optionally, the kit may further comprise instructions and / or a delivery device (e.g., a double-barrel syringe). Each of the dry particle mixture, the first pharmaceutically acceptable buffer solution, and the second pharmaceutically acceptable buffer solution may be provided in separate containers. In some examples, the kit may comprise a container containing the particle mixture of PEG particles and collagen particles, as well as the first pharmaceutically acceptable buffer solution, for example, as a slurry. In such cases, the slurry and the second pharmaceutically acceptable buffer solution may be provided in separate containers.

[0034] As described above, the weight ratio of multiple PEG particles to multiple collagen particles in the dry particle mixture or slurry may be in the range of about 10:1 to about 4:1, for example, about 8:1 to about 6:1. Therefore, for example, the dry particle mixture or slurry may contain about 1.75 g to about 3.25 g of PEG particles (for example, about 2 g to about 3 g, or about 2.25 g to about 2.75 g) and about 0.05 g to about 0.9 g of collagen particles (for example, about 0.08 g to about 0.7 g, or about 0.2 g to about 0.5 g).

[0035] In some embodiments, the kits herein may further include instructions for preparing the composition and / or administering the composition to a target site. In some examples, the instructions may include combining the dry particle mixture with a first pharmaceutically acceptable buffer solution and a second pharmaceutically acceptable buffer solution to form a gel at the target site, for example, for application to a fistula. In examples where the kit includes a delivery device such as a double-barrel syringe, the instructions may include instructions for combining the dry particle mixture with the first pharmaceutically acceptable buffer solution to form a slurry, introducing the slurry into the first barrel of the syringe and introducing the second pharmaceutically acceptable buffer solution into the second barrel of the syringe.

[0036] Exemplary components of the kit, including a delivery device 100 such as a double-barrel syringe, are shown in Figures 3A and 3B. The delivery device 100 may be configured for use with an endoscope. For example, the delivery device may include a mixing head that can administer the contents of each barrel at the same or substantially the same flow rate through the working channel of the endoscope, for example, through the respective tubes, for delivery to a target site.

[0037] Figure 3A shows an example of a delivery device 100 having three containers 120, 122, and 124 (e.g., three vials), where container 120 contains a dry particle mixture of PEG particles and collagen particles, container 122 contains a first pharmaceutically acceptable buffer solution with an acidic pH, and container 124 contains a second pharmaceutically acceptable buffer solution with an basic pH. Figure 3B shows an example of a delivery device 100 having two containers 160 and 162 (e.g., two vials), where container 160 contains a slurry containing PEG particles, collagen particles, and a first pharmaceutically acceptable buffer solution with an acidic pH, and container 162 contains a second pharmaceutically acceptable buffer solution with a basic pH. Other examples of kits according to this disclosure do not include a delivery device. Any of the kits according to this specification may include instructions for preparing a composition and / or administering the composition to a target site of interest.

[0038] The kits of this specification may be prepared by combining multiple collagen particles with multiple PEG particles to obtain a dry particle mixture, and by packaging the dry particle mixture with a first pharmaceutically acceptable buffer solution and a second pharmaceutically acceptable buffer solution. In some examples, the multiple collagen particles may be prepared from a collagen scaffold by grinding the collagen scaffold into particles of a desired size, for example, as discussed below.

[0039] method According to several aspects of this disclosure, a plurality of collagen particles may be prepared from a collagen scaffold to provide, for example, porous collagen particles for facilitating tissue repair. The collagen scaffold may be ground into particles that retain porosity. For example, collagen may be hydrated in a weakly acidic solution (e.g., acetic acid) to produce a slurry, which is then dried (e.g., freeze-dried) to form a porous scaffold. Optionally, the collagen slurry may contain a crosslinking agent that can ultimately provide a more robust gel. Conditions such as freeze-drying conditions during the production and processing of the collagen scaffold can be controlled to provide the desired porosity. The collagen scaffold may have a spongy structure and / or spongy body due to the plurality of pores formed therein. In some examples, the collagen scaffold may have an average pore diameter in the range of about 50 μm to about 250 μm, for example, about 100 μm to about 200 μm. The average pore diameter can be measured by appropriate techniques, such as by optically measuring the pore diameter by a scanning electron microscope (SEM) and / or by using analytical software in combination with SEM. The collagen scaffold may be pulverized into multiple collagen particles having an average particle size in the range of approximately 200 μm to 600 μm, such as approximately 250 μm to 550 μm, or approximately 300 μm to 500 μm.

