Compositions and related methods

Abstract

Compositions useful for medical procedures, for example, for separating tissue layers (e.g., submucosal tissue layers) for removal, are described. In some examples, the composition may comprise a pharmaceutically acceptable carrier fluid and one or more biocompatible materials at least partially or completely dissolved or suspended in the pharmaceutically acceptable carrier fluid. The one or more biocompatible materials may be selected from polymers, phospholipids, nanoclays, or combinations thereof. Advantageously, the composition may be formulated as an injectable solution, emulsion, gel, or suspension into tissue.

Description

Technical Field

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

Background Art

[0002] Colon cancer is the third most common cancer occurring in the United States. Cells within the colon mucosa have a risk of cancerization, which increases as humans age. Routine colonoscopies can identify precancerous or cancerous lesions. These lesions and other suspicious tissues can be excised endoscopically. Due to the risk of perforation of the colon wall, steps are needed to reduce the risk of wall perforation during lesion removal. Conventional methods have injected saline into the connective tissue layer (submucosal layer) of the colon to "lift" the lesion from the remaining portion of the tissue wall for removal.

Summary of the Invention

Problems to be Solved by the Invention

[0003] However, saline is rapidly absorbed by the body. Since this absorption time is shorter than that of many procedures, saline has only limited uses.

Means for Solving the Problems

[0004] The present disclosure includes compositions useful in medical procedures, such as for submucosal lifting. For example, the composition can include a pharmaceutically acceptable carrier fluid and one or more biocompatible materials at least partially or completely dissolved or suspended in the pharmaceutically acceptable carrier fluid. The pharmaceutically acceptable carrier fluid can include, for example, a buffer solution or a saline aqueous solution. The composition can be formulated as an injectable solution, emulsion, gel, or suspension in tissue.

[0005] One or more biocompatible materials may be selected from polymers, phospholipids, nanoclays, or combinations thereof. In some examples, one or more biocompatible materials may include polyethylene glycol (PEG) or its derivatives, polyhydroxyethyl methacrylate, poloxamer, 2-dimethylaminoethyl methacrylate, poly-L-lactic acid, polycaprolactone, polyoxazoline, poly(lactic acid-co-glycolic acid), poly(N-isopropylacrylamide), polyvinyl alcohol, hyaluronic acid, alginate, pectin, agar, chia, chitosan, collagen, gelatin, dextran, heparin, silk hydrogel, peptide materials, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, or combinations thereof. In some examples, one or more biocompatible materials may include PEG-succinimidyl glutarate (PEG-SG), PEG-succinimidyl succinate (PEG-SS), PEG-succinimidyl malonate (PEG-SM), or combinations thereof. The concentration of one or more biocompatible materials may range from approximately 0.1% w / v to approximately 20% w / v.

[0006] The composition may further comprise one or more additives selected from crosslinking agents, photoactivating materials, fluorescent materials, radiopaque materials, or combinations thereof. Crosslinking agents may be selected from tripolyphosphates or trilysine acetates. The composition may further comprise at least one photoactivatable material that can be crosslinked with light, such that the composition can transition from liquid to gel. The composition may comprise phospholipids, e.g., phospholipid micelles and / or phospholipid liposomes. The composition may be formulated as an emulsion. One or more biocompatible materials may be formulated as microparticles suspended in a pharmaceutically acceptable carrier fluid. In some examples, the microparticles may be suspended in a solution comprising a pharmaceutically acceptable carrier fluid and a polymer at least partially dissolved in the pharmaceutically acceptable carrier fluid. The composition may be in the form of a shear-thinning solution or a gel (e.g., a hydrogel).

[0007] The composition may be used to remove a portion of mucosal tissue from a subject. In some cases, the composition may be administered to the subject by injection into the submucosal tissue, and in some cases, the portion of mucosal tissue may include a lesion.

