Synthetic tissue barriers and their uses

Abstract

The present disclosure provides compositions, methods and kits that can make polymers grow in situ on or in a subject. In some respects, tissue active monomers, including monomers comprising macromolecules, provide a wide range of material selections for synthetic tissue barriers. In other respects, compositions, methods and kits can be used for treating or preventing diseases or obstacles.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims U.S. Provisional Patent Application USSN 62 / 947,582 filed on December 13, 2019, U.S. Provisional Patent Application USSN 63 / 050,206 filed on July 10, 2020, and U.S. Provisional Patent Application USSN 63 / 050,216 filed on July 10, 2020 under 35 U.S.C. §119(e), the contents of each of which are incorporated herein by reference in their entirety. Background Art

[0003] The tissue barriers that cover much of the body are not only protective barriers against physical abrasion, chemical stress, environmental stress, exogenous agents, and microbial pathogens, but also dynamic linings for signal sensing (e.g., of temperature, viruses, and bacteria), molecular transport (e.g., of oxygen, nutrients, and drugs), and immune coordination (e.g., cytokines, mucins, and host defense peptides). 9-19 Disruption of tissue barrier function has been implicated in the pathogenesis of many human diseases. 14-19 Selective intervention of specific tissue barriers is relevant to disease treatment and health management. At the same time, a large number of well-designed biotechnologies have been developed to address the challenge of effectively and specifically restoring or enhancing tissue barrier function. These specific technologies using tissue adhesives or tissue substitutes are effective tools to promote the restoration of tissue barrier dysfunction and the treatment of systemic diseases.

[0001] 1,

[0001] 2,

[0001] 3,

[0001] 4,

[0001] 5,

[0001] 6 Despite these advances in research laboratories, widespread adoption of these technologies in medical laboratories and healthcare clinics has been limited, inhibiting their impact. This narrow implementation is the result of multiple factors: invasive implantation, potential immunogenicity, toxicity, and most importantly, the inaccuracy, instability, and inconvenience of current tissue targeting strategies, which limit access across selective tissue barriers. Summary of the invention

[0004] Described herein are compositions, methods and kits that enable monomers such as polydopamine (PDA) to grow in contact with epithelial tissue and provide non-toxic, stable, transient synthetic tissue barriers with adjustable functionality, which make it easy to transplant non-invasively. The polymer coating relies on dopamine polymerization catalyzed by endogenous cellular enzymes (e.g., catalase or "CAT"), strong tissue adhesion produced by chemical cross-linking, and functional agents optionally introduced by facile conjugation. The present invention relates in part to a library of tissue-active monomers, which includes monomers containing macromolecules, which provide a wide range of material options for synthetic tissue barriers. Based on a whole-body survey, the library of polymeric materials accelerated by the tissue allows new formulations to be provided for various therapeutic strategies to be applied to different tissue sites, including for the treatment of hemostasis (e.g., upper gastrointestinal bleeding), and to improve the administration efficiency (e.g., sustained drug release) in the conjunctiva, cartilage and oral cavity (e.g., protecting the epithelium from environmental pressures in the oral cavity).

[0005] In one aspect, provided herein is a method of forming a polymer in situ in a subject, the method comprising administering to the subject a composition comprising a monomer and an oxygen source, wherein the monomer and oxygen source are contacted in vivo with a catalyst endogenous to the subject, and wherein the catalyst polymerizes the monomer.

[0006] In one aspect, the present disclosure provides a composition comprising (i) a monomer selected from dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a monomer comprising dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester or levodopa ethyl ester and a macromolecule selected from one or more of alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate or chitosan, (ii) an oxygen source, (iii) optionally, a buffer, and (iv) optionally, an agent.

[0007] In another aspect, the present disclosure provides a method of treating a disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a composition described herein.

[0008] Further provided are methods of preventing a disease or disorder comprising administering to a subject in need thereof an effective amount of a composition described herein.

[0009] In another aspect, provided herein is a method of treating bleeding comprising administering to a subject in need thereof an effective amount of a composition described herein.

[0010] The disclosure also provides kits comprising the compositions herein and instructions for administering the compositions.

[0011] As described below, the details of certain embodiments of the invention are set forth in the detailed description. Other features, objects and advantages of the invention will be apparent from the definitions, examples and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figures 1A-1E Tissue-accelerated polymerization technology and whole-body screening of tissue catalytic activity are demonstrated. Figure 1A This is a schematic diagram of synthetic tissue barrier technology. Tissue-accelerated polymerized monomers are rapidly oxidized under the catalysis of endogenous catalase. Figure 1B It is a polymerized coating formed on the tissue that is accelerated by the polymerized tissue. Figure 1C It is a schematic diagram of tissue accelerated polymerization active tissues in the body, where tissues are divided by body system, including respiratory system, urinary system, lymphatic system, circulatory system, integumentary system, skeletal system, muscular system, nervous system, digestive system and endocrine system. Tissue accelerated polymerization positive (active) sites are marked in dark brown and include trachea, lung, kidney, bladder, lymph nodes, heart, blood vessels, skin, cartilage, muscle, nerve, mouth, liver, spleen, gallbladder, pancreas and small intestine. Figure 1D Images showing tissue samples in different parts of the tissue before and after the accelerated polymerization process of the tissue are shown.Samples were collected at three random sites (6 mm diameter) of the polydopamine coated tissue. Figure 1E Shows Figure 1D Quantitative measurement of polydopamine signal intensity for the samples shown in .

[0013] Figures 2A-2C A pool of tissue-accelerated polymerized monomers is shown, some of which include macromolecules. Figure 2A The organization of accelerated polymerized monomers is shown. Figure 2B A schematic diagram of a tissue-accelerated polymerization molecule library including 6 tissue-accelerated polymerization monomers and 21 tissue-accelerated polymerization macromolecules is shown. Figure 2C Shown is a heat map showing the increase in polymerization rate of 1142 individual monomer preparations under catalase catalysis.

[0014] Figure 3 Shown are images of the assembly of tissue-directed polymer assembly ("TPA") monomers M1-M6 with or without the addition of CAT. The top row shows that TPA monomers M1-M6 do not initially polymerize without the addition of CAT. In the bottom row, by adding CAT, the assembly of TPA monomers M1-M6 is observed.

[0015] Figures 4A-4F The normalized extinction spectra of the polymerization standards and polymerization products accelerated by polymerization tissue are shown. Figures 4A-4F, M1-M6 respectively) The UV-Vis spectra of the polymerization standards (dotted lines) and the polymerization products (solid lines) accelerated by the polymerization tissue catalyzed by catalase are basically consistent, confirming the polymerization formation accelerated by the polymerization tissue catalyzed by catalase.

[0016] Figures 5A-5F TPA assembly kinetics are shown. For solutions containing six monomers with or without catalase catalysis over 3 hours ( Figures 5A-5F , M1-M6) measured the optical extinction of TPA monomer assembly solutions at 500nm. In the presence of CAT, the light extinction intensity increased rapidly and stabilized within a few minutes of reaction initialization. In the absence of CAT, the signal was very small even after 3 hours, and the same intensity was achieved within 1-2 minutes under CAT catalysis, indicating that the assembly rate of all TPA monomers was accelerated by about 100-200 times.

[0017] Figure 6 A photograph of TPA monomer coating on porcine cartilage is shown. Images of ex vivo tissue samples of porcine cartilage after incubation with each TPA monomer solution and washing to remove excess unbound TPA assemblies in the solution are shown. There is a clear color change in all tissue samples after incubation compared to the control.

[0018] Figures 7A-7C Schematic diagram of TPA-macromolecule conjugates is shown. Schematic diagram of 21 different TPA-macromolecule conjugates formed by the combination of TPA monomer with six different carboxyl-rich macromolecules (sodium alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, and chitosan) is shown.

[0019] Figures 8A-8C NMR spectra of 21 tissue accelerated polymerized monomers comprising macromolecules are shown. Unconjugated macromolecules (marked with asterisks (*)), tissue accelerated polymerized monomers (marked with arrows (→)) and conjugated tissue accelerated polymerized macromolecules (unmarked) are shown.

[0020] Fig. 9 A heat map illustrating the biocompatibility of TPA assemblies is shown. Cell viability of Caco-2 and HeLa cells was shown by administration of TPA assemblies (formed by a combination of M1-M6 monomers and C1-C21 TPA-macromolecule conjugates) and 24 hours of in vitro incubation. Polymer assemblies produced by C7-C12 showed relatively low cytotoxicity.

[0021] Fig.10TPA eye drop application with conjunctival specificity is shown. A schematic illustration of TPA eye drop application and specific assembly on the conjunctiva of the human eye is shown. A brown color is observed after TPA eye drops (optical properties of TPA polymerization and adhesion).

[0022] Fig.11A-11O TPAs for drug delivery, tissue protection, and hemostatic therapy are shown.

[0023] Fig.12 The adhesion of the TPA assembly to the conjunctiva is shown. Images of a pig eye and conjunctiva are shown after application of TPA eye drops, before and after irrigation with an isotonic solution. The TPA assembly remained intact after irrigation.

[0024] Fig.13 Transient coating of TPA assembly on conjunctiva is shown. Images of pig eye and conjunctiva 24 hours after application of TPA eye drops are shown. Conjunctiva is pink and does not contain TPA assembly.

[0025] Fig.14 Shown is the histology of porcine conjunctiva 24 hours after TPA administration compared to the control group.

[0026] Fig.15 The stability of the TPA patch after vigorous washing is shown. Images of a pig tongue after application and adhesion of the TPA patch before and after vigorous rinsing are shown. The TPA patch is dark brown (optical properties of TPA assembly layer polymerization and adhesion) and remains after rinsing.

[0027] Fig.16 Transient adhesion of the TPA patch after 24 hours is shown. An image of a pig tongue 24 hours after TPA patch adhesion is shown, where the patch and TPA assembly no longer adhere or appear on the tissue surface.

[0028] Fig.17 Shown is the histology of porcine tongue epithelium after TPA patch adhesion.

[0029] Fig.18 The stability of the TPA-lead patch over 3 hours is shown. An X-ray image of the pig head profile is shown after the TPA-lead patch is applied to the buccal surface of a sedated pig. After 3 hours, the TPA-lead patch is fixed in its original orientation.

[0030] Fig.19 Shows the gelation of blood when mixed with TPA powder. An image showing fresh pig blood collected through a tube containing sodium citrate anticoagulant and then mixed with TPA hemostatic powder (M1 and C7 as TPA molecules). Once mixed with TPA powder, the blood (red liquid) immediately turns into a black gel.

[0031] Figures 20A-20B An image of an in vivo hemostasis study is shown. Endoscopic images show the bleeding site before and after treatment with the tissue accelerated polymer powder, as shown in Fig. 20A As shown, as well as the accelerated polymerization powder without H2O2 as a control treatment, as Fig. 20B As shown. Images from a gastrointestinal endoscopy video of a porcine model of acute gastric bleeding with a powder without a TPA gel component (control) applied under endoscopic vision are shown. Under moderate sedation, endoscopic biopsy forceps were used to create a 10-20 mm puncture wound (without perforation) in the stomach, resulting in bleeding from the puncture site (exudative bleeding). There was no color change or reduction in bleeding 10 minutes after the endoscopic powder was applied.

[0032] Fig.21 Images showing tissue recovery after hemostatic treatment. Endoscopic images show bleeding sites in the stomach 24 hours later. Different treatments were applied to the bleeding sites. Tissue-accelerated polymer powder can help tissue regeneration and recovery, with less obvious scars and smooth tissue surfaces. From left to right: 1) an image of a pig stomach after puncture and subsequent TPA hemostatic treatment, where a flat wound was observed at the puncture site; 2) an image of a pig stomach 24 hours after puncture and application of a control powder; and 3) an image of a pig stomach 24 hours after puncture without subsequent treatment.

[0033] Fig. 22 Shown is the histology of damaged tissue after hemostatic treatment. Histology image shows damaged / bleeding tissue in the stomach after 24 hours. Different treatments were applied to the bleeding site. Tissue accelerated polymeric powders can help tissue regeneration and recovery, where tissue returns to a state similar to healthy tissue.

[0034] Figures 23A-23F Evaluation of TPA in human tissue is shown. Fig.23A The M1 assembly was shown to stably adhere to various human tissues. Fig. 23B Quantitative signal analysis for confirming the TPA barrier on the tissue surface is shown. Figures 23C-23F The kinetics of M1 assembly formation are shown.

[0035] definition

[0036] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0037] The language "in some embodiments" and "in certain embodiments" are used interchangeably.

[0038] The following definitions are of more general terms used in this application:

[0039] The singular terms "a", "an" and "the" include plural forms unless the context clearly indicates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise.

[0040] Except in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions herein are to be understood as modified in all cases by the term "about". "About" and "approximately" generally refer to an acceptable degree of error for the amount measured, given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically within 10%, or more typically within 5%, 4%, 3%, 2%, or 1% of a given value or range of values.

[0041] When a numerical range ("range") is listed, it is intended to include every value and sub-range within that range. Unless otherwise stated, a range includes values ​​at both ends of the range.

[0042] The terms "composition" and "formulation" are used interchangeably.

[0043] A "subject" to which administration is contemplated refers to a human (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, a middle-aged adult, or an elderly adult)) or a non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., a primate (e.g., a cynomolgus monkey or a rhesus monkey), a commercially relevant mammal (e.g., a cow, a pig, a horse, a sheep, a goat, a cat, or a dog), or a bird (e.g., a commercially relevant bird, such as a chicken, a duck, a goose, or a turkey)). In certain embodiments, the non-human animal is a fish, a reptile, or an amphibian. The non-human animal can be male or female at any stage of development. The non-human animal can be a transgenic animal or a genetically engineered animal. The term "patient" refers to a human subject in need of treatment for a disease.

[0044] The terms "administering," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a composition described herein into or onto a subject.

[0045] The terms "treat" and "treat" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease described herein. In some embodiments, treatment may be administered after the disease has appeared or one or more signs or symptoms have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to pathogens). Treatment may also continue after symptoms disappear, for example, to delay and / or prevent recurrence.

[0046] The terms "condition," "disease," and "disorder" are used interchangeably.

[0047] An "effective amount" of a polymer or composition as described herein refers to an amount sufficient to cause a desired biological response. The effective amount of a polymer or composition as described herein may vary according to the following factors: the expected biological endpoint, the pharmacokinetics of the polymer or composition, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactic effective amount. In certain embodiments, the effective amount is the amount of a compound, polymer, or composition as described herein in a single dose. In some embodiments, the effective amount is the combined amount of a compound, polymer, or composition as described herein in multiple doses.

[0048] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman's Medical Dictionary, 25th ed.; Hensyl, ed.; Williams & Wilkins: Philadelphia, 1990.

[0049] "Autoimmune disease" refers to a disease caused by an inappropriate immune response by the subject's body against substances and tissues normally present in the body. In other words, the immune system mistakes certain parts of the body for pathogens and attacks its own cells. This can be localized to certain organs (e.g., in autoimmune thyroiditis) or involve specific tissues in different locations (e.g., Goodpasture's disease, which can affect the basement membranes in the lungs and kidneys). Treatment of autoimmune diseases often employs immunosuppression, such as drugs that reduce the immune response.

[0050] The term "inflammatory disease" refers to a disease caused by, resulting from, or leading to inflammation. The term "inflammatory disease" may also refer to a dysregulated inflammatory response that causes an overreaction of macrophages, granulocytes, and / or T lymphocytes, leading to abnormal tissue damage and / or cell death. Inflammatory diseases may be acute or chronic inflammatory conditions and may be caused by infectious or non-infectious causes.

[0051] The term "polymer" refers to a compound comprising 11 or more covalently linked repeating units. In certain embodiments, the polymer is naturally occurring. In certain embodiments, the polymer is synthetic (i.e., not naturally occurring).

[0052] As used herein, the term "assembly" or "assembly" refers to the formation of a polymer by covalent bonding of repeating units. For example, a polymer can be assembled from any monomer disclosed herein.

[0053] The term "nanoparticle" refers to particles having an average (e.g., mean) size (e.g., diameter) between about 1 nanometer (nm) and about 1 micrometer (μm) (e.g., between about 1 nm and about 300 nm), between about 1 nm and about 100 nm, between about 1 nm and about 30 nm, between about 1 nm and about 10 nm, or between about 1 nm and about 3 nm), inclusive.

[0054] As used herein, the term "agent" refers to a molecule, group of molecules, complex or substance administered to an organism for diagnostic, therapeutic, preventive medical or veterinary purposes. In certain embodiments, the agent is an active agent, a diagnostic agent or a preventive agent. In certain embodiments, the polymers and compositions disclosed herein include an agent, such as a first agent (e.g., at least one (including, for example, at least two, at least three). In some embodiments, the polymers and compositions may also include a second agent. In some embodiments, the agent is an enzyme (e.g., a digestive enzyme), a nutritional blocker (e.g., a cross-linking agent), an aptamer, an antibody, a neutralizer, a diagnostic agent, a radioprotectant, a nutrient, an active agent or a combination thereof.