[0040] In some aspects of this disclosure, the compositions of this specification may be formed by combining a plurality of collagen particles with a plurality of PEG particles to form a dry particle mixture (which may be packaged in a container such as a vial). A first pharmaceutically acceptable buffer solution having pH 4 and a second pharmaceutically acceptable buffer solution having pH 10 may be stored separately in their respective containers. Either the dry particle mixture, the first pharmaceutically acceptable buffer solution, and / or the second pharmaceutically acceptable buffer solution may further contain at least one of a crosslinking agent, an antimicrobial agent, or a radiopaque material. The composition may be formed at a target site, such as a fistula, by combining the dry particle mixture with the buffer solution at the target site as described above. The target site may be examined in detail and / or washed in preparation for administration of the composition. The target may be rotated to allow gravity to assist in the placement of the composition within the area of ​​the target site. In some cases, the dry particle mixture may be combined with the first pharmaceutically acceptable buffer solution to form, for example, a precursor slurry. The precursor slurry and a second pharmaceutically acceptable buffer solution (e.g., acting as an accelerator buffer solution) are administered at the same or substantially the same flow rate to the target site. The precursor slurry and accelerator buffer solution may be administered until the target site is substantially or completely filled with the composition. Once the precursor solution and accelerator buffer solution are combined at the target site, the composition may form a gel, such as a hydrogel, within about 30 seconds, about 20 seconds, or about 15 seconds, and solidify and adhere to the tissue of the target site (e.g., mucosa or submucosa). Once the gel has solidified and adhered, it can inhibit or prevent the entry of undesirable substances while allowing the passage of biological components to aid in tissue repair, as described above. If the target site is an anal fistula, for example, the gel can inhibit or prevent the entry of fecal matter into the anal fistula.

[0041] The compositions herein may help limit recovery time. For example, in some cases where the target site is a fistula, closure of the fistula may occur within about 2 to 6 months, e.g., about 2 to 4 months, about 2.5 to 3.5 months, or about 3 months. The body in question may absorb the gel over time, e.g., within about 5 to 7 months, e.g., about 6 months. In some cases (e.g., in cases where the composition does not contain an antimicrobial agent), antibiotics or other antimicrobial agents may be administered to suppress or prevent infection at the target site.

[0042] Other aspects of this disclosure will become apparent to those skilled in the art from the discussion herein and the practice of the examples disclosed herein. This specification and the examples are for illustrative purposes only, and the true scope and spirit of this disclosure are intended to be shown by the following claims.

Claims

1. A dry particle mixture containing multiple polyethylene glycol particles and multiple collagen particles, A first pharmaceutically acceptable buffer solution having a pH in the range of approximately 3 to approximately 5, A kit for treating fistulas, comprising a second pharmaceutically acceptable buffer solution having a pH in the range of approximately 9 to 11.

2. The kit according to claim 1, wherein the first pharmaceutically acceptable buffer solution comprises at least one crosslinking agent, optionally the crosslinking agent comprising trilysine acetate, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, or N-hydroxysuccinimide.

3. The kit according to claim 1 or 2, further comprising instructions for combining the dry particle mixture with the first and second pharmaceutically acceptable buffer solutions to form a gel for application to a fistula.

4. The kit according to any one of claims 1 to 3, wherein the weight ratio of the plurality of polyethylene glycol particles to the plurality of collagen particles in the dry particle mixture is in the range of about 8:1 to about 6:

1.

5. The kit according to any one of claims 1 to 4, wherein the plurality of collagen particles have an average particle size in the range of about 300 μm to about 500 μm.

6. The kit according to any one of claims 1 to 5, wherein the plurality of polyethylene glycol particles comprises a chemically modified polyethylene glycol such as a polyethylene glycol polymer containing one or more functional groups selected from a carboxylic acid group, an ester group, an amine group, or a combination thereof, and optionally, the one or more functional groups contain a succinimide group.

7. The kit according to any one of claims 1 to 6, wherein the first pharmaceutically acceptable buffer solution or the second pharmaceutically acceptable buffer solution comprises a radiopaque material.

8. The kit according to any one of claims 1 to 7, wherein the first pharmaceutically acceptable buffer solution or the second pharmaceutically acceptable buffer solution contains an antimicrobial agent.

9. Double-barrel syringe and The kit according to any one of claims 1 to 8, further comprising instructions for combining the dry particle mixture with the first pharmaceutically acceptable buffer solution to form a slurry, introducing the slurry into the first barrel of the syringe, and introducing the second pharmaceutically acceptable buffer solution into the second barrel of the syringe.

10. Use of the kit according to any one of claims 1 to 9 for treating the target fistula.

11. The use according to claim 10, wherein the fistula is a fistula of the digestive tract of the subject.

12. The use according to claim 10 or 11, wherein the dry particle mixture is combined with the first pharmaceutically acceptable buffer solution to form a slurry, and the slurry is combined with the second pharmaceutically acceptable buffer solution to form a gel.

13. The use according to claim 12, wherein the slurry is combined with the second pharmaceutically acceptable buffer solution in the fistula to form a gel.

14. The use according to claim 12 or 13, wherein the gel is formed within 30 seconds, for example, 20 seconds, after the slurry is combined with the second pharmaceutically acceptable buffer.

15. The present invention relates to the preparation of a collagen scaffold, wherein the collagen scaffold has an average pore size in the range of approximately 100 μm to approximately 200 μm. The collagen scaffold is crushed to obtain the plurality of collagen particles, The plurality of collagen particles are combined with the plurality of polyethylene glycol particles to obtain the dry particle mixture, A method for preparing the kit according to any one of claims 1 to 9, comprising packaging the dry particle mixture together with the first pharmaceutically acceptable buffer solution and the second pharmaceutically acceptable buffer solution.

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