[0008] According to some aspects of this disclosure, a composition for submucosal lifting may comprise a pharmaceutically acceptable carrier fluid and one or more biocompatible materials. The one or more biocompatible materials may be selected from polyethylene glycol (PEG), succinimidyl PEG-glutarate (PEG-SG), succinimidyl PEG-succinate (PEG-SS), succinimidyl PEG-malonate (PEG-SM), chitosan, gelatin, alginate, or a combination thereof. The concentration of one or more biocompatible materials in the composition may range from about 0.1% w / v to about 20% w / v. In some examples, the composition may comprise tripolyphosphate or trilysine acetate. In some examples, the composition may comprise one or more additives selected from crosslinking agents, photoactivating materials, fluorescent materials, radiopaque materials, or a combination thereof.

[0009] According to some aspects of this disclosure, a composition for submucosal lifting may comprise a pharmaceutically acceptable carrier fluid, one or more biocompatible materials at least partially or completely dissolved or suspended in the pharmaceutically acceptable carrier fluid, and a crosslinking agent selected from tripolyphosphates or trilysine acetates. The one or more biocompatible materials may be selected from polyethylene glycol (PEG), succinimidyl PEG-glutarate (PEG-SG), succinimidyl PEG-succinate (PEG-SS), succinimidyl PEG-malonate (PEG-SM), chitosan, gelatin, alginates, or combinations thereof. In some examples, the composition may be formulated as a gel or microparticles. [Modes for carrying out the invention]

[0010] Specific aspects of this disclosure are described in more detail below. In the event of any conflict between terms and / or definitions invoked by reference and those provided herein, the terms and definitions provided herein shall prevail. As used herein, the terms “comprises,” “comprising,” or any other variation thereof are intended to encompass non-exclusive inclusions, and as a result, any process, method, composition, article, or apparatus containing a list of elements may not contain only those elements, but may also contain 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.”

[0011] As 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. As 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 both endpoints; for example, a quantity in the range of 0.1g to 10g includes 0.1g, 10g, and all values ​​in between.

[0012] This disclosure includes compositions useful in medical procedures for separating tissue layers (e.g., submucosal tissue layers) for removal. For example, the compositions herein may be useful in endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) procedures. The compositions herein may be in the form of solutions, emulsions, suspensions, gels (e.g., hydrogels), microparticles (e.g., in suspensions), or combinations thereof.

[0013] The compositions herein may comprise one or more biocompatible materials and a pharmaceutically acceptable carrier fluid. For example, the biocompatible material(s) may be dissolved, dispersed, or suspended in the pharmaceutically acceptable carrier fluid. Biocompatible materials useful in this disclosure include biopolymers, e.g., natural and synthetic polymers, including chemically modified biopolymers. Suitable biocompatible materials for compositions include, for example, polymers, phospholipids, nanoclays, and combinations thereof. Exemplary polymers include, for example, polyethylene glycol (PEG) and its derivatives (e.g., PEG-succinimidyl glutarate (PEG-SG), PEG-succinimidyl succinate (PEG-SS), PEG-succinimidyl malonate (PEG-SM)), polyhydroxyethyl methacrylate (polyHEMA), thermogelling polymers such as poloxamer, 2-dimethylaminoethyl methacrylate (DMEMA), poly-L-lactic acid (PLLA), polycaprolactone (PCL), polyoxazoline, and poly This includes (lactic acid-co-glycolic acid) (PLGA), poly(N-isopropylacrylamide) (polyNIPAM), polyvinyl alcohol (PVA), hyaluronic acid, alginates (e.g., sodium alginate, calcium alginate, and barium alginate), pectin, agar, thia, chitosan, collagen, gelatin, dextran, heparin, silk hydrogel, peptide materials, hydroxypropyl methylcellulose (HPMC), methylcellulose, and carboxymethylcellulose. Exemplary phospholipids include, for example, phospholipid micelles and phospholipid liposomes. Exemplary nanoclays include, for example, laponite (smectite clay).

[0014] pharmaceutically acceptable carrier fluids may include aqueous liquids (e.g., buffers such as phosphate buffer or borate buffer, or physiological saline solution). In some examples herein, the composition includes a 0.9% w / v physiological saline solution. The composition may be pH-adjusted with a suitable acid (e.g., hydrochloric acid (HCl) or acetic acid) or base (e.g., sodium hydroxide (NaOH)).