[0055] As used herein, the term "radioprotectant" refers to an agent that protects biological systems from exposure to radiation, either naturally or through radiation leakage. In certain embodiments, a radioprotectant protects normal cells of a cancer patient who is undergoing radiation therapy from radiation damage.

[0056] As used herein, the term "neutralizer" refers to an agent that neutralizes an acid or a base. In some embodiments, the neutralizer is an acid. In some embodiments, the neutralizer is a base. In certain embodiments, the neutralizer is a buffer.

[0057] As used herein, the term "diagnostic agent" refers to an imaging agent or a contrast agent. The terms "imaging agent" and "contrast agent" refer to a substance used in medical imaging to enhance the contrast of structures or fluids in the body. It is typically used to enhance the visibility of blood vessels and the gastrointestinal tract in medical imaging.

[0058] As used herein, the term "active agent" includes agents that are capable of providing a local or systemic biological, physiological or therapeutic effect in the biological system to which it is applied. For example, active agents can act to control tumor growth, control infection or inflammation, act as analgesics, promote anti-cell attachment and enhance bone growth, etc. Other suitable active agents may include antiviral agents, hormones, antibodies or therapeutic proteins. Other active agents include prodrugs, which are agents that are not biologically active when administered but are converted to biologically active agents by metabolism or some other mechanism when administered to a subject.

[0059] The active agent can be a compound, such as an organic or inorganic small molecule; saccharin; an oligosaccharide; a polysaccharide; a biological macromolecule, such as a peptide, protein, peptide analogs and derivatives; a peptide mimetic; an antibody and its antigen-binding fragment; a nucleic acid; a nucleic acid analog and derivative; an extract made from biological material such as bacteria, plant, fungal or animal cells; an animal tissue; a naturally occurring or synthetic composition; and any combination thereof.

[0060] Examples of active agents include, but are not limited to, antimicrobial agents, analgesics, anti-inflammatory agents, anti-irritants, coagulation regulators, diuretics, sympathomimetics, anorexia, antacids and other gastrointestinal drugs; antiparasitics, antidepressants, antihypertensives, anticholinergics, stimulants, antihormones, central and respiratory stimulants, drug antagonists, lipid regulators, uricosurics, cardiac glycosides, electrolytes, ergot and its derivatives, expectorants, hypnotics and sedatives, antidiabetics, dopaminergics, antiemetics, muscle relaxants, parasympathetics, anticonvulsants, antihistamines, beta-blockers, laxatives, antiarrhythmics, contrast media, radiopharmaceuticals, antiallergics, tranquilizers, vasodilators, antivirals and antineoplastic agents or cytostatics or other drugs with anticancer properties, or combinations thereof. Other suitable active agents include contraceptives and vitamins and micro- and macronutrients. Other examples include anti-infectives, such as antibiotics and antivirals; analgesics and analgesic combinations; appetite suppressants; anthelmintics; antiarthritics; antiasthmatics; anticonvulsants; antidepressants; antidiuretics; antidiarrheals; antihistamines; anti-inflammatory drugs; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonian drugs; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations, including calcium channel blockers and beta-blockers, For example, pindolol and antiarrhythmic drugs; antihypertensive drugs; diuretics; vasodilators, including general coronary, peripheral and cerebral vasodilators; central nervous system stimulants; cough and cold medicines, including decongestants; hormones such as estrogens and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympathetic drugs; psychostimulants; sedatives; tranquilizers; and proteins, polysaccharides, glycoproteins or lipoproteins of natural origin or genetic engineering. The present disclosure is not intended to be limited in any way by the above exemplary terms. Additional terms may be defined in other parts of the present disclosure. DETAILED DESCRIPTION

[0061] Before describing the disclosed systems, hydrogel compositions, methods, uses, and kits in greater detail, it should be understood that the aspects described herein are not limited to specific embodiments, methods, systems, devices, or configurations and as such can, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting unless specifically defined herein.

[0062] Methods and uses

[0063] In one aspect, the disclosure provides a method of forming a polymer in situ in a subject, the method comprising administering to the subject a composition comprising a monomer and an oxygen source, wherein the monomer and oxygen source are contacted with a catalyst endogenous to the subject, and the catalyst polymerizes the monomer.

[0064] In some embodiments, the monomer is catalyzed when the oxygen source and the monomer contact an endogenous catalyst. In some embodiments, the monomer is catalyzed when the oxygen source and the monomer contact a blood cell.

[0065] In some embodiments, the oxygen source is hydrogen peroxide or urea hydrogen peroxide. In some embodiments, the oxygen source is hydrogen peroxide. In some embodiments, the oxygen source is urea hydrogen peroxide.

[0066] In some embodiments, the endogenous catalyst is selected from catalase or peroxidase. In some embodiments, the endogenous catalyst is a peroxidase. In certain embodiments, the peroxidase is eosinophil peroxidase, lactoperoxidase, or myeloperoxidase.

[0067] In some embodiments, the endogenous catalyst is catalase. In some embodiments, the catalase is bacterial catalase. In some embodiments, the catalase is human catalase.

[0068] In certain embodiments, the endogenous catalyst is located in the respiratory system, urinary system, lymphatic system, circulatory system, epidermal system, skeletal system, muscular system, nervous system, digestive system or endocrine system. In some embodiments, the endogenous catalyst is located in the gastrointestinal tract (GI) of the subject. In some embodiments, the endogenous catalyst is located in the upper gastrointestinal tract of the subject. In some embodiments, the endogenous catalyst is located in the intestine of the subject. In some embodiments, the endogenous catalyst is located in the stomach of the subject. In some embodiments, the endogenous catalyst is located in the cell. In some embodiments, the endogenous catalyst is located in the blood cells. In some embodiments, the endogenous catalyst is located on the cell. In some embodiments, the endogenous catalyst is located on the blood cells. In some embodiments, the endogenous catalyst is located in the cell. In some embodiments, the endogenous catalyst is secreted by the blood cells. In some embodiments, the endogenous catalyst is located on the cell. In some embodiments, the endogenous catalyst is secreted by the blood cells.

[0069] In some embodiments, the monomer is a catechol-based monomer. In some embodiments, the monomer comprises a 1,2-dihydroxybenzene moiety. In some embodiments, the monomer comprises an optionally substituted 1,2-dihydroxybenzene moiety. In some embodiments, the monomer includes a 1,2-dihydroxyphenyl. In some embodiments, the monomer comprises an optionally substituted 1,2-dihydroxyphenyl.

[0070] In some embodiments, the monomer is a monomer based on 2-(3,4-dihydroxyphenyl)ethylamine. In certain embodiments, the monomer comprises a 3,4-dihydroxyphenylethylamine moiety. In certain embodiments, the monomer comprises an optionally substituted 3,4-dihydroxyphenylethylamine moiety. In certain embodiments, the monomer comprises 2-(3,4-dihydroxyphenyl)ethylamine. In certain embodiments, the monomer comprises an optionally substituted 2-(3,4-dihydroxyphenyl)ethylamine moiety.

[0071] In some embodiments, the monomer is selected from dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, derivatives thereof, and combinations thereof. In certain embodiments, the monomer is selected from dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester.

[0072] In certain embodiments, the monomer is a derivative of dopamine. In some embodiments, the monomer comprises dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, or levodopa ethyl ester.

[0073] In some embodiments, the derivative of monomer includes macromolecule.In some embodiments, monomer includes dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester or levodopa ethyl ester and at least one macromolecule.In certain embodiments, the macromolecule is alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate, chitosan or its combination.In certain embodiments, the macromolecule is alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate or chitosan.In certain embodiments, monomer includes (A) dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester or levodopa ethyl ester part, and it is combined with (B) alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate or chitosan. In certain embodiments, monomer comprises more than one dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester and levodopa ethyl ester moiety, which is combined with (B) alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate or chitosan. In certain embodiments, monomer comprises (A) more than one dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester and levodopa ethyl ester moiety, which is combined with (B) more than one alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate and chitosan.

[0074] In certain embodiments, the monomer is selected from the structures listed in Table 1 or 2.

[0075] Table 1: Monomers

[0076]

[0077] Table 2: Macromolecules

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084] In some embodiments, monomer is made up of a single type of monomer. In certain embodiments, monomer comprises a combination of monomers. In certain embodiments, monomer comprises a combination of monomers listed in Tables 1 and 2. In some embodiments, the combination of monomers is made up of two different monomers. In some embodiments, the combination of monomers is made up of three different monomers. In some embodiments, the combination of monomers is made up of four different monomers.

[0085] In some embodiments, the composition further comprises an agent selected from an active agent, a cosmetic agent, a nutrient, an imaging agent, a diagnostic agent, a radioprotectant, a nutrient, an enzyme, a nutrient blocker, an aptamer, an antibody, a neutralizer, and a combination thereof. In some embodiments, the composition further comprises an enzyme. In some embodiments, the composition further comprises a nutrient blocker. In some embodiments, the composition further comprises a radioprotectant. In some embodiments, the composition further comprises an active agent. In some embodiments, the composition further comprises a diagnostic agent. In some embodiments, the composition further comprises a combination of two or more enzymes, nutrient blockers, radioprotectants, active agents, and diagnostic agents.

[0086] In certain embodiments, the composition further comprises a buffer.

[0087] In some embodiments, the composition further comprises an exogenous catalyst.

[0088] In some embodiments, at least one of the monomer and the source of oxygen is stable in the stomach of a subject. In some embodiments, at least one of the monomer and the source of oxygen is stable in the stomach of a subject for at least 30 minutes. In some embodiments, at least one of the monomer and the source of oxygen is stable in the stomach of a subject for at least 60 minutes.

[0089] In some embodiments, the composition is stable in the stomach of the subject. In some embodiments, the composition is stable in the stomach of the subject for at least 30 minutes. In some embodiments, the composition is stable in the stomach of the subject for at least 60 minutes.

[0090] In some embodiments, at least one of the monomer and the oxygen source is stable in that it does not decompose in the stomach of a subject. In some embodiments, at least 95% of at least one of the monomer and the oxygen source remains after the composition passes through the stomach of a subject. In some embodiments, at least 90% of at least one of the monomer and the oxygen source remains after the composition passes through the stomach of a subject. In some embodiments, at least 80% of at least one of the monomer and the oxygen source remains after the composition passes through the stomach of a subject.

[0091] In some embodiments, the composition comprises about 0.001 to about 1000 mg / ml of monomer. In some embodiments, the composition comprises about 0.01 to about 100 mg / ml of monomer. In some embodiments, the composition comprises about 0.01 to about 50 mg / ml of monomer. In some embodiments, the composition comprises about 1 to about 20 mg / ml of monomer. In some embodiments, the composition comprises 10 mg / ml of monomer. In some embodiments, the composition comprises 20 mg / ml of monomer.

[0092] In some embodiments, the composition comprises about 0.01 to about 100 mM of an oxygen source. In some embodiments, the composition comprises about 0.1 to about 50 mM of an oxygen source. In some embodiments, the composition comprises about 1 to about 30 mM of an oxygen source. In some embodiments, the composition comprises about 20 mM of an oxygen source.

[0093] In some embodiments, the composition comprises a concentration of an oxygen source that is compatible with ingestion by a subject.

[0094] In some embodiments, the pH of the composition is about 7 to about 10. In some embodiments, the pH of the composition is about 7 to about 9. In some embodiments, the pH of the composition is about 8.5. In some embodiments, the pH of the composition is about 7.4.

[0095] In certain embodiments, the composition is administered directly to the target site of polymerization. In some embodiments, the composition is applied directly to the site of polymerization. In certain embodiments, the composition is administered to the eye where polymerization occurs. In some embodiments, the composition is administered indirectly to the target site of polymerization. In certain embodiments, the composition is administered orally and the site of polymerization is in the gastrointestinal tract. In some embodiments, the composition is administered by intra-articular injection and the site of polymerization is in the joint.

[0096] In some embodiments, the composition is administered by a route selected from oral, rectal, injection, sublingual, buccal, vaginal, ocular, otic, inhalation, or dermal. In some embodiments, the composition is administered orally. In certain embodiments, the composition is administered by intraarticular injection. In certain embodiments, the composition is administered topically. In certain embodiments, the composition is administered transdermally. In certain embodiments, the composition is administered ocularly.

[0097] In some embodiments, the composition is a liquid or solid dosage form.

[0098] In some embodiments, the composition is in the form of a solution, gel, tablet, powder, capsule, eye drops, foam, transdermal patch, or a combination thereof. In some embodiments, the composition is in the form of a solution, gel, tablet, or capsule. In some embodiments, the composition is in the form of a solution. In some embodiments, the composition is in the form of a solution. In some embodiments, the composition is in the form of eye drops. In some embodiments, the composition is in the form of a powder. In some embodiments, the composition is in the form of a transdermal patch.

[0099] In some embodiments, the polymer adheres to the tissue of the subject. In certain embodiments, the polymer forms and adheres to the tissue in the subject when in contact with the tissue in the subject. In some embodiments, the polymer adheres to the tissue of the subject.

[0100] In some embodiments, the location of polymer formation is based on the expression level of the catalyst. In certain embodiments, based on the high expression level of the catalyst, the polymer is substantially formed on a specific tissue. In some embodiments, due to the low expression level of the catalyst, the polymer is substantially not formed on a specific tissue. In some embodiments, the location of polymer formation is based on the expression level of catalase. In certain embodiments, the polymer is substantially formed on a specific tissue based on the expression level of catalase. In some embodiments, due to the low expression level of catalase, the polymer is substantially not formed on a specific tissue.

[0101] In certain embodiments, the polymer forms and adheres to tissue in one or more of the respiratory, urinary, lymphatic, circulatory, epidermal, skeletal, muscular, nervous, digestive, or endocrine systems. In certain embodiments, the polymer forms and adheres to tissue in contact with one or more of the following: the back portion of the tongue, buccal mucosa, lip mucosa, palate, nasal mucosa, conjunctiva, hypodermal tissue, muscle, tracheal mucosa, lung surface, lung tissue, gallbladder mucosa, gallbladder serosa, lining, cartilage, lymph nodes, bladder mucosa, bladder serosa, kidney surface, kidney tissue, endocardium, myocardium, pancreatic tissue, nerves, liver surface, liver tissue, spleen tissue, small intestine, colon, tongue ventral, sclera, epidermis, bladder serosa, epicardium, liver surface, esophagus, peritoneum, or stomach. In some embodiments, the polymer is formed in or on the back of the tongue, buccal mucosa, lip mucosa, palate, nasal mucosa, conjunctiva, hypodermis, muscle, tracheal mucosa, lung surface, lung tissue, gallbladder mucosa, gallbladder serosa, lining, cartilage, lymph nodes, bladder mucosa, bladder serosa, kidney surface, kidney tissue, endocardium, myocardium, pancreatic tissue, nerve, liver surface, liver tissue, spleen tissue, small intestine or colon. In some embodiments, the polymer is formed in or on the trachea, lung, kidney, bladder, lymph nodes, heart, blood vessels, skin, cartilage, muscle, nerve, mouth, liver, spleen, gallbladder, pancreas or small intestine. In certain embodiments, the polymer is formed on one or more of the tongue, buccal mucosa and lip mucosa. In some embodiments, the polymer is formed on the conjunctiva of the eye. In some embodiments, the polymer is formed on cartilage. In some embodiments, the polymer is formed on cartilage in the joint.

[0102] In some embodiments, the polymer does not substantially form on the ventral portion of the tongue. In some embodiments, the polymer does not substantially form on the palate. In some embodiments, the polymer does not substantially form on the sclera. In some embodiments, the polymer does not substantially form on the ventral portion of the tongue, sclera, epidermis, bladder serosa, epicardium, liver surface, esophagus, or stomach. In some embodiments, the polymer does not substantially form on the ventral portion of the tongue, sclera, epidermis, epicardium, esophagus, or stomach.

[0103] In certain embodiments, the tissue is an epithelium. In certain embodiments, the epithelium is an intestinal epithelium. In certain embodiments, the polymer is formed when in contact with the epithelium of the subject. In certain embodiments, the epithelium is an intestinal epithelium. In certain embodiments, the polymer is formed on the small intestine. In certain embodiments, the polymer is formed in the lumen of the small intestine. In certain embodiments, the polymer is formed on the epithelium of the duodenum of the subject.

[0104] In some embodiments, the polymer is formed on the epithelium of the gastrointestinal tract of the subject. In some embodiments, the polymer is formed on the epithelium of the small intestine of the subject.

[0105] In some embodiments, the polymer does not form on the epithelium of the gastrointestinal tract outside the small intestine of the subject.