[0015] The compositions herein may further include one or more additives, such as crosslinking agents, photoactivatable materials(s), fluorescent materials(s), radiopaque materials(s), or combinations thereof. In some examples, the compositions may include one or more crosslinking agents that crosslink, for example, biocompatible materials(s). Suitable exemplary crosslinking agents for the compositions herein include, but are not limited to, tripolyphosphates (TPP), trilysine acetate (TLA), MMP-degradable peptides that function as crosslinking agents (e.g., CGPQGIWGQC, CGPQGIAGQGCR, QPQGLAK), hydrolyzable crosslinking agents (e.g., organic compounds having ester bonds or RO-Si-O-R' groups), photocleavable crosslinking agents (e.g., o-nitrobenzyl alcohol (ONB) or bis(maleimidoethyl) 3,3'-diceranediyldipropionate (BMEDSeDP)), and combinations thereof. Examples of photoactivatable materials include, but are not limited to, organic compounds containing nitrobenzyl alcohol functional groups, acrylate / methacrylate functional groups, and photoinitiators including, for example, irgacure and benzoyl peroxide. For example, the compositions herein may contain benzoyl peroxide in the range of about 0.01% to about 5% w / v. Examples of fluorescent materials include, but are not limited to, compounds chemically modified with fluorophores (e.g., green fluorescent protein (GFP), fluorescein isothiocyanate (FITC), cyanine dyes, and / or combinations thereof) and / or compounds mixed with fluorophores. Examples of radiopaque materials include, but are not limited to, compounds containing radiopaque atoms such as iodine, for example, PEG and / or polymers containing radiopaque atoms such as iodized linear PEG or iodized star-type PEG.

[0016] The compositions described herein can be formulated for injection. For example, the composition may be injected into the submucosal layer, where the composition creates a space between the area to be excised (e.g., a lesion) and the underlying tissue. This space may facilitate the removal of the area to be excised while minimizing damage to the underlying tissue. The following considerations include, for example, examples of biocompatible materials useful for formulating the compositions as solutions, emulsions, gels (e.g., hydrogels), microparticles, nanoparticles, and suspensions, together with pharmaceutically acceptable fluids and optionally one or more additives.

[0017] solution In some aspects of this disclosure, a composition comprises one or more biocompatible materials, for example, partially or completely dissolved in a pharmaceutically acceptable carrier fluid, forming a solution. The composition may be a shear-thinning solution. The solution may be formulated for injection. Exemplary compositions formulated as solutions may comprise one or more polymers, such as, for example, one or more thermogelling polymers such as PEG, polyHEMA, poloxamer(s), DMEMA, PLLA, PCL, polyoxazoline(s), PLGA, polyNIPAM, hyaluronic acid, alginates (e.g., sodium alginate), pectin, agar, thia, collagen, gelatin, dextran, heparin, silk hydrogel(s), peptide materials(s), HPMC, methylcellulose, or carboxymethylcellulose, their derivatives, and combinations thereof. The solution may contain biocompatible materials(s) in concentrations ranging from approximately 0.1% w / v to approximately 20% w / v, for example, approximately 1% w / v to approximately 15% w / v, or approximately 5% w / v to approximately 10% w / v. In some examples, the composition may contain a combination of two or three biocompatible materials. In some examples, the composition may exhibit thermally enhanced viscosity. For example, the composition may contain one or more thermogelling polymers, such as polymers that can thicken at body temperature (e.g., approximately 36.5°C to 37.5°C). For example, the composition may contain poloxamer and / or polyNIPAM.

[0018] As described above, the composition can be formulated as a shear-thinning solution. The shear force of the composition can facilitate injection using a suitable injection device such as a syringe. Once injected, the composition may become viscous in the submucosal layer and maintain a bleb-like shape.

[0019] gel The compositions herein may be formulated, for example, as a gel that can be injected into tissue. One or more biocompatible materials may be dispersed in a pharmaceutically acceptable carrier fluid, for example, with a certain amount of crosslinking to form a gel, or at least partially or completely dissolved. For example, a composition may be formulated as a loosely crosslinked hydrogel suitable for injection. In some examples, the biocompatible material(s) may comprise one or more polymers. For example, a composition may comprise PEG (including its derivatives such as PEG-SG, PEG-SS, PEG-SM), chitosan, gelatin, alginates (e.g., sodium alginate, calcium alginate, barium alginate, etc.), or a combination thereof. The biocompatible material(s) may be present at concentrations ranging from about 0.1% w / v to about 20% w / v, for example, about 1% w / v to about 15% w / v, for example, about 5% w / v to about 10% w / v. Optionally, the composition may contain one or more crosslinking agents, such as TPP and / or TLA.

[0020] Examples of compositions formulated as gels include, but are not limited to, the following, in which each component is present in concentrations ranging from about 0.1% w / v to about 20% w / v (e.g., about 1% w / v to about 15% w / v, more preferably about 5% w / v to about 10% w / v): (1) chitosan and TPP, (2) PEG-SG and TLA, (3) PEG-SS and TLA, (4) PEG-SM and TLA, (5) PEG-SG and chitosan, (6) PEG-SS and chitosan, (7) PEG-SM and chitosan, (8) gelatin, (9) alginate and calcium (Ca), (10) alginate and barium (Ba), (11) combinations thereof.

[0021] While not bound by any particular theory, biocompatible materials(s) can be crosslinked via non-covalent interactions such as hydrogen bonding, van der Waals forces, and / or electrostatic interactions. As mentioned above, in some examples, the composition includes one or more crosslinking agents to facilitate crosslinking.

[0022] Optionally, the gel may be further processed into microparticles or otherwise manufactured. For example, following the formation of the gel, the gel may be formed into microparticles by grinding it to produce smaller particles.

[0023] The composition may be provided in a pre-gelled form, for example, as a pre-mixed, separated composition in one or more containers. For example, the composition may be provided as components in two or more separate containers (e.g., a first biocompatible material and a second biocompatible material, or a biocompatible material and a crosslinking agent) that are mixed to form a gel suitable for injection. In some examples, the components may be provided in two or more syringes that, when pressed down simultaneously, can be combined in a suitable delivery device for administration to a subject (e.g., an infusion catheter) to form a gel.

[0024] Emulsion The compositions herein may be formulated as injectable emulsions, such as shear-thinning emulsions. In some examples, the biocompatible material(s) of the emulsion may include phospholipids (e.g., phospholipid micelles, phospholipid liposomes, or combinations thereof). Additionally or alternatively, the biocompatible material(s) of the emulsion may include polymer nanoemulsions (e.g., nanoemulsions including PLLA, PCL, or combinations thereof), and / or the biocompatible material(s) may include nanoclay. An example nanoclay is, for example, laponite. The biocompatible material(s) may be present in the emulsion at concentrations ranging from about 0.1% w / v to about 10% w / v, for example, from about 1% w / v to about 4% w / v.

[0025] The composition may contain two or more biocompatible materials at a concentration in the range of about 0.1% w / v to about 10% w / v, such as about 1% w / v to about 4% w / v. In at least one example, the composition in the form of an emulsion contains nanoclay at a concentration in the range of about 1% w / v to about 4% w / v.

[0026] Micro-particles The compositions herein may be formulated as micro-particles, e.g., as a plurality of particles each having a size on the order of microns. The micro-particles may be gel micro-particles. As described above, the gel may be formed by the preparation of the gel and then treated to break the gel into a plurality of particles. Optionally, this composition may contain micro-particles and a pharmaceutically acceptable carrier (e.g., a buffer or an aqueous saline solution). For example, the composition may contain micro-particles comprising one or more biocompatible materials, and the micro-particles are suspended in a pharmaceutically acceptable carrier fluid and formulated, for example, as a suspension suitable for injection. The biocompatible material(s) of the micro-particles may include, for example, PEG (including its derivatives such as PEG-SG, PEG-SS, PEG-SM, etc.), chitosan, gelatin, alginate (including sodium alginate, calcium alginate, barium alginate, etc.), or combinations thereof. Optionally, the micro-particles may contain one or more cross-linking agents (e.g., TPP, TLA, or combinations thereof) that facilitate the formation of the gel of the particles.