[0106] In some embodiments, the polymer is formed on the epithelium of one or more of the duodenum, jejunum, ileum, colon, esophagus, or stomach of the subject. In some embodiments, the polymer is formed on the epithelium of the duodenum of the subject. In some embodiments, the polymer is formed on the epithelium of the jejunum of the subject. In some embodiments, the polymer is formed on the epithelium of the ileum of the subject. In some embodiments, the polymer is formed on the epithelium of the colon of the subject.

[0107] In some embodiments, the polymer is substantially not formed on the epithelium of one or more of the esophagus or stomach of the subject. In some embodiments, substantially no polymer is formed on the stomach and esophagus of the subject. In some embodiments, the polymer is not formed on the stomach and esophagus of the subject.

[0108] In some embodiments, less polymer is formed in the ileum and colon of the subject compared to the duodenum and jejunum of the subject.

[0109] In some embodiments, the polymer is formed on epithelial villi of a subject.

[0110] In some embodiments, the polymer is bound to a chemical moiety exposed on the surface of tissue in the respiratory, urinary, lymphatic, circulatory, integumentary, skeletal, muscular, nervous, digestive, or endocrine systems. In some embodiments, the polymer is bound to an amine moiety exposed on the surface of tissue in the respiratory, urinary, lymphatic, circulatory, integumentary, skeletal, muscular, nervous, digestive, or endocrine systems.

[0111] In some embodiments, the polymer is bound to an amine moiety exposed on a luminal surface of an epithelium of a subject. In some embodiments, the polymer is cross-linked to an amine moiety exposed on a luminal surface of an epithelium of a subject.

[0112] In some embodiments, the polymer forms quickly. In some embodiments, the polymer forms in less than about 20 minutes. In some embodiments, the polymer forms in less than about 15 minutes. In some embodiments, the polymer forms in less than about 12 minutes. In some embodiments, the polymer forms in less than about 10 minutes. In some embodiments, the polymer forms in less than about 5 minutes. In some embodiments, the polymer forms in less than about 3 minutes. In some embodiments, the polymer forms in less than about 2 minutes. In some embodiments, the polymer forms in less than about 1 minute. In some embodiments, the polymer forms almost immediately.

[0113] In some embodiments, the polymerization rate is increased by at least 10 times compared to the polymer formation without endogenous catalase. In some embodiments, the polymerization rate is increased by at least 50 times compared to the polymer formation without endogenous catalase. In some embodiments, the polymerization rate is increased by at least 100 times compared to the polymer formation without endogenous catalase. In some embodiments, the polymerization rate is increased by at least 150 times compared to the polymer formation without endogenous catalase. In some embodiments, the polymerization rate is increased by at least 200 times compared to the polymer formation without endogenous catalase.

[0114] In some embodiments, the polymer forms a transient barrier in vivo. In some embodiments, the polymer forms a transient barrier in vivo.

[0115] In some embodiments, the polymer lasts for about 30 minutes. In some embodiments, the polymer lasts for about 1 hour. In some embodiments, the polymer lasts for about 6 hours. In some embodiments, the polymer lasts for about 12 hours. In some embodiments, the polymer lasts for about 24 hours.

[0116] In some embodiments, about 20% to about 70% of the transient barrier still exists after 12 hours. In some embodiments, about 30% to about 50% of the transient barrier still exists after 12 hours. In some embodiments, about 20% of the transient barrier still exists after 12 hours. In some embodiments, about 20% to about 70% of the transient barrier still exists after 6 hours. In some embodiments, about 30% to about 50% of the transient barrier still exists after 6 hours. In some embodiments, about 20% of the transient barrier still exists after 6 hours. In some embodiments, about 20% to about 70% of the transient barrier still exists after 3 hours. In some embodiments, about 30% to about 50% of the transient barrier still exists after 3 hours. In some embodiments, about 20% of the transient barrier still exists after 3 hours.

[0117] In some embodiments, the polymer is cleared from the subject after about 3 hours. In some embodiments, the polymer is cleared from the subject after about 6 hours. In some embodiments, the polymer is cleared from the subject after about 12 hours. In some embodiments, the polymer is cleared from the subject after about 24 hours. In some embodiments, the polymer is cleared from the subject after about 48 hours.

[0118] In some embodiments, the polymer barrier provides selective molecular transport in a patient.

[0119] In some embodiments, the method is a method of modulating diffusion in a subject at a polymerization site. In some embodiments, the method modulates diffusion of one or more of a salt, ion, water, oxygen, carbon dioxide, carbonate anion, acid, base, carbohydrate, lipid, protein, nucleic acid, nutrient, or active agent in a subject.

[0120] In some embodiments, the polymer modulates the absorption of one or more nutrients or active pharmaceutical agents in the small intestine.

[0121] In some embodiments, the polymer substantially prevents absorption of one or more nutrients into the epithelium in which the polymer is formed, the intestinal wall of the subject, or the bloodstream of the subject.

[0122] In some embodiments, the method is a method of delivering an agent to a subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotectant.

[0123] In some embodiments, the method enables sustained release of an agent in a subject. In some embodiments, the agent is an active agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotectant. In certain embodiments, the method enables sustained release of an active agent in the conjunctiva of the eye. In certain embodiments, the method enables sustained release of an active agent in cartilage. In certain embodiments, the method enables sustained release of an active agent in the oral cavity.

[0124] In some embodiments, the method is a method of immobilizing an agent in a subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotectant.

[0125] In some embodiments, the method is a method of locally delivering an agent in a subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotectant.

[0126] In some embodiments, the method is a method of reducing the frequency of administration of an agent. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotectant.

[0127] In some embodiments, the method is a method of increasing the half-life of an agent in a subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotectant.

[0128] In some embodiments, the method is a method of increasing the retention time of an agent in a subject. In some embodiments, the agent is an active pharmaceutical agent. In some embodiments, the agent is an enzyme. In some embodiments, the agent is a radioprotectant.

[0129] In some embodiments, the method is a method of treating or preventing a disease in a subject. In some embodiments, the method is a method of treating a disease in a subject. In some embodiments, the method is a method of preventing a disease in a subject.

[0130] In some embodiments, the method is a method of assisting tissue restoration and regeneration at a subject aggregation site. In some embodiments, the method is a method of assisting tissue restoration at a subject aggregation site. In some embodiments, the method is a method of assisting tissue regeneration at a subject aggregation site.

[0131] In some embodiments, the method maintains the intestinal lumen of the subject distended.

[0132] In some embodiments, the method is a method of preventing intestinal adhesion in a subject.

[0133] In some embodiments, the method is a method of preventing intestinal obstruction in a subject.

[0134] In some embodiments, the method is a method of treating bleeding in a subject. In some embodiments, the bleeding is in the upper gastrointestinal tract.

[0135] In some embodiments, the polymers and compositions further comprise an enzyme. In some embodiments, the enzyme is a digestive enzyme. In some embodiments, the digestive enzyme is lactase, peptidase, sucrase, maltase, amylase, lipase, or protease. In some embodiments, the digestive enzyme is β-galactosidase.

[0136] In some embodiments, the method is a method of increasing digestive efficiency in a subject.

[0137] In some embodiments, the method is a method of increasing a subject's digestion of sugars. In some embodiments, the method is a method of enhancing a subject's digestion of lactose.

[0138] In some embodiments, the method is a method of treating lactose intolerance in a subject.

[0139] In some embodiments, the enzyme increases the digestion efficiency of sugars in a subject by about 5 times. In some embodiments, the enzyme increases the digestion efficiency of sugars in a subject by about 10 times. In some embodiments, the enzyme increases the digestion efficiency of sugars in a subject by about 20 times. In some embodiments, the enzyme increases the digestion efficiency of lactose in a subject by about 40 times. In some embodiments, the enzyme increases the digestion efficiency of sugars in a subject by about 50 times.

[0140] In some embodiments, the β-galactosidase increases the efficiency of lactose digestion in a subject by about 5 times. In some embodiments, the β-galactosidase increases the efficiency of lactose digestion in a subject by about 10 times. In some embodiments, the β-galactosidase increases the efficiency of lactose digestion in a subject by about 20 times. In some embodiments, the β-galactosidase increases the efficiency of lactose digestion in a subject by about 40 times. In some embodiments, the β-galactosidase increases the efficiency of lactose digestion in a subject by about 50 times.

[0141] In some embodiments, the polymeric barrier does not inhibit the intrinsic digestive enzyme activity of the subject's epithelium.

[0142] In some embodiments, the polymers and compositions further comprise a nutrient blocker.

[0143] In some embodiments, the method is a method of preventing nutrient absorption in a subject.

[0144] In some embodiments, the method is a method for adjusting or regulating a subject's sugar absorption. In some embodiments, the sugar is selected from glucose, lactose, fructose, maltose, dextrose, galactose, sucrose and isomaltose. In some embodiments, the method is a method for adjusting or regulating a subject's glucose absorption.

[0145] In some embodiments, the method prevents absorption for less than about 48 hours. In some embodiments, the method prevents absorption for less than about 24 hours. In some embodiments, the method prevents absorption for less than about 12 hours. In some embodiments, the method prevents absorption for less than about 6 hours. In some embodiments, the method prevents absorption for less than about 3 hours.

[0146] In some embodiments, the method is a method of treating obesity in a subject.

[0147] In some embodiments, the method is a method of treating hyperinsulinemia in a subject.

[0148] In some embodiments, the method is a method of treating diabetes in a subject. In some embodiments, the diabetes is type 2 diabetes.

[0149] In some embodiments, the method is a method of treating nonalcoholic fatty liver disease. In some embodiments, the method is a method of treating nonalcoholic steatohepatitis.

[0150] In some embodiments, the composition further comprises a cross-linking agent.

[0151] In some embodiments, the crosslinking agent comprises nanoparticles. In some embodiments, the crosslinking agent comprises polydopamine. In some embodiments, the crosslinking agent is a nutrient blocking agent. In some embodiments, the crosslinking agent increases the nutrient blocking ability of the polymer.

[0152] In some embodiments, glucose absorption is modulated by adjusting the cross-link density of the polymer.

[0153] In some embodiments, the method reduces the absorption of glucose by the subject by at least about 50%, at least about 60%, or at least about 70% within 3 hours after administration of the composition. In some embodiments, the method reduces the absorption of glucose by the subject by at least about 70% within 3 hours after administration of the composition. In some embodiments, the method reduces the absorption of glucose by the subject by at least about 50%, at least about 60%, or at least about 70% within 2 hours after administration of the composition. In some embodiments, the method reduces the absorption of glucose by the subject by at least about 50%, at least about 60%, or at least about 70% within 1 hour after administration of the composition.

[0154] In some embodiments, the method is a method of regulating or modulating nutrient absorption in a subject.

[0155] In some embodiments, the composition further comprises an active agent. In some embodiments, the active agent treats infectious diseases. In some embodiments, the active agent is an antiparasitic drug. In some embodiments, the active agent is an anthelmintic. In some embodiments, the active agent is praziquantel. In some embodiments, the active agent is an antiviral drug. In some embodiments, the active agent treats influenza. In some embodiments, the active agent treats SARS-CoV-2.

[0156] In certain embodiments, the active pharmaceutical ingredient is a contraceptive, a statin, an antihypertensive, or an antibiotic.

[0157] In some embodiments, the active agent treats a psychiatric disorder, Alzheimer's disease, an infectious disease, or transplant rejection.

[0158] In some embodiments, the active agent treats type 2 diabetes.

[0159] In some embodiments, the active agent treats non-alcoholic fatty liver disease. In some embodiments, the active agent treats non-alcoholic steatohepatitis.

[0160] In some embodiments, the active agent treats an eye disease.

[0161] In some embodiments, the active agent treats Crohn's disease.

[0162] In some embodiments, the active agent treats osteoarthritis.

[0163] In some embodiments, the active agent treats Alzheimer's disease.

[0164] In some embodiments, the active agent is an anticancer agent. Anticancer agents include biotherapeutic anticancer agents and chemotherapeutic agents. Exemplary biotherapeutic anticancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serum therapy, immunostimulants and / or immunomodulators (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF), and antibodies (e.g., HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplary chemotherapeutic agents include, but are not limited to, antiestrogens (e.g., tamoxifen, raloxifene, and megestrol acetate), LHRH agonists (e.g., goserelin and leuprolide), antiandrogens (e.g., flutamide and bicalutamide), photodynamic therapy (e.g., vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and desmethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkyl sulfonates (e.g., busulfan and treoxazole), triazenes (e.g., dacarbazine, temozolomide), platinum-containing compounds (e.g., cisplatin, carboplatin, oxadiazine, tadalafil ... vinorelbine), vinca alkaloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine), taxanes (e.g., paclitaxel or paclitaxel equivalents such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamic acid-bound paclitaxel (PG-paclitaxel, polyglutamic acid paclitaxel, CT-2103, XYOTAX), tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 conjugated to three paclitaxel molecules), paclitaxel-EC-1 (paclitaxel conjugated to the erbB2-recognition peptide EC-1), and glucose-conjugated paclitaxel, such as 2'-paclitaxel methyl 2-pyranosyl glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mitomycin C), antimetabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, thiazofurine, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, raltitrexed, tegafururacil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside (cytosine arabinoside) and fludarabine), purine analogs (e.g. mercaptopurine and thioguanine), vitamin D3 analogs (e.g. EB 1089, CB1093 and KH1060), prenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycins (e.g. actinomycin D, dactinomycin), bleomycins (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracyclines (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca; 2+ ATPase inhibitors (eg, thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (eg, axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN TM , AZD2171), dasatinib ( BMS-354825), erlotinib Gefitinib Imatinib ( CGP57148B, STI-571), lapatinib Lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib semaxinib (semaxinib, SU5416), sunitinib ( SU11248), toceranib Vandetanib ZD6474), varanib (PTK787, PTK / ZK), trastuzumab Bevacizumab Rituximab Cetuximab Panitumumab Ranibizumab Nilotinib Sorafenib Everolimus Alemtuzumab Gemtuzumab ozogamicin Temsirolimus ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW2992 (TOVOK TM ), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647 and / or XL228, proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), rifolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe), and OSI-027 (OSI), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbazine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methylpterin, porfibrinocin, melphalan, isovistrine, vinblastine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine.

[0165] In certain embodiments, the active agent is selected from, but not limited to, antiproliferative agents, anticancer agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressants, antibacterial agents, antiviral agents, cardiovascular agents, cholesterol lowering agents, antidiabetic agents, antiallergic agents, contraceptive agents, and analgesics. In certain embodiments, the active agent is an antiproliferative agent. In certain embodiments, the active agent is an anticancer agent. In certain embodiments, the active agent is an antiviral agent.

[0166] Exemplary active pharmaceutical agents include, but are not limited to, antibiotics, antivirals, anesthetics, anticoagulants, enzyme inhibitors, steroids, steroidal or nonsteroidal anti-inflammatory agents, antihistamines, immunosuppressants, antigens, vaccines, antibodies, decongestants, sedatives, opioids, pain relievers, analgesics, antipyretics, hormones, and prostaglandins, etc. Active pharmaceutical agents include small organic molecules, such as pharmaceutical compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0167] In certain embodiments, the active agent is an antibiotic. Exemplary antibiotics include, but are not limited to, penicillins (e.g., penicillin, amoxicillin), cephalosporins (e.g., cephalexin), macrolides (e.g., erythromycin, clarithromycin, azithromycin, troleandomycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin), sulfonamides (e.g., trimethoprim), tetracyclines (e.g., tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, chlortetracycline, oxytetracycline, minocycline, 6-deoxytetracycline, lymecycline, meclocycline, methacycline, hydropyracycline, and glycylcycline antibiotics (e.g., tigecycline)), aminoglycosides (e.g., gentamicin, tobramycin, paromomycin), aminocyclines (e.g., spectinomycin), chloramphenicol, sparsemycin, and quinupristin / dalfoprisin (Syndercid TM ). In certain embodiments, the antibiotic is a ribosome-targeting antibiotic.

[0168] In some embodiments, the active agent is retained or encapsulated in the polymer. In some embodiments, the active agent is retained on the polymer.

[0169] In some embodiments, the method is a method of extending the residence time of an active agent in a subject compared to administration of the active agent in the absence of a polymer. In some embodiments, the method is a method of extending the residence time of an active agent at a polymerized site in a subject compared to administration of the active agent in the absence of a polymer.

[0170] In some embodiments, the method is one that provides sustained release of the active agent compared to administration of the active agent in the absence of a polymer.

[0171] In some embodiments, the method is a method of reducing the frequency of administration of the active agent compared to administering the active agent in the absence of a polymer. In some embodiments, the frequency of administration is once a day. In some embodiments, the frequency of administration is twice a day.

[0172] In some embodiments, the method is a method of increasing the half-life of an active agent compared to administering the active agent without a polymer. In some embodiments, the method increases the half-life of an active agent by at least about 2 times compared to administering the active agent without a polymer. In some embodiments, the method increases the half-life of an active agent by at least about 4 times compared to administering the active agent without a polymer. In some embodiments, the method increases the half-life of an active agent by at least about 6 times compared to administering the active agent without a polymer. In some embodiments, the method increases the half-life of an active agent by at least about 10 times compared to administering the active agent without a polymer.

[0173] In some embodiments, the method is a method of increasing the AUC of the active agent compared to administration of the active agent in the absence of a polymer. In some embodiments, the method increases the AUC by at least about 2-fold compared to administration of the active agent in the absence of a polymer. In some embodiments, the method increases the AUC by at least about 3-fold compared to administration of the active agent in the absence of a polymer. In some embodiments, the method increases the AUC by at least about 4-fold compared to administration of the active agent in the absence of a polymer.

[0174] In some embodiments, the method is to modulate the C of the active agent compared to administering the active agent in the absence of the polymer. max In certain embodiments, the method of regulating is increasing. In certain embodiments, the method of regulating is decreasing.

[0175] In some embodiments, the method is to modulate the T of the active agent compared to administration of the active agent in the absence of the polymer. maxIn certain embodiments, the method of regulating is increasing. In certain embodiments, the method of regulating is decreasing.

[0176] In some embodiments, the method does not affect drug metabolism once the active agent is absorbed by the small intestine.

[0177] In some embodiments, the method is a method of treating schistosomiasis in a subject.

[0178] In some embodiments, the composition further comprises a radioprotectant. In certain embodiments, the radioprotectant is an antioxidant, a thiol-containing compound, or a nitrogen oxide. In certain embodiments, the radioprotectant is thalidomide, cysteine, amifostine, palifermin, or 1-carnitine. In certain embodiments, the radioprotectant is thalidomide.

[0179] In some embodiments, the nutritional agent is vitamin D or iron.

[0180] In some embodiments, the methods provide for targeting the small intestine.

[0181] In some embodiments, the method is a method of reducing small intestinal uptake. In some embodiments, the method is a method of reducing small intestinal uptake of one or more nutrients and active agents. In some embodiments, the method is a method of reducing small intestinal uptake of one or more nutrients. In some embodiments, the method is a method of reducing small intestinal uptake of one or more active agents.

[0182] In some embodiments, the method is a method of increasing the retention time in the small intestine. In some embodiments, the method is a method of increasing the retention time of one or more nutrients and active agents in the small intestine. In some embodiments, the method is a method of increasing the retention time of one or more nutrients in the small intestine. In some embodiments, the method is a method of increasing the retention time of one or more active agents in the small intestine.

[0183] In some embodiments, the method maintains the intestinal lumen distended.

[0184] In some embodiments, the method is a method of treating or preventing intestinal adhesions in a subject. In some embodiments, the method is a method of preventing intestinal adhesions in a subject.

[0185] In some embodiments, the method is a method of treating or preventing intestinal obstruction in a subject. In some embodiments, the method is a method of preventing intestinal obstruction in a subject.

[0186] In some embodiments, the method is a method for treating bleeding in a subject. In some embodiments, the method is a method for treating small intestinal bleeding in a subject. In some embodiments, the bleeding is in the upper gastrointestinal tract. In some embodiments, the bleeding is in the stomach. In some embodiments, the method for treating bleeding is a method for treating hemostasis.

[0187] In some embodiments, the polymer regulates absorption in the small intestine. In some embodiments, the polymer regulates absorption of one or more nutrients or active agents or a combination thereof in the small intestine. In some embodiments, the polymer regulates absorption of one or more nutrients and active agents in the small intestine. In some embodiments, the polymer regulates absorption of one or more nutrients in the small intestine. In some embodiments, the polymer regulates absorption of one or more active agents in the small intestine.

[0188] In some embodiments, the polymer modulates digestion in the small intestine. In some embodiments, the polymer modulates digestion of one or more nutrients in the small intestine.

[0189] In certain embodiments, the polymer substantially blocks absorption in the small intestine. In some embodiments, the polymer substantially blocks one or more nutrients or active agents or combinations thereof from being absorbed into the epithelium on which the polymer is formed. In some embodiments, the polymer substantially blocks one or more nutrients from being absorbed into the epithelium on which the polymer is formed. In some embodiments, the polymer substantially blocks one or more active agents from being absorbed into the epithelium on which the polymer is formed.

[0190] In some embodiments, the polymer substantially blocks one or more nutrients or active agents or a combination thereof from being absorbed into the intestinal wall of a subject. In some embodiments, the polymer substantially blocks one or more nutrients from being absorbed into the intestinal wall of a subject. In some embodiments, the polymer substantially blocks one or more active agents from being absorbed into the intestinal wall of a subject.

[0191] In some embodiments, the polymer substantially blocks the absorption of one or more nutrients or active agents or a combination thereof into the bloodstream of a subject. In some embodiments, the polymer substantially blocks the absorption of one or more nutrients into the bloodstream of a subject. In some embodiments, the polymer substantially blocks the absorption of one or more active agents into the bloodstream of a subject.

[0192] In some embodiments, the method is a method of immobilizing an enzyme in a subject.

[0193] In some embodiments, the method is a method of delivering an active pharmaceutical agent to a subject.

[0194] In some embodiments, the method is a method of supplementing a subject's digestion.

[0195] In some embodiments, the polymer induces gelation of blood. In some embodiments, the polymer induces coagulation. In some embodiments, the composition is in powder form. In some embodiments, the method comprises spraying the powder onto the subject or onto the diseased area in the subject.

[0196] In some embodiments, the composition is administered by a scope. In certain embodiments, the composition is administered by an endoscope, arthroscope, cystoscope, colposcope, colonoscope, bronchoscope, ureteroscope, anoscope, esophagoscope, gastroscope, laparoscope, laryngoscope, neuroendoscope, proctoscopy, sigmoidoscope or thoracoscope.

[0197] In some embodiments, the polymer is non-toxic. In some embodiments, the composition is non-toxic. In some embodiments, the composition and its components are non-toxic.

[0198] In some embodiments, polymer is stable to physical and chemical forces. In some embodiments, polymer is stable to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol and saline. In some embodiments, polymer is decomposed less than about 25% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol or saline. In some embodiments, polymer is decomposed less than about 20% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol or saline. In some embodiments, polymer is decomposed less than about 10% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol or saline. In some embodiments, polymer is decomposed less than about 5% when exposed to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol or saline. In some embodiments, physical force is selected from one or more of peristalsis and segmentation (segmentation).

[0199] In another aspect, the present disclosure provides a method of treating a disease or disorder comprising administering to a subject in need thereof an effective amount of a composition described herein.

[0200] The present disclosure further provides methods of preventing a disease or disorder comprising administering to a subject in need thereof an effective amount of a composition described herein.

[0201] In some embodiments, the disease or disorder is an eye disease, an arthropathy, a metabolic disorder, a systemic disease, a digestive disorder, a cancer, a hemorrhage, an ulcer, an intestinal obstruction, an infectious disease, mesenteric ischemia, obesity, a psychiatric disorder, Alzheimer's disease, or a transplant rejection. In some embodiments, the disease or disorder is an eye disease, an arthropathy, a metabolic disorder, a systemic disease, a digestive disease, a cancer, a hemorrhage, an ulcer, an intestinal obstruction, an infectious disease, mesenteric ischemia, or obesity. In some embodiments, the disease or disorder is a psychiatric disorder, Alzheimer's disease, or a transplant rejection.

[0202] In some embodiments, the disease is cancer. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangioepithelial carcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast carcinoma, breast medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; Chordoma; Craniopharyngioma; Colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); Connective tissue cancer; Epithelial cancer; Ependymoma; Endothelial sarcoma (e.g., Kaposi sarcoma, multiple idiopathic hemorrhagic sarcomas); Endometrial cancer (e.g., uterine cancer, uterine sarcoma); Esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing sarcoma; Eye cancer (e.g., intraocular melanoma, retinoblastoma); Familial eosinophilia; Gallbladder cancer; Gastric cancer (e.g., gastric adenocarcinoma); Gastrointestinal stromal tumors (GIST); Germ cell cancer; Head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), Laryngeal cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancer (e.g., leukemias, such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomas, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); mixed conditions of one or more of the above leukemias / lymphomas; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease ); hemangioblastoma; hypopharyngeal cancer; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney cancer (e.g., Wilms' tumor, also known as Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); myoma; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown cause (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine tumors (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NET, carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell carcinoma); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell tumor; paraneoplastic syndrome (paraneoplastic syndromes); intraepithelial neoplasia; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma);Thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva). ;

[0203] In some embodiments, the disease is glaucoma.

[0204] In some embodiments, the metabolic disorder is hyperinsulinemia.

[0205] In some embodiments, the digestive disease is Crohn's disease, ulcerative colitis, malabsorption, inflammatory bowel disease, irritable bowel syndrome, lactose intolerance, or celiac disease. In some embodiments, the disease is Crohn's disease.

[0206] In some embodiments, the disease is a psychiatric disorder.

[0207] In some embodiments, the disease is Alzheimer's disease.

[0208] In some embodiments, the disorder is transplant rejection.

[0209] In some embodiments, the systemic disease is an autoimmune disease. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, nodular periarteritis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis / polymyositis, antiphospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjögren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

[0210] In some embodiments, the systemic disease is mastocytosis, chronic fatigue syndrome, systemic vasculitis, sarcoidosis, hypothyroidism, diabetes, fibromyalgia, adrenal insufficiency, celiac disease, ulcerative colitis, Crohn's disease, hypertension, metabolic syndrome, AIDS, Graves' disease, systemic lupus erythematosus, arthritis, atherosclerosis, sickle cell disease, myasthenia gravis, systemic sclerosis, inflammatory disease, or sinusitis.

[0211] In some embodiments, the disease is an inflammatory disease. Inflammatory diseases include, but are not limited to, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendinitis, bursitis, psoriasis, cystic fibrosis, osteoarthritis, rheumatoid arthritis, inflammatory arthritis, Sjögren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory skin diseases, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory skin diseases, hepatitis, delayed hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, respiratory distress in adults syndrome (ARDS), encephalitis, immediate hypersensitivity reaction, asthma, hay fever, allergy, acute allergic reaction, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis , ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis and necrotizing enterocolitis. Inflammatory eye diseases include, but are not limited to, postoperative inflammation. In some embodiments, the disease is inflammatory joint disease. In some embodiments, the disease is arthritis. In certain embodiments, the disease is osteoarthritis. In some embodiments, the disease is rheumatoid arthritis.

[0212] In some embodiments, the disease is conjunctivitis.

[0213] In some embodiments, the disease is aphthous stomatitis.

[0214] In some embodiments, the disease is obesity, hyperinsulinemia, or diabetes. In some embodiments, the disease is obesity. In some embodiments, the disease is hyperinsulinemia. In some embodiments, the disease is diabetes. In some embodiments, the disease is type 2 diabetes. In some embodiments, the disease is nonalcoholic fatty liver disease. In some embodiments, the disease is nonalcoholic steatohepatitis.

[0215] In some embodiments, the disease is an infectious disease. In some embodiments, the disease is a bacterial, viral, fungal, or parasitic infection. In some embodiments, the disease is a parasitic disease. In some embodiments, the disease is giardiasis, ascariasis, or a tapeworm infection. In some embodiments, the disease is schistosomiasis. In some embodiments, the disease is a viral infection. In some embodiments, the disease is influenza. In some embodiments, the disease is SARS-COV-2 (COVID-19).

[0216] In some embodiments, the disease is lactose intolerance.

[0217] In certain embodiments, the disease or disorder is mucosal damage. In some embodiments, the mucosal damage is caused by an external agent. In certain embodiments, the mucosal damage is associated with radiation or chemotherapy. In certain embodiments, the mucosal damage is caused by radiation or chemotherapy. In some embodiments, the disease or disorder is mucositis.

[0218] In some embodiments, the disorder is intestinal obstruction. In some embodiments, the disorder is intestinal adhesion. In certain embodiments, the methods and compositions described herein prevent re-adhesion and / or re-obstruction of the intestine.

[0219] In some embodiments, the disease is trauma.

[0220] In some embodiments, the disease is Alzheimer's disease.

[0221] In certain embodiments, the polymers and compositions provided herein are contraceptives.

[0222] In certain embodiments, the disease is trauma.

[0223] On the other hand, the present disclosure provides the use of a composition in forming a polymer in vivo, comprising administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source are in contact with a catalyst endogenous to the subject in vivo, and the catalyst polymerizes the monomer, or a salt thereof in situ, and wherein the oxygen source is hydrogen peroxide or urea hydrogen peroxide, and the endogenous catalyst is selected from catalase or peroxidase. In an embodiment, provided is the use of a composition in forming a polymer in vivo, comprising administering to a subject a composition comprising a monomer and an oxygen source, wherein the monomer and the oxygen source are in contact with a catalyst endogenous to the subject in vivo, and the catalyst polymerizes the monomer, or a salt thereof in situ, and wherein the endogenous catalyst is selected from catalase or peroxidase.

[0224] In one aspect, the present disclosure provides for the use of an effective amount of a composition described herein for treating a disease or disorder in a subject in need thereof.

[0225] In another aspect, the present disclosure provides use of an effective amount of a composition described herein to prevent a disease or disorder in a subject in need thereof.

[0226] Composition

[0227] In certain aspects, further provided herein are compositions comprising a monomer, an oxygen source, optionally a buffer, and optionally a reagent. In some embodiments, the composition further comprises an exogenous catalyst.

[0228] In some embodiments, the composition comprises a monomer selected from dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, or a monomer comprising: dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester or levodopa ethyl ester; and a macromolecule selected from one or more of alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate or chitosan; an oxygen source; optionally, a buffer; and optionally, an agent. In some embodiments, the agent is selected from an active pharmaceutical agent, a cosmetic agent, a nutrient, an imaging agent, a radioprotectant, a nutrient, an enzyme, an aptamer, an antibody, a neutralizer or a nutrient blocking agent.

[0229] In some embodiments, the composition comprises about 0.001 to about 1000 mg / ml of monomer, about 0.01 to about 100 mM of an oxygen source, and optionally, a buffer.

[0230] In some embodiments, the composition comprises about 0.001 to about 1000 mg / ml of monomer. In some embodiments, the composition comprises about 0.001 to about 500 mg / ml of monomer. In some embodiments, the composition comprises about 0.01 to about 100 mg / ml of monomer. In some embodiments, the composition comprises about 1 to about 20 mg / ml of monomer. In some embodiments, the composition comprises about 10 mg / ml of monomer. In some embodiments, the composition comprises about 20 mg / ml of monomer.

[0231] In some embodiments, the composition comprises 10 mg / ml of a monomer selected from Table 1. In certain embodiments, the composition comprises 10 mg / ml of a monomer selected from Table 1 and 10 mg / ml of a monomer selected from Table 2. In certain embodiments, the composition comprises 10 mg / ml of a monomer selected from Table 1 and 5 mg / ml of each of two separate monomers selected from Table 2.

[0232] In some embodiments, the composition comprises about 0.01 to about 100 mM of an oxygen source. In some embodiments, the composition comprises about 0.1 to about 50 mM of an oxygen source. In some embodiments, the composition comprises about 1 to about 30 mM of an oxygen source. In some embodiments, the composition comprises about 20 mM of an oxygen source. In some embodiments, the composition comprises an oxygen source concentration compatible with ingestion by the subject.

[0233] In some embodiments, the pH of the composition is about 7 to about 10. In some embodiments, the pH of the composition is about 7 to about 9. In some embodiments, the pH of the composition is about 8.5. In some embodiments, the pH of the composition is about 7.4.

[0234] In some embodiments, the composition comprises about 10 mg / ml monomer, about 20 mM hydrogen peroxide or urea hydrogen peroxide, and optionally, a buffer. In some embodiments, the composition comprises about 20 mg / ml monomer, about 20 mM hydrogen peroxide or urea hydrogen peroxide, and optionally, a buffer.

[0235] In some embodiments, the buffer comprises phosphate, acetate, citrate, N-[tris(hydroxymethyl)methyl]glycine), (tris(hydroxymethyl)aminomethane), or (2-(bis(2-hydroxyethyl)amino)acetic acid). In some embodiments, the buffer comprises tris(hydroxymethyl)aminomethane.

[0236] In some embodiments, the composition is a liquid or solid dosage form. In some embodiments, the composition is in the form of a solution, foam, gel, tablet or capsule, or a combination thereof.

[0237] In another aspect, the present disclosure provides a method for treating bleeding, comprising administering an effective amount of a composition as described herein to a subject in need thereof. In some embodiments, the bleeding is in the upper gastrointestinal tract. In certain embodiments, the bleeding is in the stomach. In some embodiments, the method for treating bleeding is a method for treating hemostasis.