[0027] Biocompatible materials(s) may be present in microparticles at concentrations ranging from approximately 0.1% w / v to approximately 20% w / v, for example, from approximately 1% w / v to approximately 15% w / v, or for example, from approximately 5% w / v to approximately 10% w / v. Exemplary microparticles according to some aspects of this disclosure may include, for example, the following at concentrations ranging from about 0.1% w / v to about 20% w / v, for example from about 1% w / v to about 15% w / v, for example from about 5% w / v to about 10% w / v, and each component may include: (1) chitosan and TPP, (2) PEG-SG and TLA, (3) PEG-SS and TLA, (4) PEG-SM and TLA, (5) PEG-SG and chitosan, (6) PEG-SS and chitosan, (7) PEG-SM and chitosan, (8) gelatin, (9) alginate and Ca, (10) alginate and Ba, (11) PVA, and (12) combinations thereof.

[0028] In some examples, the composition comprises microparticles combined with a solution containing a pharmaceutically acceptable carrier fluid and one or more biocompatible materials selected from PEG (and its derivatives), polyHEMA, poloxamer, DMEMA, PLLA, PCL, polyoxazoline, PLGA, hyaluronic acid, alginates (e.g., sodium alginate, calcium alginate, barium alginate), pectin, agar, thia, collagen, gelatin, dextran, heparin, silk hydrogel, peptide materials, HPMC, methylcellulose, carboxymethylcellulose, and combinations thereof. The biocompatible material(s) may be present in the composition at concentrations ranging from about 5% w / v to about 50% w / v, for example, about 15% w / v to about 35% w / v, for example, about 20% w / v to about 30% w / v.

[0029] It is understood that the compositions herein (e.g., solutions, emulsions, gels, suspensions, microparticles, etc.) may be formulated with desired viscosity, shear strength, degradability, and ability to lift / separate tissue layers to suit specific medical procedures and patient needs. For example, a composition may have a viscosity of at least about 0.001 Pa·s, for example, greater than about 0.1 Pa·s. As stated above, any of the compositions herein may contain one or more additives that may contribute to and / or impart the desired properties. Exemplary additives include, for example, crosslinking agents, photoactivating materials, fluorescent materials, and radiopaque materials.

[0030] The crosslinking agent may be selected depending on the desired degree of crosslinking and / or the desired degradability of the composition. The compositions herein are generally biodegradable, but one or more crosslinking agents may be added to influence the degradability, for example, through the manipulated degradability provided by the crosslinking agent(s). The compositions herein may include, for example, one or more crosslinking agents selected from MMP-degradable crosslinking agents (e.g., CGPQGIWGQC, CGPQGIAGQGCR, QPQGLAK), hydrolyzable crosslinking agents (e.g., polymers containing ester bonds or RO-Si-O-R' groups), photocleavable crosslinking agents (e.g., o-nitrobenzyl alcohol (ONB) or bis(maleimidoethyl) 3,3'-diceranediyldipropionate (BMEDSeDP)), or a combination thereof. The crosslinking agents may be designed to be degraded by the body's natural mechanisms (e.g., MMP, hydrolysis) or by external stimuli (e.g., near-infrared light, enzyme injection). Crosslinking agents can introduce weaknesses into a composition, for example, to provide controllability of the composition's degradation rate and forced activation.

[0031] Photoactivatable materials (e.g., materials that can be crosslinked by light) may also be useful for imparting desired properties such as viscosity, shear strength, and / or degradability. The compositions herein may comprise one or more photoactivatable materials, such as polymers containing nitrobenzyl alcohol functional groups or acrylate / methacrylate functional groups, and / or photoinitiators, such as Irgacure or benzoyl peroxide. The photoactivatable material(s) may be capable of crosslinking and increasing viscosity when exposed to light (e.g., transforming the composition from a liquid to a gel, e.g., a relatively firm gel). The compositions herein have improved ease of injection, as well as properties and / or features useful for bleb formation, function, and / or maintenance.

[0032] Fluorescent materials useful in this disclosure include fluorophores (e.g., green fluorescent protein (GFP), fluorescein isothiocyanate (FITC), or compounds containing cyanine dyes). Fluorescent materials may be useful for in situ visualization, such as bleb visualization and / or post-excision identification of composition residues.