[0238] Reagent test kit

[0239] The present disclosure also includes kits (eg, pharmaceutical packs). The provided kits can include a composition described herein and a container (eg, a vial, ampoule, bottle, syringe and / or dispenser package, or other suitable container).

[0240] The present disclosure also provides a kit. On the one hand, the present disclosure provides a kit comprising: a composition as described herein, and instructions for administering the composition to a subject. In some embodiments, the composition comprises: a monomer as described herein; an oxygen source as described herein; optionally, a buffer as described herein; and optionally, one or more reagents as described herein. In some embodiments, the composition comprises: a monomer; an oxygen source; optionally, a buffer; and optionally, one or more reagents; and instructions for administering the monomer and oxygen source and optionally, the buffer and / or one or more reagents to a subject, so that the monomer and oxygen source are in contact with a catalyst endogenous to the subject in vivo, and wherein the catalyst polymerizes the monomer in situ. In some embodiments, the kit also comprises an exogenous catalyst.

[0241] In some embodiments, the kit provided may optionally further comprise a second container comprising a pharmaceutical excipient for diluting or suspending a composition described herein. In some embodiments, the composition described herein provided in the first container and the second container are combined to form a unit dosage form.

[0242] Thus, in one aspect, a kit is provided, comprising a first container comprising a composition as described herein. In certain embodiments, the kit can be used to treat a disease in a subject in need thereof. In certain embodiments, the kit can be used to prevent a disease in a subject in need thereof. In certain embodiments, the kit can be used to reduce the risk of a disease in a subject in need thereof.

[0243] In certain embodiments, the kit described herein also includes instructions for using the kit. Kits described herein may also include information required by regulatory agencies such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kit is prescription information. In certain embodiments, the kit and instructions are provided for the treatment of a disease of a subject in need thereof. In certain embodiments, the kit and instructions are provided for the prevention of disease (in a subject in need thereof). In certain embodiments, the kit and instructions are provided for the reduction of the risk of disease occurring in a subject in need thereof. Kits described herein may include one or more additional reagents described herein as a separate composition.

[0244] Application

[0245] The methods and uses described herein comprise administering to a subject an effective amount of a composition comprising a monomer and an oxygen source (ie, forming a polymer in situ (eg, to treat or prevent a disease).

[0246] In some embodiments, the composition is administered orally. In some embodiments, the composition is a liquid or solid dosage form. In some embodiments, the composition is in the form of a solution, gel, foam, tablet or capsule, or a combination thereof.

[0247] In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is an effective amount for treating an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an infectious disease in a subject in need thereof. In certain embodiments, the effective amount is a preventive effective amount. In certain embodiments, the effective amount is an amount effective for treating a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a proliferative disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a hematological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a pain condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a pain condition in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a psychiatric disorder in a subject in need thereof. In certain embodiments, an effective amount is an amount that effectively prevents a psychiatric disorder in a subject in need thereof. In certain embodiments, an effective amount is an amount that effectively treats a metabolic disorder in a subject in need thereof. In certain embodiments, an effective amount is an amount that effectively prevents a metabolic disorder in a subject in need thereof. In certain embodiments, an effective amount is an amount that effectively reduces the risk of a disease (e.g., infectious disease, proliferative disease, hematological disease, neurological disease, pain disorder, psychiatric disorder or metabolic disorder) in a subject in need thereof. In certain embodiments, an effective amount is an amount that effectively suppresses the activity (e.g., abnormal activity, e.g., increased activity) of an organism in a subject or cell.

[0248] In certain embodiments, the subject is an animal. The animal can be of any gender and can be at any stage of development. In certain embodiments, the subject described herein is a person. In some embodiments, the subject is an adult. In certain embodiments, the subject is a child. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cattle, pig, horse, sheep or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cattle, pig, horse, sheep or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mouse and transgenic pig). In certain embodiments, the subject is a fish or a reptile.

[0249] The composition can be prepared, packaged and / or sold in bulk as a single unit dose and / or as multiple single unit doses. A "unit dose" is a discrete amount of a composition containing a predetermined amount of an agent or active ingredient. The amount of an agent or active ingredient is generally equal to the dose of the agent or active ingredient to be administered to a subject and / or a convenient portion of such a dose, such as one-half or one-third of such a dose.

[0250] Although the description of the compositions provided herein is primarily directed to compositions suitable for administration to humans, it will be appreciated by those skilled in the art that such compositions are generally suitable for administration to animals of all kinds. In order to make the compositions suitable for administration to various animals, modifications of the compositions suitable for administration to humans are well known, and such modifications can be designed and / or performed by ordinary skilled veterinary pharmacists using ordinary experiments.

[0251] The compositions provided herein are generally formulated in dosage unit form for ease of administration and uniformity of dosage. However, it should be understood that the total daily dosage of the compositions described herein will be determined by the physician within the scope of reasonable medical judgment. The specific therapeutically effective dosage level for any particular subject or organism will depend on a variety of factors, including the disease being treated, and the severity of the disorder; the activity of the specific agent or active ingredient used; the specific composition used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and the excretion rate of the specific agent or active ingredient used; the duration of treatment; the drugs used in combination or concurrently with the specific agent or active ingredient used; and similar factors well known in the medical field.

[0252] The compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, ocular, intravaginal, intraperitoneal, topical, mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation and / or inhalation; and / or as oral spray, nasal spray and / or aerosol. Moreover, the approach considered is to apply directly to the diseased site. Generally, the most suitable route of administration will depend on a variety of factors, including the nature of the reagent (e.g., its stability in the gastrointestinal environment), and / or the condition of the subject (e.g., whether the subject can tolerate oral administration). In some embodiments, the route of administration is local (to the skin, eyes, ears, mouth or diseased site).

[0253] The exact amount of the reagent or active ingredient required to reach an effective amount varies from subject to subject, depending on, for example, the species, age and general condition of the subject, the severity of the side effects or obstacles, the characteristics of the specific reagent or active ingredient, the mode of administration, etc. The effective amount may be included in a single dose (e.g., a single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or multiple doses are applied to a tissue or cell, any two doses of the multiple doses include different amounts or substantially the same amount of reagents or active ingredients as described herein. In certain embodiments, when multiple doses are administered to a subject or multiple doses are applied to a tissue or cell, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every three days, one dose a week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is one dose a day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is two doses a day. In certain embodiments, the frequency of administering multiple doses to a subject or applying multiple doses to a tissue or cell is three doses a day. In certain embodiments, when administering multiple doses to a subject or applying multiple doses to a tissue or cell, the time span between the first dose of multiple doses and the last dose is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years or the life of a subject, tissue or cell. In certain embodiments, the time span between the first dose of multiple doses and the last dose is three months, six months or one year. In certain embodiments, the time span between the first dose of multiple doses and the last dose is the life of a subject, tissue or cell.

[0254] The compositions described herein can be administered in combination with one or more additional agents (e.g., therapeutic and / or prophylactic agents). The compositions can be administered in combination with additional agents that increase their activity (e.g., treating a disease in a subject in need thereof, preventing a disease in a subject in need thereof, reducing the risk of disease in a subject in need thereof, and / or inhibiting the activity of an organism in a subject or cell (e.g., efficacy and / or effectiveness)), increase bioavailability, increase safety, reduce drug resistance, reduce and / or improve metabolism, inhibit excretion, and / or improve distribution. It should also be understood that the treatment used can achieve the desired effect on the same condition, and / or different effects can be achieved.

[0255] The compositions can be administered simultaneously with, before or after one or more additional pharmaceutical agents, which can be used, for example, as a combination therapy.

[0256] Example

[0257] In order to more fully understand the present disclosure, the following examples are listed.The synthetic and biological examples described in this application are intended to illustrate the compounds, pharmaceutical compositions, methods and uses provided herein, and are not to be construed in any way as limiting their scope.

[0258] Example 1: Evaluation of CAT-accelerated polymer assembly in vivo

[0259] To develop a comprehensive TPA-positive tissue map, fresh tissues from 10 major body systems were collected, including respiratory, urinary, lymphatic, circulatory, integumentary, skeletal, muscular, nervous, digestive, and endocrine systems ( Figure 1C ), and tested the ability of endogenous catalase (CAT) to accelerate dopamine polymerization and coating on tissue to achieve tissue accelerated polymerization (TP). The tissue map included 35 different test sites across 21 major organs and tissue types, which were selected for their potential as sites for therapeutic and injury intervention. In order to fully characterize the TPA reactivity of various fresh tissues, porcine tissue was selected as the first model tissue due to the genomic similarities between humans and pigs. It has been previously shown that human and porcine tissues exhibit similar mRNA and protein expression patterns of CAT 30,42 The ex vivo tissue was incubated with a tissue-accelerated polymerization solution containing dopamine and hydrogen peroxide at concentrations within safe oral consumption levels (0.066 wt % in solution). 43 .like Figure 1CAs shown, TPA-positive tissue sites indicate the presence of endogenous CAT that is capable of catalyzing polymer assembly on tissue surfaces. CAT is one of the most common enzymes present in the human body and is able to decompose hydrogen peroxide into oxygen, thereby accelerating oxygen-driven polymer assembly by multiple orders of magnitude. 30 Polydopamine (PDA), a mussel-inspired tissue adhesive 44,45 ) can be rapidly accelerated when exposed to hydrogen peroxide and CAT 22 Without being bound by theory, the inventors believe that hydrogen peroxide (endogenous or supplied as part of the methods or compositions of the present disclosure) diffuses into the cells and is rapidly broken down into oxygen by CAT within the cells. The oxygen is then released from the cells and mixes with extracellular TPA molecules. These TPA molecules near the tissue surface are oxidized into TPA assemblies, which cross-link with biomolecules rich in reactive chemical groups such as amines, sulfhydryls, and phenolic groups exposed on the cell surface. The inventors believe that the transiently cross-linked TPA molecules have a high molecular weight and are cross-linked to the cell surface, which limits their diffusion into the cells. 30Therefore, TPA assembly is a surface-based reaction accelerated by extracellular oxygen produced on the cell surface to form a strong polymer barrier on the tissue. TPA-positive sites can be easily distinguished and quantitatively characterized using dopamine (colorless) (Figure ID), because PDA assemblies (dark brown) can be characterized as forming a dark color (6 mm in diameter) on the tissue. TPA reactivity was quantitatively evaluated by comparing the signal intensity of the tissue before and after PDA assembly (Figure IE), and the increase in signal indicates a color PDA assembly. Different levels of PDA assembly were observed at 35 tissue sites, among which 26 tissue sites of 18 major organs (trachea, lungs, kidneys, bladder, lymph nodes, heart, blood vessels, eyes, skin, cartilage, muscles, nerves, mouth, liver, spleen, gallbladder, pancreas and small intestine) had significantly increased PDA levels (P<0.05), and no significant increase in PDA signals was observed in the other 9 tissue sites. Due to the color development of polydopamine, these polydopamine coating processes can be visualized. Interestingly, the coating efficiency varies along the tissue, even within the same organ. In the oral region, polydopamine coatings were observed on the tongue (dorsal site), buccal mucosa, and labial mucosa, but negligible polydopamine coatings were detected on the tongue (ventral site) and palate. In the ocular region, polydopamine coatings were observed on the conjunctiva, but no dopamine coatings were observed on the sclera. In the gastrointestinal tract, polydopamine coatings were observed on the small intestine, but not on the stomach and esophagus. These coating differences and specificities are due to the different expression levels of catalase in different parts of the tissue. This extraordinary effectiveness and specificity of tissue-accelerated polymerization opens the way for downstream in vivo applications. In addition, within the same organ, different tissue types can perform different PDA assembly performances, showing the potential for in vivo targeted drugs in these tissues (e.g., tongue, cheek, conjunctiva, skin, trachea, cartilage, bladder, nerves, and small intestine).

[0260] Example 2: Extensive Library of CAT-Responsive Polymer Assemblies

[0261] The combinatorial library of CAT-responsive polymer assemblies was created in three steps: (1) screening dopamine analogs to find additional types of TPA monomers; (2) conjugating these TPA monomers to various polymer backbones to synthesize a series of TPA conjugates; and (3) combining TPA monomers with TPA conjugates to provide a TPA assembly library. The test solution contained: 10 mg / ml M1-M6 (one of each), 20 mM H2O2 and 50 mM Tris (pH 8.5). The above solutions (180 μl each, 6 solutions in total) were freshly prepared and added to a 96-well plate, followed by the addition of 10 ul of catalase (1 mg / ml). The reaction mixture was maintained at 37 ° C. The extinction of the solution at 700 nm was measured using a plate reader (TECAN). For the control, the solution was maintained at 37 ° C without the addition of catalase.

[0262] In order to expand the material portfolio for synthetic tissue barriers, monomers other than dopamine were investigated for tissue-accelerated polymerization. After screening molecules with similar chemical structures to dopamine, five other TPA monomers (M2-M6), including levodopa, norepinephrine, methyldopa, levodopa methyl ester, and levodopa ethyl ester, were found to be tissue-accelerated polymerization monomers ( Figure 2A ). In the screen, the assembly process of dopamine analogs was studied in the presence or absence of commercially purified CAT. Analogs with increased assembly speed in the presence of CAT are good candidates for TPA monomers. Figure 3As shown, each originally colorless TPA monomer (M1-M6) solution undergoes a rapid color change upon assembly, allowing visual tracking of the assembly process. It was observed that the color change of the TPA monomer solution (without CAT) was relatively slow compared to the solution to which CAT was added, indicating that CAT accelerated the formation of the TPA assembly. In this study, the structure of the TPA assembly catalyzed by CAT was confirmed to be almost identical to the structure of the assembly product without CAT catalysis by ultraviolet-visible (UV-VIS) spectroscopy (Figure 4). In order to quantify the effect of catalase on the polymerization rate of these tissue-accelerated polymerization monomers (M1-M6), a comparison diagram of the reaction kinetics was drawn by measuring the optical extinction of the solution at 500nm for 3 hours, in which all polymerization tissue-accelerated polymerizations have light absorption characteristics. The signal of the catalase-H2O2 combination grew rapidly and stabilized within 10 minutes of reaction for all 6 tissue-accelerated polymerization monomers (Figure 5). However, the light extinction intensity under normal conditions (in air) was relatively low, and even after 3 hours, the same intensity was achieved within 1-2 minutes under catalase-catalyzed conditions, indicating that the polymerization rate of all TPA monomers increased by about 100-200 times. In addition, it was evaluated whether endogenous CAT in tissues could accelerate the assembly of these TPA monomers and subsequently enable the TPA assemblies to adhere to the tissue. Excised tissue samples of porcine cartilage were incubated with each TPA monomer solution and then washed to remove excess unbound TPA assemblies in the solution. Figure 6 As shown, when white opaque cartilage samples were exposed to TPA monomer solution, TPA assemblies of corresponding colors were observed on the tissue surface, demonstrating that the TPA assemblies were generated in situ in the tissue and bonded to the biomolecules exposed to the tissue surface. In addition, the color change of the TPA assemblies provides tunable optical properties for the TPA molecular library and allows the barrier appearance to be adjusted for further applications in vivo. Notably, all six identified TPA molecules have similar chemical structures: at least one benzene ring with two hydroxyl groups adjacent to each other, an intermediate ethyl chain, and a terminal amine group, classifying these six molecules as catecholamines.

[0263] Next, these 6 monomers are conjugated with different biocompatible macromolecules to produce a series of TPA-macromolecule conjugates, including alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate and chitosan. After the TPA component is conjugated to the macromolecular skeleton, the additional physical and biological functions of these macromolecules can be incorporated into the TPA molecule. In this study, 6 different carboxyl-rich macromolecules (sodium alginate, hyaluronic acid, polyacrylic acid, polyethylene glycol, chondroitin sulfate and chitosan) were selected to synthesize 21 different TPA-macromolecule conjugates (C1-C21; Figure 7). As shown in Figure 8, the successful conjugation of these macromolecular tissue-accelerated polymerization monomers was confirmed by using nuclear magnetic resonance (NMR) spectroscopy, in which macromolecules, TPA monomers and conjugated products were analyzed and compared for structural similarity and purity respectively.

[0264] Next, 6 tissue-accelerated polymerization monomers (M1-M6) and 21 tissue-accelerated polymerization monomers containing macromolecules (C1-C21) were systematically combined, leading to the cross-linking of multiple polymer networks and the subsequent synthesis of 1142-membered TPA assemblies. Figure 2C As shown, the effect of catalase on the polymerization rate was measured for all 1142 preparations and displayed as a heat map. All preparations had a response of at least 10X to 200X in the polymerization rate increase to catalase, indicating that all materials in the library can be used for tissue-accelerated polymerization and its related potential applications. Moreover, after adding the tissue-accelerated polymerization monomer containing macromolecules to the tissue-accelerated polymerization monomer, it was observed that some solutions were transformed from liquid to gel after tissue-accelerated polymerization, which was due to the cross-linking of macromolecules. About 80% of the tested preparations showed the ability to form gels due to the chemical cross-linking structure in these polymer assemblies, while the remaining preparations remained in a liquid state. The tunability of materials and preparations provides flexibility that allows specific compositions to be customized for specific medical uses. The results show that in terms of gelation ability, M1 is one of the most excellent TPA monomers, and the assembly rate of the reaction (M1 with C1-C21) is relatively slower than that of other reactions (M2-M6 with C1-C21), which may be due to the limited diffusion of TPA molecules in fast gelling solutions with high viscosity. In addition, the biocompatibility of TPA assemblies was evaluated in vitro on HeLa and Caco-2 cell lines ( Fig. 9). The cytotoxicity of all representative polymer assemblies on two cell lines was characterized, and no significant cytotoxicity was observed after 24 hours of in vitro incubation. It was also noted that polymer assemblies produced from C7-C12 showed relatively low cytotoxicity, which may be due to the biocompatibility of the hyaluronic acid backbone in C7-C12. In summary, the TPA library provides more than 1,000 formulations of CAT-responsive polymer assemblies with various physical and biological properties, maintaining therapeutic potential for different in vivo applications throughout the body.

[0265] Example 3: Tissue-accelerated polymerization for drug delivery

[0266] To evaluate the therapeutic value of TPA maps and the TPA library, three different clinical scenarios were illustrated: improving the efficiency of intraocular drug administration, protecting the epithelium from environmental pressures within the oral cavity, and hemostatic treatment of gastric bleeding. The TPA maps were used as a guide for specific tissue targeting in multiple different tissue sites including the conjunctiva, tongue, cheek, and gastric mucosa. In addition, the TPA library was applied to develop functional barriers in different therapeutic formulations involving droplets, composite patches, and sprayable powders. In vivo TPA performance was evaluated in a large animal model, Yorkshire pigs (45-75 kg). Of note, pigs were chosen as a model because their genome and anatomy are similar to the human system. 30,46 .

[0267] First, TPA technology was investigated as a system for ocular drug delivery, demonstrating its ability to release therapeutic agents in a sustained manner within the eye (e.g., for the treatment of conjunctivitis). Conjunctivitis is an eye disease caused by inflammation or infection of the conjunctiva, which affects millions of people each year and carries a huge economic and social burden. 31 Corticosteroids, such as dexamethasone, are frequently used to treat conjunctivitis and are recommended to be administered as eye drops often six times daily, which can lead to poor patient compliance and an increased risk of glaucoma. 32-33 The development of ophthalmic sustained-release corticosteroids is limited due to the protective mechanism of the eye, which causes drug spillage, tear production, blinking, and nasolacrimal drainage, resulting in low bioavailability of corticosteroids. The TPA technology disclosed herein can provide a topically applied conjunctival targeting platform for prolonged conjunctival retention and sustained release of drugs in the eye, reducing dosing frequency, and enhancing drug adhesion. TPA Figure ( Figure 1D ) showed efficient polymer assembly in the conjunctiva but not in other parts of the eye, enabling targeted growth of polymer barriers on the conjunctival surface ( Fig.10 To demonstrate the in vivo conjunctival targeting ability of TPA in pigs ( Fig.11A ), TPA eye drops ( Fig. 11B; no drug) was applied directly to the eyes of sedated pigs. Eye drops (colorless) were applied into the space created by pulling down the lower eyelid, and the eyelid was released after the eye drops were applied. Fig. 11C As shown, a dark brown M1 assembly layer was observed on the conjunctival surface 15 minutes after application, while no such assembly was observed on the sclera and corneal surfaces, demonstrating the targeted M1 assembly and adhesion to the conjunctiva. In addition, no visible signal attenuation was detected after flushing the conjunctiva with water ( Fig.12 ), which supports the strong adhesion and stability of the assemblies. Notably, these M1 assemblies fell off from the eye 24 hours after application ( Fig.13 ), confirming the transient nature of the assemblies. The polymer assemblies, along with the self-renewing conjunctival epithelium beneath the polymers, were shed from the eye, likely due to rapid cellular turnover and continuous secretion of mucins in the conjunctiva. 47,48 .

[0268] Histological analysis of the conjunctival epithelium was also performed 24 hours after polymer assembly. Fig.14 As shown, the epithelium remained intact with a staining pattern similar to that of unexposed controls, supporting the lack of tissue toxicity and potential safety of TPA eye drops.

[0269] Next, dexamethasone was selected as a model drug to be incorporated into TPA eye drops. The surface of the dexamethasone particles was first coated with M1 (this makes it possible to chemically crosslink and incorporate the M1-coated dexamethasone into the polymer assembly on the conjunctival surface), washed and freeze-dried, and then suspended in a solution of trace H2O2 and M1. Due to the suspension of TP-coated dexamethasone particles, the coated dexamethasone solution is dark. The coating process enables the drug to be cross-linked within the TP polymer when exposed to CAT on the conjunctiva. Ocular drug release studies were conducted using monocular administration of TPA-dexamethasone eye drops in pigs. TPA eye drops containing suspended M1-coated dexamethasone particles (dark black) were applied to the eyes of pigs in the same manner as described above. After application, an isotonic solution was applied to extract the drug from the conjunctival epithelium at different time points. The drug concentration in the extract was analyzed by liquid chromatography-tandem mass spectrometry. TPA eye drops (Figure 1 ID) and conventional eye drops (without TPA) had comparable initial concentrations of dexamethasone. However, at later times, when administered using the TPA technique, higher concentrations of dexamethasone were observed, indicating a slower rate of drug elimination. This resulted in a 3-fold increase in the area under the curve (AUC) in the TPA-dexamethasone treatment group compared to the conventional dexamethasone treatment control group ( Fig.11E ), demonstrating sustained drug release. Thus, conjunctival-targeted TPA eye drops expand the effectiveness of treatment options for conjunctivitis, with the potential to treat other ocular diseases where drug adhesion is essential for therapeutic efficacy.

[0270] Example 4: Tissue-accelerated polymerization for tissue protection

[0271] A functional TPA barrier was developed to protect tissues from environmental stressors. The ability of the TPA barrier to protect the oral mucosa from chemical and radiation stressors was demonstrated. Oral mucosal diseases, especially mucositis and aphthous stomatitis, are common diseases that affect a large number of people worldwide. 34-35 Oral mucositis, inflammation and ulceration of the oral mucosae, is a particularly common complication in patients undergoing radiation and chemotherapy. 34 This unintentional damage to healthy mucosal tissue may lead to interruption of treatment and even to treatment failure and death. 36 In addition to mucositis, aphthous stomatitis can cause painful inflammatory ulcers in the mouth. 35 Treatment of aphthous stomatitis may take several weeks, during which time there are many conditions that can worsen pain, injury, and re-injury due to abrasion or exposure to acidic or spicy foods or beverages. Applying the TP-patch to the ulcer before eating can prevent further injury or rupture. In addition, intraoral radiation for the treatment of oral and oropharyngeal cancers can result in unintentional damage to surrounding healthy tissue. Protective splints made of lead or low-melting-point alloys are widely used to prevent damage to adjacent tissue during radiation therapy. Covering mucosal tissue with different protective TPA barriers can block radiation and chemical (acidic) stress, improving patient outcomes and quality of life. To achieve strong tissue adhesion and flexible protection, the TPA barrier is designed as a composite patch ( Fig.11G The patch consists of two layers, including a protective layer made of functional (e.g., radiation shielding and chemical impermeability) material and a tissue-adhesive layer made of TPA molecules ( Fig.11H ). These patches are provided in the form of flexible sheets that can be designed into various shapes and applied to non-planar tissue surfaces. Based on the TPA diagram ( Figure 1D ), oral mucosa, such as tongue and buccal mucosa, can promote TPA and deposit the assembly on the tissue surface. Therefore, the reactivity of the TPA molecular layer in the porcine oral mucosa was first tested. A dry tissue-adhesive TPA layer (white) containing TPA monomer (M1) and TPA-macromolecule conjugate (C7) was placed on the tongue of a sedated pig, and a dark brown hydrogel barrier ( Fig.11I ), demonstrating the rapid tissue-directed gelation of TPA molecules on the oral mucosal surface. The gelation is based on a mussel-inspired dry cross-linking mechanism 44,49 In this study, the TPA molecule C7 ( Fig. 9) is incorporated into a formulation that provides a hydrogel matrix. The hydrogel matrix can effectively dissipate the energy during deformation and help the upper protective layer to adhere stably to the tissue. To test the tissue adhesion stability of the hydrogel, the tongue surface was vigorously rinsed with water ( Fig.15 ), during which time the hydrogel remained strongly attached to the tongue surface.

[0272] In addition, the hydrogel fell off the tongue after 24 hours of application ( Fig.16 ), confirming its transient nature, which may be due to the rapid turnover of the oral epithelium through rapid stem cell proliferation 50 The absence of tissue toxicity was confirmed by histological analysis of the tissue 24 hours after hydrogel formation ( Fig.17 ), showing the potential safety of the TPA oral patch. Secondly, two different protective layers, lead sheet and thin polyvinyl chloride (PVC) foam, were attached to the back of the tissue-adhesive TPA layer. Lead with a high atomic number can attenuate radiation dose exposure and is widely used to protect healthy tissue in radiation diagnosis and treatment. In this study, the TPA-lead patch was placed on the cheek surface of sedated pigs, and a series of X-ray images of the same anatomical position were taken periodically. Fig.11J and Fig.18 As shown, the TPA-lead patch adhered strongly to the buccal mucosa for 3 hours, which is long enough to achieve the duration of usual radiation therapy (within minutes). 51 .

[0273] A variant of the TP-patch was designed for testing with pH paper in contact with the tongue tissue. When acid was applied on the tongue without the TP-patch, the pH dropped to an average of 3. When the TP-patch was adhered and acid was applied, the pH remained at a level comparable to the control normal pH of the tongue. The resilience of the pH level in the presence of acid using the TP-patch demonstrated that the TP-patch has the ability to protect against acidic foods that may further irritate ulcers in the mouth.

[0274] Next, the tissue adhesion and chemical permeability of the TPA-PVC patch were tested. To verify the blocking effect on chemicals, especially acid, the TPA-PVC patch was placed on the tongue surface of a sedated pig, citric acid solution (pH 3) was applied on top of the patch 15 minutes after application, and the pH of the mucosa under the patch was measured to quantify the acid blocking efficiency. Figure 11KAs shown, control pigs without TPA-PVC patches exhibited a significant decrease in mucosal pH after application of citric acid solution. However, the pH of mucosa treated with TPA-PVC patches remained at a level comparable to healthy control values. This resistance to pH changes demonstrates the protective ability of TPA-PVC patches against acid or chemical penetration, which may be due to the hydrophobicity of the PVC foam layer, supporting the application of these patches for protecting ulcers from acidic stress that can aggravate pain and damage in the oral cavity. These results meet the clinical need for protective patches in the oral cavity and support the flexibility of TPA technology to potentially shield various environmental stresses by combining different blocking materials.

[0275] Example 5: Tissue Accelerated Polymerization for Hemostatic Therapy

[0276] TPA technology is used to treat upper gastrointestinal bleeding by specifically creating a TPA barrier at the bleeding site in the stomach. Fig.11L ). Gastrointestinal bleeding is one of the most urgent clinical emergencies and represents the most frequent reason for hospitalization. 37 Ineffective hemostasis of upper gastrointestinal bleeding (mainly due to peptic ulcers) can lead to massive blood loss, risk of perforation, and even complications or death. 38 The mortality rate for patients with gastrointestinal bleeding is approximately 10%.

[0001] 7 The most common treatment for acute upper gastrointestinal bleeding is endoscopic hemostasis, such as epinephrine injection, thermal coagulation, mechanical hemostasis using hemostatic clips, and noncontact modalities.

[0001] 8,39-40 However, these approaches require expertise in rapid identification of bleeding sites, which often leads to rebleeding and limits the efficacy of treatment. 41 Furthermore, these methods can be challenging, especially for difficult to access bleeding sites. The present disclosure provides an alternative technology that can specifically target bleeding sites to effectively control bleeding and simplify existing endoscopic hemostasis. In particular, a hemostasis method based on tissue accelerated polymerization is disclosed that does not require direct contact with the bleeding site, preventing further damage or more severe induced bleeding. Without wishing to be bound by theory, the inventors believe that strong catalase expression in blood cells will lead to gel formation upon contact with the tissue accelerated polymerized powder according to the present disclosure. Targeting of bleeding sites is achieved due to the high CAT activity of blood relative to the stomach. 52,53 Based on the TPA diagram ( Figure 1D), the stomach is a TPA-negative site, and healthy gastric mucosa cannot accelerate the formation of TPA barrier and adhesion on tissue surface. However, blood from bleeding peptic ulcer can promote the formation of TPA barrier, which will cover the bleeding point and then achieve hemostasis. In order to demonstrate the catalytic ability of blood to TPA reaction, fresh porcine blood was collected through a tube containing sodium citrate anticoagulant and then mixed with TPA hemostatic powder (M1 and C7 as TPA molecules). Here, M1C7 was used as a proof-of-concept formulation and was used as a powder containing M1 (500 mg), C7 (50 mg), Tris or sodium carbonate or potassium carbonate powder (60 mg), solid urea H2O2 (50 mg). The powders were mixed and sprayed onto the bleeding site through an endoscopic catheter powered by compressed air. This proves that M1C7, together with other excipients, can induce blood gelation and coagulation to resolve gastrointestinal bleeding.

[0277] Blood coagulation in Yorkshire pigs was then tested in a gastric bleeding model. The advantages of using pigs as a large animal model include their extensive homology with the human genome, anatomical similarities with the human gastrointestinal tract, and physiological similarities with the human digestive system. A gastrointestinal endoscope was used with surgical forceps to induce intragastric bleeding to mimic acute upper gastrointestinal bleeding. After inducing bleeding, the tissue-accelerated polymerization powder (T1 (500 mg), M7 (50 mg), Tris or sodium carbonate or potassium carbonate powder (60 mg), solid urea H2O2 (50 mg)) was continuously sprayed to the bleeding site through a delivery catheter inserted into the working channel of the endoscope. The end of the spraying device was connected to a compressed air device to push the tissue-accelerated polymerization powder out of the catheter. After spraying the tissue-accelerated polymerization powder, a gastrointestinal endoscope was used to record blood gelation and coagulation in real time. As shown in Figure 20, dark brown tissue-accelerated polymerization gel was observed at the bleeding site immediately after the tissue-accelerated polymerization powder was sprayed, while this tissue-accelerated polymerization gel was not observed in areas without bleeding or after the same spraying with control powder. The bleeding site was effectively covered by the tissue-accelerated polymeric gel, which formed a barrier on the vessel wall and stopped the bleeding. The formation of the tissue-accelerated polymeric barrier specifically targets the blood and has no effect on healthy tissue in the stomach. Compared with conventional hemostatic powders, this specific targeting has the potential to reduce side effects caused by nonspecific tissue adhesion of the powder. Moreover, the tissue-accelerated polymeric powder can help tissue recovery and regeneration, which was demonstrated by endoscopic imaging and histology ( Fig. 9 and 10 ).