[0033] Radiopaque materials useful in this disclosure include compounds containing radiopaque atoms and / or functionalized with a moiety containing radiopaque atoms. Suitable radiopaque materials may include, for example, iodine (e.g., PEG containing a moiety with radiopaque atoms, such as iodized linear PEG or iodized star-type PEG), but the composition is not limited to iodine. Radiopaque materials may be useful for visualization of compositions after treatment.

[0034] The compositions herein may be useful in a variety of medical procedures, for example, including the removal of selected tissue to separate a portion of tissue from an underlying tissue layer while minimizing damage to the underlying tissue layer. Such medical procedures may include endoscopic procedures to lift cell growths (e.g., polyps or lesions) from the mucosal layer of tissue. Such tissue may be tissue from the gastrointestinal tract (e.g., the colon). As described above, when a sufficient and / or predetermined amount of the composition is injected into the submucosal layer, the viscosity and / or structural integrity of the composition may allow the outermost portion of the tissue relative to the injection site to be physically lifted from the underlying mucosal layer. In addition to providing a physical lift, the compositions herein may be able to provide a long-lasting lift, for example, suitable for medical professionals to complete the removal of a selected portion of tissue.

[0035] Other aspects of this disclosure will be 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 merely illustrative, and the true scope and spirit of this disclosure are intended to be shown by the following claims.

Claims

1. A composition for submucosal lifting, A pharmaceutically acceptable carrier fluid, One or more biocompatible materials, at least partially or completely dissolved or suspended in the pharmaceutically acceptable carrier fluid, the one or more biocompatible materials selected from polymers, phospholipids, nanoclays, or combinations thereof, and Includes, The composition is formulated as a solution, emulsion, gel, or suspension that can be injected into tissue.

2. The composition according to claim 1, wherein the one or more biocompatible materials include polyethylene glycol (PEG) or its derivatives, polyhydroxyethyl methacrylate, poloxamer, 2-dimethylaminoethyl methacrylate, poly-L-lactic acid, polycaprolactone, polyoxazoline, poly(lactic acid-co-glycolic acid), poly(N-isopropylacrylamide), polyvinyl alcohol, hyaluronic acid, alginate, pectin, agar, thia, chitosan, collagen, gelatin, dextran, heparin, silk hydrogel, peptide-based materials, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, or a combination thereof.

3. The composition according to claim 1 or 2, wherein the one or more biocompatible materials include PEG-glutarinate succinimidyl (PEG-SG), PEG-succinimidyl succinate (PEG-SS), PEG-malonate succinimidyl (PEG-SM), or a combination thereof.

4. The composition according to any one of claims 1 to 3, wherein the pharmaceutically acceptable carrier fluid comprises a buffer solution or a physiological saline solution.

5. The composition according to any one of claims 1 to 4, wherein the concentration of one or more biocompatible materials in the composition is in the range of about 0.1% w / v to about 20% w / v.

6. The composition One or more additives selected from crosslinking agents, photoactivating materials, fluorescent materials, radiopaque materials, or combinations thereof; and / or One or more crosslinking agents selected from tripolyphosphate or trilysine acetate A composition according to any one of claims 1 to 5, further comprising:

7. The composition according to any one of claims 1 to 6, wherein the composition further comprises at least one photoactivatable material that can be crosslinked with light, such that the composition transitions from a liquid to a gel.

8. The composition according to any one of claims 1 to 7, wherein the composition comprises a phospholipid.

9. The composition according to claim 8, wherein the composition comprises phospholipid micelles or phospholipid liposomes.

10. The composition according to any one of claims 1 to 9, wherein the composition is formulated as an emulsion.

11. The composition according to any one of claims 1 to 9, wherein the one or more biocompatible materials are formulated as microparticles suspended in the pharmaceutically acceptable carrier fluid.

12. The composition according to claim 11, wherein the microparticles are suspended in a solution comprising the pharmaceutically acceptable carrier fluid and a polymer at least partially dissolved in the pharmaceutically acceptable carrier fluid.

13. The composition according to any one of claims 1 to 9, wherein the composition is in the form of a shear-reducing solution or a gel.

14. Use of the composition according to any one of claims 1 to 13 for removing a portion of mucosal tissue from a subject, wherein the composition is administered to the subject by injection into the submucosal tissue.

15. The use according to claim 14, wherein a portion of the mucosal tissue includes a lesion.

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