[0278] Example 6: Further Examples of Tissue Accelerated Polymerization for Hemostatic Therapy

[0279] like Fig.19As shown, blood (red liquid) immediately transformed into a black gel once mixed with TPA powder, demonstrating the accelerated polymer assembly and cross-linking of TPA molecules catalyzed by blood. To further evaluate the hemostatic ability of TPA technology, an acute gastric bleeding (Forrest IB bleeding) pig model was used to test the safety and efficacy of endoscopically applied TPA hemostatic powder in vivo. 54 Under moderate sedation, an endoscopic biopsy forceps was used to create a 10-20 mm puncture wound (without perforation) in the stomach, resulting in bleeding from the puncture site (exudative bleeding). The biopsy was then stopped under endoscopic visual guidance using the TPA hemostasis device ( Fig.11M The TPA hemostatic powder was sprayed onto the bleeding site by an endoscope (which consists of a delivery catheter inserted through the working channel of the endoscope and a hemostatic powder container connected to compressed air that pushes the hemostatic powder out of the delivery catheter). Gastrointestinal endoscopic video was used to record the treatment process. Within 10 minutes after the application of the hemostatic powder (white), a black gel barrier ( Fig.11N ), where hemostasis was achieved due to accelerated coagulation. However, when the control powder (without TPA gelling component) was applied, no such barrier formation was observed ( Fig. 20B ), and the bleeding cannot be controlled in time. It is worth noting that during the delivery of TPA hemostatic powder, some powder is also inevitably deployed on the healthy tissue around the bleeding site ( Fig.11O ), while these powders remained unreacted in a light yellow / white color, indicating specific targeting of the TPA technique to bleeding sites rather than healthy tissue. These results support the hemostatic ability of endoscopic TPA hemostasis and its effectiveness may be due to immediate adhesion of the powder upon contact with wet tissue surfaces, increased concentrations of coagulation factors due to blood dehydration, rapid blood-directed gelation of TPA molecules at the targeted bleeding site, and strong adhesion of the gel-barrier due to chemical cross-linking between TPA molecules, blood, and gastric epithelium. In addition, no powder or gel barrier was identified endoscopically in the stomach 24 hours after hemostatic treatment ( Fig.21 ), indicating that all hemostatic material is eliminated from the stomach due to rapid epithelial restoration 55 In addition, in animals not treated with TPA for hemostasis, non-flat ulcers were observed endoscopically at the gastric puncture site ( Fig.21 ), which is a result of normal wound healing 56 However, when TPA was applied to stop bleeding, flat and almost completely healed wounds were observed by endoscopy, indicating that the TPA gel barrier also promotes wound healing. The mechanism of accelerated healing of the gastric mucosa may be due to two factors, including the physical protection of the TPA gel-barrier against the pressure of the gastric environment and the physiological function of the hyaluronic acid skeleton in the TPA molecule that can improve wound healing. 57In the study, it was also observed that the control powder (hyaluronic acid-based TPA molecule alone) could help wound healing ( Fig.21 ), but was less efficient than TPA hemostatic powder. To further confirm the therapeutic efficacy of TPA hemostasis at the cellular and tissue levels, gastric tissue from the trauma site was collected for histological examination 24 hours after hemostatic treatment. Consistent with the endoscopic results, microscopic and histological analysis of formalin-fixed paraffin-embedded (FFPE) tissue samples showed significant epithelial regeneration of the damaged gastric mucosa exposed to TPA hemostatic powder, while incomplete regenerated epithelium and loss of mucosal integrity were observed in unexposed controls ( Fig.11O and Fig. 22 In addition, these histological images were scored to assess the severity of mucosal damage in different cases. 58 (Figure 11P), indicating a significant difference between the TPA hemostatic treatment group and the untreated group (p<0.05). However, there was no significant difference in the score of mucosal integrity between the TPA-treated group and the healthy control group (p>0.05), demonstrating successful epithelial restoration after TPA treatment. No hemostatic powder or gel barrier was histologically identified in all tissue samples ( Fig. 22 ), indicating that none of the TPA material was absorbed by mucosal tissue, suggesting minimal risk of systemic toxicity for future human studies. In summary, these results show that TPA hemostatic powder promotes wound healing by providing a protective, transient, and therapeutic barrier over the wound site. Thus, TPA technology opens up a pathway for specific targeting of bleeding sites in the stomach and a promising mechanism for controlling gastrointestinal bleeding and promoting lesion healing.

[0280] Example 7: Tissue-accelerated polymerization for material retention in the conjunctiva, cartilage, and oral cavity for potential sustained drug release

[0281] To demonstrate the versatility of the tissue-accelerated polymerization platform, tissue-accelerated polymerization formulations were evaluated for material retention in the conjunctiva, cartilage, and oral cavity.

[0282] An ophthalmic solution formulation was prepared, comprising 10 mg / ml M1 and 20 mM H2O2 dissolved in 50 mM Tris buffer (pH 8.5). The solution (1 ml) was applied to the conjunctiva for 15 minutes and then washed with water.

[0283] A solution preparation for cartilage was prepared, which contained 10 mg / ml M1 and 20 mM H2O2 dissolved in 50 mM Tris buffer (pH 8.5). The solution (3 ml) was injected intraarticularly into the cartilage through a needle. After 15 minutes, the cartilage was removed and washed with water for evaluation.

[0284] Prepare an oral powder formulation comprising M1 (500 mg), M7 (50 mg), Tris or sodium carbonate or potassium carbonate powder (60 mg), solid urea H2O2 (50 mg). Spray the powder on the top of the tongue or cheek, and after 15 minutes, wash the tissue with water for evaluation. In some embodiments, different drugs are incorporated into the system to treat eye diseases (e.g., glaucoma) through eye drop formulations, treat joint diseases (e.g., osteoarthritis) with intra-articular injection formulations, and serve as barrier coatings or drug patches to protect the oral mucosa from damage. In some embodiments, the drug is incorporated in the form of powder, granules, oil, or dissolved liquid and co-delivered with a tissue-accelerated polymerization formulation. After in situ polymerization and cross-linking, these drugs are trapped in the polymer, which enables slow and sustained release. In an embodiment, the drug is timolol, latanoprost, or bimatoprost, and is used to treat the eye. In certain embodiments, the drug is an interleukin-1 receptor antagonist, insulin-like growth factor 1, dexamethasone, or triamcinolone acetonide, and is used for intra-articular injection. In some embodiments, the drug is nystatin, clotrimazole, fluconazole, or dexamethasone and is intended for delivery to the oral cavity.

[0285] Example 8: Evaluation of TPA in human tissue

[0286] The TPA technique has been developed for application to human tissue and is suitable for clinical translation. To confirm the reliability of the above porcine-based TPA-positive tissue maps for potential human trials, freshly excised tissue samples from humans were tested for compatibility with the TPA technique. Similar to the porcine TPA-map studies, human tissue samples were incubated with a TPA solution containing M1, followed by identification of CAT-accelerated chromogenic M1 assemblies. Fig.23A As shown, stably adherent M1 assemblies were observed on various human tissues including cartilage, cheek, tongue, and blood. The TPA barrier on these tissue surfaces was determined by quantitative signal analysis ( Fig. 23B ) further confirmed that the signal intensity of the M1 assembly was highly consistent with the pig results. In addition, the M1 assembly formation kinetics showed rapid signal development in all tissue types, with 95% completion achieved within approximately 4-23 minutes ( Fig.23C -F), supporting rapid TPA barrier growth in human tissues. These results reveal a high correlation in TPA activity between porcine and human tissues, which may be due to their similar CAT distribution in vivo and ultimately their genomic similarities 30,42,53 Therefore, the porcine-based TPA map covering 35 different testing sites across 21 major organs and tissue types can serve as a potential guide for future drug development in various human tissue sites and in upcoming preclinical and clinical trials.

[0287] Reference

[0288] 1. Anselmo, A.C., Gokarn, Y. & Mitragotri, S. Non-invasive delivery strategies for biologics. Nat. Rev. Drug Discov. 18, 19–40 (2018).

[0289] 2. Zelikin, A.N., Ehrhardt, C. & Healy, A.M. Materials and methods for delivery of biological drugs. Nat. Chem. 8, 997–1007 (2016).

[0290] 3. Lee, Y. et al. Therapeutic luminal coating of the intestine. Nat. Mater. 17, 834–842 (2018).

[0291] 4. Yui, S. et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 18, 618–623 (2012).

[0292] 5. Kitano, K. et al. Bioengineering of functional human induced pluripotent stem cell-derived intestinal grafts. Nat. Commun. 8, 765 (2017).

[0293] 6. Elloumi-Hannachi, I., Yamato, M. & Okano, T. Cell sheet engineering: a unique nanotechnology for scaffold-free tissue reconstruction with clinical applications in regenerative medicine. J. Intern. Med. 267, 54–70 (2010).

[0294] 7.Nahon,S.et al.Epidemiological and prognostic factors involved inupper gastrointestinal bleeding:Results of a French prospective multicenterstudy.Endoscopy 44,998–1006(2012).

[0295] 8.Vanleerdam,M.et al.Acute upper GI bleeding:did anything change?Am.J.Gastroenterol.98,1494–1499(2003).

[0296] 9.Candi,E.,Schmidt,R.&Melino,G.The cornified envelope:A model of celldeath in the skin.Nat.Rev.Mol.Cell Biol.6,328–340(2005).

[0297] 10.Lambrecht,B.N.&Hammad,H.The airway epithelium inasthma.Nat.Med.18,684–692(2012).

[0298] 11.Obermeier,B.,Daneman,R.&Ransohoff,R.M.Development,maintenance anddisruption of the blood-brain barrier.Nature Medicine vol.191584–1596(2013).

[0299] 12.Peterson,L.W.&Artis,D.Intestinal epithelial cells:regulators ofbarrier function and immune homeostasis.Nat.Rev.Immunol.14,141–153(2014).

[0300] 13.Zihni,C.,Mills,C.,Matter,K.&Balda,M.S.Tight junctions:From simplebarriers to multifunctional molecular gates.Nat.Rev.Mol.Cell Biol.17,564–580(2016).

[0301] 14.Varga,Z.et al.Endothelial cell infection and endotheliitis inCOVID-19.Lancet 395,1417–1418(2020).

[0302] 15.Richard,M.et al.Influenza A viruses are transmitted via the airfrom the nasal respiratory epithelium of ferrets.Nat.Commun.11,1–11(2020).

[0303] 16.Nishida,K.et al.Corneal reconstruction with tissue-engineered cellsheets composed of autologous oral mucosal epithelium.N.Engl.J.Med.351,1187–1196(2004).

[0304] 17.Gallico,G.G.,O’Connor,N.E.,Compton,C.C.,Kehinde,O.&Green,H.Permanent coverage of large burn wounds with autologous cultured humanepithelium.N.Engl.J.Med.311,448–451(1984).

[0305] 18.Torres,J.,Mehandru,S.,Colombel,J.F.&Peyrin-Biroulet,L.Crohn’sdisease.Lancet 389,1741–1755(2017).

[0306] 19.Sweeney,M.D.,Sagare,A.P.&Zlokovic,B.V.Blood-brain barrierbreakdown in Alzheimer disease and other neurodegenerativedisorders.Nat.Rev.Neurol.14,133–150(2018).

[0307] 20.Sun,Y.et al.Inhibition of autophagy ameliorates acute lung injurycaused by avian influenza A H5N1 infection.Sci.Signal.5,ra16–ra16(2012).

[0308] 21.Lee,Y.et al.Therapeutic luminal coating of theintestine.Nat.Mater.17,834–842(2018).

[0309] 22.Vacanti,J.P.&Langer,R.Tissue engineering:The design andfabrication of living replacement devices for surgical reconstruction andtransplantation.Lancet 354,32–34(1999).

[0310] 23.Anselmo,A.C.,Gokarn,Y.&Mitragotri,S.Non-invasive deliverystrategies for biologics.Nature Reviews Drug Discovery vol.18 19–40(2018).

[0311] 24.Mohanaruban,A.et al.PTH-003 a safe and effectivenovel treatment for obesity and type 2 diabetes?Endoscopy 66,A205.1-A205(2017).

[0312] 25.Khademhosseini,A.&Langer,R.A decade of progress in tissueengineering.Nat.Protoc.11,1775–1781(2016).

[0313] 26.Carino,G.P.&Mathiowitz,E.Oral insulin delivery.Adv.DrugDeliv.Rev.35,249–257(1999).

[0314] 27.Freedman,B.R.&Mooney,D.J.Biomaterials to mimic and heal connectivetissues.Adv.Mater.31,(2019).

[0315] 28.Taboada,G.M.et al.Overcoming the translational barriers of tissueadhesives.Nat.Rev.Mater.5,310–329(2020).

[0316] 29.Odenwald,M.A.&Turner,J.R.The intestinal epithelial barrier:atherapeutic target?Nat.Rev.Gastroenterol.Hepatol.14,9–21(2017).

[0317] 30.Li,J.et al.Gastrointestinal synthetic epitheliallinings.Sci.Transl.Med.12,441(2020).

[0318] 31.Azari,A.A.&Barney,N.P.Conjunctivitis:A systematic review ofdiagnosis and treatment.JAMA-Journal of the American Medical Associationvol.310 1721–1729(2013).

[0319] 32.FDA. -dexamethasone ophthalmic suspension Label.FDA,US.(2019).

[0320] 33.Kersey,J.P.&Broadway,D.C.Corticosteroid-induced glaucoma:A reviewof the literature.Eye vol.20 407–416(2006).

[0321] 34.Sonis,S.T.The pathobiology of mucositis.Nat.Rev.Cancer 4,277–284(2004).

[0322] 35.Scully,C.Aphthous Ulceration.N.Engl.J.Med.355,165–172(2006).

[0323] 36.Vera-Llonch,M.,Oster,G.,Hagiwara,M.&Sonis,S.Oral mucositis inpatients undergoing radiation treatment for head and neck carcinoma:Riskfactors and clinical consequences.Cancer 106,329–336(2006).

[0324] 37.Lanas,A.et al.Non-variceal upper gastrointestinalbleeding.Nat.Rev.Dis.Prim.4,18020(2018).

[0325] 38.Laine,L.Upper Gastrointestinal Bleeding Due to a PepticUlcer.N.Engl.J.Med.374,2367–2376(2016).

[0326] 39.Gralnek,I.M.,Barkun,A.N.&Bardou,M.Management of acute bleedingfrom a peptic ulcer.N.Engl.J.Med.359,928–937(2008).

[0327] 40.Barkun,A.N.,Moosavi,S.&Martel,M.Topical hemostatic agents:Asystematic review with particular emphasis on endoscopic application in GIbleeding.Gastrointest.Endosc.77,692–700(2013).

[0328] 41.Chahal,D.,Lee,J.G.H.,Ali-Mohamad,N.&Donnellan,F.High rate of re-bleeding after application of Hemospray for upper and lower gastrointestinalbleeds.Dig.Liver Dis.52,768–772(2020).

[0329] 42.Godin,D.V.&Garnett,M.E.Species-related variations in tissueantioxidant status-I.Differences in antioxidant enzymeprofiles.Comp.Biochem.Physiol.-Part B Biochem.Mol.Biol.103,737–742(1992).

[0330] 43.U.S.Food and Drug Administration.Oral health care drug productsfor over-the-counter human use;antigingivitis / antiplaque drug products;establishment of a monograph;proposed rules.Fed.Regist.68,32232–32287(2003).

[0331] 44.Maier,G.P.,Rapp,M.V.,Waite,J.H.,Israelachvili,J.N.&Butler,A.Adaptive synergy between catechol and lysine promotes wet adhesion bysurface salt displacement.Science(80-.).349,628–632(2015).

[0332] 45.Lee,H.,Dellatore,S.M.,Miller,W.M.&Messersmith,P.B.Mussel-inspiredsurface chemistry for multifunctional coatings.Science 318,426–30(2007).

[0333] 46.Traverso,G.&Langer,R.Perspective:special delivery for thegut.Nature 519,S19–S19(2015).

[0334] 47.Lavker,R.M.&Sun,T.T.Epithelial stem cells:The eye provides avision.Eye 17,937–942(2003).

[0335] 48.Gipson,I.K.Goblet cells of the conjunctiva:A review of recentfindings.Progress in Retinal and Eye Research vol.54 49–63(2016).

[0336] 49.Yuk,H.et al.Dry double-sided tape for adhesion of wet tissues anddevices.Nature(2019)doi:10.1038 / s41586-019-1710-5.

[0337] 50.Squier,C.&Brogden,K.A.Human Oral Mucosa:Development,Structure andFunction.John Wiley&Sons(2010).

[0338] 51.Gerber,D.E.&Chan,T.A.Recent Advances in RadiationTherapy.Am.Fam.Physician 78,1254–1262(2008).

[0339] 52.Goyal,M.M.&Basak,A.Human catalase:Looking for completeidentity.Protein Cell 1,888–897(2010).

[0340] 53.Fagerberg,L.et al.Analysis of the human tissue-specific expressionby genome-wide integration of transcriptomics and antibody-basedproteomics.Mol.Cell.Proteomics 13,397(2014).

[0341] 54.Forrest,J.A.H.,Finlayson,N.D.C.&Shearman,D.J.C.Endoscopy ingastrointestinal bleeding.Lancet 304,394–397(1974).

[0342] 55.Sáenz,J.B.&Mills,J.C.Acid and the basis for cellular plasticityand reprogramming in gastric repair and cancer.Nat.Rev.Gastroenterol.Hepatol.15,257–273(2018).

[0343] 56. Arakawa, T. et al. Quality of ulcer healing in gastrointestinaltract: Its pathophysiology and clinical relevance. World J. Gastroenterol. 18, 4811–4822 (2012).

[0344] 57. Xu, X. et al. Bioadhesive hydrogels demonstrating pH-independent and ultrafast gelation promote gastric ulcer healing in pigs. Sci. Transl. Med. 12, (2020).

[0345] 58.ANDREWS, FM et al. Comparison of endoscopic, necropsy and histologyscoring of equine gastric ulcers. Equine Vet. J. 34, 475–478 (2010).

[0346] Equivalent programs and scope

[0347] In the claims, words such as "a," "an," and "the" may refer to one or more than one, unless the context indicates otherwise or is otherwise clear. For claims or specifications that contain "or" between one or more group members, the requirements are considered satisfied if one, more than one, or all of the members of the group are present, employed, or otherwise related to a given product or process, unless otherwise indicated or obvious from the context. The invention includes embodiments in which only one member of the group is present, employed, or otherwise related to a given product or process. The invention includes embodiments in which more than one or all of the members of the group are present, employed, or otherwise related to a given product or process, unless otherwise indicated or obvious from the context.

[0348] In addition, the present invention includes all variations, combinations and arrangements, wherein one or more limitations, elements, words and descriptive terms in one or more listed claims are introduced into another claim. For example, any claim subordinate to another claim may be modified to include one or more limitations in any other claim subordinate to the same basic claim. When an element is presented in a list, for example, in the form of a Markush group, each subset of the element is also disclosed, and any element may be removed from the group. It should be understood that, in general, when the present invention or various aspects of the present invention are specified to include specific elements and / or features, some embodiments of the present invention or various aspects of the present invention are composed of such elements and / or features, or are substantially composed of such elements and / or features. For the purpose of simplicity, those embodiments are not specifically described herein. It should also be noted that the terms "include", "comprising" are intended to be open and allow the inclusion of other elements or steps. When a range is given, endpoints are included. In addition, unless otherwise mentioned or otherwise clearly indicated in the context and understanding of those skilled in the art, values ​​expressed in ranges may adopt any specific value or sub-range within the range stated in different embodiments of the present invention, to one-tenth of the lower limit unit of the range, unless the context clearly indicates otherwise.

[0349] The present application relates to various published patents, published patent applications, periodicals and other publications, all of which are incorporated herein by reference. If there is a conflict between any reference cited and the present application, this specification shall prevail. In addition, any specific embodiment of the present invention that falls into the prior art may be clearly excluded from any one or more claims. Because such embodiments are considered to be known to those skilled in the art, even if the exclusion is not clearly mentioned in this article, they may also be excluded. Any specific embodiment of the present invention may be excluded from any claim for any reason, whether or not it relates to the existence of the prior art.

[0350] Those skilled in the art will appreciate or be able to determine by using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the specific embodiments described herein is not intended to be limited by the above description, but is referred to in the appended claims. Those skilled in the art will appreciate that various changes and modifications may be made to this description without departing from the spirit or scope of the invention as defined in the claims.

Claims

1. Use of a composition comprising a monomer and an oxygen source in the preparation of a medicament for forming a polymer in a subject to treat or prevent a disease or disorder, wherein the oxygen source contacts a catalyst in a tissue of the subject and releases oxygen from the oxygen source to polymerize the monomer or a salt thereof on the tissue, The monomers include: Wherein R is tripentaerythritol; The oxygen source is selected from hydrogen peroxide or urea hydrogen peroxide; and The catalyst is selected from catalase or peroxidase; wherein the disease or disorder is selected from the group consisting of: gastrointestinal bleeding, oral mucosal disease, conjunctivitis, glaucoma, inflammatory joint disease, and peptic ulcer; The composition further comprises: Optionally, a buffer; and optionally, a reagent, The agent is selected from the group consisting of active pharmaceutical agents, cosmetic agents, nutritional agents, imaging agents, diagnostic agents, radioprotectants, nutritional blocking agents, neutralizing agents, and combinations thereof.

2. The use according to claim 1, wherein the gastrointestinal bleeding is small intestinal bleeding.

3. The use according to claim 1, wherein the gastrointestinal bleeding is upper gastrointestinal bleeding.

4. The method of claim 1, wherein the gastrointestinal bleeding is acute upper gastrointestinal bleeding.

5. The use of claim 1, wherein the treatment of gastrointestinal bleeding is a hemostatic treatment of gastrointestinal bleeding.

6. Use of a composition comprising a monomer and an oxygen source in the preparation of a medicament for forming a polymer in a subject to protect the oral cavity from environmental stress, wherein the oxygen source contacts a catalyst in the tissue of the subject and releases oxygen from the oxygen source to polymerize the monomer or a salt thereof on the tissue, The monomers include: wherein R is tripentaerythritol; the oxygen source is selected from hydrogen peroxide and urea hydrogen peroxide; and the catalyst is selected from catalase and peroxidase; wherein the composition further comprises: Optionally, a buffer; and optionally, a reagent, The agent is selected from the group consisting of active pharmaceutical agents, cosmetic agents, nutritional agents, imaging agents, diagnostic agents, radioprotectants, nutritional blocking agents, neutralizing agents, and combinations thereof.

7. The use according to claim 6, wherein the environmental pressure is chemical pressure or radiation pressure.

8. The use according to claim 7, wherein the chemical pressure is acidic pressure.

9. The use of claim 1, wherein the disease or disorder is an oral mucosal disease.

10. The use according to claim 9, wherein the oral mucosal disease is mucositis.

11. The use according to claim 9, wherein the oral mucosal disease is aphthous stomatitis.

12. The use according to claim 9, wherein the oral mucosal disease is inflammation or ulcer of the oral mucosa.

13. Use of a composition comprising a monomer and an oxygen source in the preparation of a medicament for forming a polymer in a subject to treat or prevent mucosal damage, wherein the oxygen source contacts a catalyst in the subject's tissue and releases oxygen from the oxygen source to polymerize the monomer or a salt thereof on the tissue, The monomers include: Wherein R is tripentaerythritol; The oxygen source is selected from hydrogen peroxide and urea hydrogen peroxide; and The catalyst is selected from catalase and peroxidase; The composition further comprises: Optionally, a buffer; and optionally, a reagent, The agent is selected from the group consisting of active pharmaceutical agents, cosmetic agents, nutritional agents, imaging agents, diagnostic agents, radioprotectants, nutritional blocking agents, neutralizing agents, and combinations thereof.

14. The use according to claim 13, wherein the mucosal damage is caused by an external agent.

15. The use of claim 13, wherein the mucosal injury is associated with radiation or chemotherapy.

16. The use of claim 1, wherein the disease or disorder is inflammatory joint disease.

17. The use according to claim 16, wherein the inflammatory joint disease is arthritis.

18. The use according to claim 17, wherein the arthritis is osteoarthritis or rheumatoid arthritis.

19. The use of claim 1, wherein the disease or disorder is conjunctivitis.

20. The use of claim 1, wherein the disease or disorder is glaucoma.

21. The use of claim 1, wherein the disease or disorder is peptic ulcer.

22. The use of any one of claims 1, 6, and 13, wherein the composition does not contain an exogenous catalyst.

23. The use of any one of claims 1-21, wherein the catalyst is a peroxidase selected from the group consisting of eosinophil peroxidase, lactoperoxidase and myeloperoxidase.

24. The use of any one of claims 1-21, wherein the catalyst is catalase.

25. The use of any one of claims 1-21, wherein the catalyst is human catalase or bacterial catalase.

26. The use of any one of claims 1-21, wherein the catalyst is located in the respiratory system, urinary system, lymphatic system, circulatory system, integumentary system, skeletal system, muscular system, nervous system, digestive system or endocrine system.

27. The use of any one of claims 1-21, wherein the catalyst is located in the gastrointestinal tract of a subject.

28. The use of any one of claims 1-21, wherein the monomer is selected from dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester, levodopa ethyl ester, and combinations thereof.

29. The use of any one of claims 1-21, wherein the monomer comprises dopamine, levodopa, norepinephrine, methyldopa, levodopa methyl ester or levodopa ethyl ester and at least one macromolecule.

30. The use according to any one of claims 1 to 21, wherein the monomer is selected from: Wherein R is tripentaerythritol.

31. The use of any one of claims 1-21, wherein the monomer consists of a single type of monomer.

32. The use of any one of claims 1-21, wherein the monomer comprises a combination of monomers.

33. The use according to any one of claims 1 to 21, wherein the combination of monomers consists of two or three different monomers.

34. The use of any one of claims 1-21, wherein the composition further comprises an agent selected from the group consisting of an active pharmaceutical agent, a cosmetic agent, a nutritional agent, an imaging agent, a diagnostic agent, a radioprotectant, a nutritional blocking agent, a neutralizing agent, and combinations thereof.

35. The use of any one of claims 1-21, wherein the composition further comprises an agent selected from the group consisting of an enzyme, an aptamer, an antibody, and a combination thereof.

36. The use of any one of claims 1-21, wherein the composition further comprises a buffer.

37. The use of any one of claims 1-21, wherein the composition comprises 1 to 20 mg / ml of monomer.

38. The use of any one of claims 1-21, wherein the composition comprises 10 mg / ml monomer.

39. The use of any one of claims 1-21, wherein the composition comprises 1 to 30 mM of an oxygen source.

40. The use of any one of claims 1-21, wherein the composition comprises 20 mM of an oxygen source.

41. The use of any one of claims 1-21, wherein at least 80% of the monomer and oxygen source remain after the composition leaves the stomach of a subject.

42. The use of any one of claims 1-21, wherein the composition is administered directly or indirectly to a polymerized target site.

43. The use of any one of claims 1-21, wherein the composition is administered orally, by intra-articular injection, transdermally or ophthalmically.

44. The use of any one of claims 1-21, wherein the composition is administered topically.

45. The use of any one of claims 1-21, wherein the composition is a liquid or solid dosage form.

46. ​​The use of any one of claims 1-21, wherein the composition is in the form of a solution, gel, tablet, powder, foam, capsule or transdermal patch.

47. The use of any one of claims 1-21, wherein the composition is in the form of eye drops.

48. The use of any one of claims 1-21, wherein the polymer forms and adheres to tissue in the subject when in contact with the tissue in the subject.

49. The use of any one of claims 1-21, wherein the polymer forms and adheres to one or more of the following when in contact: the dorsal portion of the tongue, buccal mucosa, labial mucosa, palate, conjunctiva, muscle, cartilage, small intestine, colon, ventral tongue, esophagus, or stomach.

50. The use of any one of claims 1-21, wherein the polymer is formed in or on: cartilage, muscle, mouth, or small intestine.

51. The use of any one of claims 1-21, wherein the polymer is formed on one or more of the tongue, buccal mucosa, and labial mucosa.

52. The use of any one of claims 1-21, wherein the polymer is formed on the conjunctiva of the eye.

53. The use of any one of claims 1-21, wherein the polymer is formed on cartilage.

54. The use of any one of claims 1-21, wherein the tissue is epithelium.

55. The use of claim 54, wherein the epithelium is intestinal epithelium.

56. The use of any one of claims 1-21, wherein the polymer is formed in the small intestine.

57. The use of any one of claims 1-21, wherein the polymer is formed in the lumen of the small intestine.

58. The use of any one of claims 1-21, wherein the polymer is formed on the epithelium of the duodenum of a subject.

59. The use of any one of claims 1-21, wherein the polymer is conjugated to an amine moiety exposed on a luminal surface of an epithelium of a subject.

60. The use of any one of claims 1-21, wherein the polymer is formed in less than 10 minutes.

61. The use of any one of claims 1-21, wherein the polymerization rate is increased at least 100-fold compared to polymer formation in the absence of catalase.

62. The use of any one of claims 1-21, wherein the polymer forms a transient barrier in vivo.

63. The use of claim 62, wherein the barrier provides selective molecular transport in the patient.

64. The use of claim 62, wherein the polymer persists for at least 6 hours.

65. The use of claim 62, wherein 20% to 70% of the transient barrier is still present after 6 hours.

66. The use of any one of claims 1-21, wherein the polymer is cleared from the subject after 24 hours.

67. The use of claim 34 or 35, wherein the medicament delivers an agent to a subject.

68. The use of claim 67, wherein the medicament enables sustained release of the agent in the subject.

69. The use of claim 67, wherein the medicament immobilizes an agent in a subject.

70. The use of claim 67, wherein the medicament is for local delivery of an agent in a subject.

71. The use of claim 67, wherein the medicament is used to reduce the frequency of administration of an agent.

72. The use of claim 67, wherein the medicament is for increasing the half-life of an agent in a subject.

73. The use of claim 67, wherein the medicament is used to increase the residence time of an agent in a subject.

74. The use of claim 67, wherein the agent is an active pharmaceutical agent.

75. The use of claim 67, wherein the agent is an enzyme.

76. The use of claim 67, wherein the agent is a radioprotectant.

77. The use of any one of claims 1-21, wherein the medicament is used to aid in tissue restoration and regeneration at a polymerization site in a subject.

78. The use of any one of claims 1-21, wherein the medicament modulates the diffusion of one or more of ions, water, oxygen, carbon dioxide, nutrients, or an active agent in a subject.

79. The use of any one of claims 1-21, wherein the medicament modulates salt diffusion in a subject.

80. The use of any one of claims 1-21, wherein the medicament modulates the diffusion of one or more of a carbonate anion, an acid, a base, a carbohydrate, a lipid, a protein, or a nucleic acid in a subject.

81. The use of any one of claims 1-21, wherein the composition further comprises an enzyme.

82. The use of claim 81, wherein the enzyme is a digestive enzyme.

83. The use of claim 82, wherein the digestive enzyme is lactase, peptidase, sucrase, maltase, amylase, lipase or protease.

84. The use of claim 82, wherein the digestive enzyme is β-galactosidase.

85. The use of claim 84, wherein the β-galactosidase increases the efficiency of lactose digestion in the subject by 20 times.

86. The use of claim 62, wherein the polymer barrier does not inhibit the intrinsic digestive enzyme activity of the subject's epithelium.

87. The use of any one of claims 1-21, wherein the polymer and composition further comprises a nutrient blocking agent.

88. The use of any one of claims 1-21, wherein the composition further comprises a cross-linking agent.

89. The use of claim 88, wherein the cross-linking agent comprises nanoparticles.

90. The use of claim 88, wherein the cross-linking agent comprises polydopamine.

91. The use of claim 88, wherein the cross-linking agent is a nutrient blocking agent.

92. The use of claim 88, wherein the cross-linking agent increases the nutrient blocking ability of the polymer.

93. The use of any one of claims 1-21, wherein the absorption is modulated by adjusting the crosslinking density of the polymer.

94. The use of any one of claims 1-21, wherein the composition further comprises an active pharmaceutical agent.

95. The use of claim 94, wherein the active agent is retained or encapsulated in a polymer.

96. The use of claim 94, wherein the medicament is used to prolong the residence time of the active agent at the polymerized site in the subject compared to administration of the active agent in the absence of the polymer.

97. The use of claim 94, wherein the medicament is for providing sustained release of the active agent compared to administration of the active agent in the absence of a polymer.

98. The use of claim 94, wherein the medicament is used to reduce the frequency of administration of the active agent compared to administration of the active agent in the absence of the polymer.

99. The use of claim 94, wherein the medicament is used to increase the half-life of the active agent compared to administration of the active agent in the absence of the polymer.

100. The use of claim 94, wherein the medicament is used to increase the AUC of the active agent compared to administration of the active agent in the absence of a polymer.

101. The use of claim 94, wherein the medicament is used to modulate the Cmax of the active agent compared to administration of the active agent in the absence of a polymer.

102. The use of claim 94, wherein the medicament is used to modulate the Tmax of the active agent compared to administration of the active agent in the absence of a polymer.

103. The use of claim 101 or 102, wherein the modulation is an increase.

104. The use of claim 101 or 102, wherein the modulation is a decrease.

105. The use of any one of claims 1-21, wherein the drug does not affect drug metabolism.

106. The use of any one of claims 1-21, wherein the composition and its components are non-toxic.

107. The use of any one of claims 1-21, wherein the polymer is non-toxic.

108. The use of any one of claims 1-21, wherein the polymer is stable to physical and chemical forces.

109. The use of any one of claims 1-21, wherein the polymer decomposes less than 10% after exposure to one or more of intestinal fluid, intestinal acid, gastric acid, chyme, ethanol, or saline for 6 hours.

110. The use of claim 108, wherein the physical force is selected from one or more of peristalsis and segmentation.

111. The use of any one of claims 1-21, wherein the composition comprises 0.001 to 1000 mg / mL of monomer, 0.01 to 100 mM of an oxygen source, and optionally, a buffer.

112. The use of any one of claims 1-21, wherein the buffer comprises phosphate, acetate, citrate, N-[tris(hydroxymethyl)methyl]glycine), (tris(hydroxymethyl)aminomethane), or (2-(bis(2-hydroxyethyl)amino)acetic acid).

113. The use of any one of claims 1-21, wherein the buffer comprises tris(hydroxymethyl)aminomethane.

114. The use of any one of claims 1-21, wherein the composition is in powder form.

115. The use of any one of claims 1-21, wherein the medicament is administered by spraying a powder onto a subject or onto an affected area within a subject.

116. The use of any one of claims 1-21, wherein the composition is administered endoscopically.

117. The use of any one of claims 1-21, wherein the composition is administered via a cystoscope, colposcope, colonoscope, bronchoscope, ureteroscope, anoscope, esophagoscope, gastroscope, laparoscope, laryngoscope, proctoscopy, or thoracoscope.

118. The use of any one of claims 1-21, wherein the composition is administered arthroendoscopically, neuroendoscopically, or sigmoidoscopically.

Images