Pedot-PPCN compositions and uses thereof

Abstract

Provided herein are thermoresponsive composite hydrogel compositions comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) matrix to form a PEDOT-PPCN composite hydrogel. The compositions undergo a sol-gel transition at physiological temperature, enabling in situ gelation upon contact with a wound site or tissue. Also provided are methods of treating wounds and inhibiting microbial growth using the PEDOT-PPCN composite hydrogels, methods of preparing the composite hydrogels, wound dressings and medical devices comprising the composite hydrogels, and kits comprising PPCN and PEDOT components with instructions for forming the composite.

Description

[0001] Attorney Docket No. NWEST-44869.601

[0002] Client Ref. No. NU2025-017-02 PEDOT-PPCN COMPOSITIONS AND USES THEREOF

[0003] CROSS-REFERENCE

[0004] This application claims the benefit of U.S. Provisional Patent Application No.

[0005] 63 / 776,495, filed March 24, 2025, and is incorporated by reference herein in its entirety.

[0006] FIELD

[0007] The present disclosure relates generally to thermoresponsive composite hydrogel compositions comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component (e.g„ PEDOT-S, which is poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l-sulfonic acid)) incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) matrix, and methods of making and using such compositions for wound treatment, tissue repair, antimicrobial, and other applications.

[0008] BACKGROUND

[0009] Wound healing is a complex biological process involving coordinated cellular responses including hemostasis, inflammation, proliferation, and remodeling. Disruption of this process, for example in chronic wounds, diabetic ulcers, or large traumatic injuries, can result in delayed healing, infection, and impaired tissue function. There remains a need for wound treatment materials that conform to wound geometry, provide antimicrobial protection, support cell viability, and / or are biocompatible and biodegradable.

[0010] SUMMARY

[0011] In certain aspects, provided herein is a thermoresponsive hydrogel composition comprising a poly (poly ethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component and a poly(3,4-ethylenedioxythiophene) (PEDOT) component (e.g., PEDOT-S, which is poly(4-(2, 3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l -sulfonic acid) incorporated into said PPCN component to form a PEDOT-PPCN composite hydrogel.

[0012] In some embodiments, provided herein are thermoresponsive hydrogel compositions comprising: a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component; and a poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l-sulfonic acid) (PEDOT-S)Attorney Docket No. NWEST-44869.601

[0013] Client Ref. No. NU2025-017-02 component incorporated into said PPCN component to form a PEDOT-PPCN composite hydrogel.

[0014] In some embodiments, the composition undergoes a sol-gel transition at a temperature between about 25°C and about 42°C (e.g., 25°C, 26°C, 27°C, 28°C529°C, 30°C, 31 °C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C540°C, 41°C, 42°C). In some embodiments, the PEDOT component comprises PEDOT:PSS, PEDOT-S, or a combination thereof. In certain embodiments, the PEDOT component is a self-doped poly(3,4-ethylenedioxythiophene) (PEDOT-S). In certain embodiments, the PEDOT component is poly(3,4-ethylenedioxythiophene): poly (styrene sulfonate) (PEDOT:PSS). In some embodiments, the PEDOT component is present at a concentration derived from a PEDOT solution having a PEDOT concentration of from about 2 mg / mL to about 20 mg / mL. In some embodiments, the PEDOT component is present in an amount of from about 0.1% to about 100% (v / v) of a PEDOT solution relative to a total solvent volume used to dissolve the PPCN component. In certain embodiments, the PEDOT solution has a PEDOT concentration of about 2 mg / mL. In certain embodiments, the PEDOT solution has a PEDOT concentration of about 20 mg / mL.

[0015] In some embodiments, the PPCN component comprises the reaction product of citric acid, polyethylene glycol, glycerol 1,3-diglycerolate diacrylate (GDD), and N-isopropylacrylamide (NIPAAm). In certain embodiments, the citric acid, polyethylene glycol, and GDD are combined under polycondensation conditions to form a PPCacrylate prepolymer, wherein the citric acid, polyethylene glycol, and GDD are present in a molar ratio of COOH to OH groups of about 1:1.8:0.2, and the PPCacrylate prepolymer is copolymerized with NIPAAm at about a 1:1 molar ratio. In certain embodiments, the polyethylene glycol is polyethylene glycol-400 (PEG 400). In some embodiments, the PPCN component is present at a concentration of about 100 mg / mL. In some embodiments, the composition has a sol-gel transition temperature of from about 30°C to about 40°C.

[0016] In some embodiments, the composition exhibits antimicrobial activity against at least one Gram-positive bacterial species. In certain embodiments, the Gram-positive bacterial species is Staphylococcus aureus. In some embodiments, the composition maintains at least about 70% viability of mammalian cells contacted by the composition after 24 hours as measured by a cell viability assay. In certain embodiments, the mammalian cells are fibroblasts. In some embodiments, the PPCN component is biodegradable. In some embodiments, the PPCNAttorney Docket No. NWEST-44869.601

[0017] Client Ref. No. NU2025-017-02 component exhibits intrinsic antioxidant properties. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the composition is formulated as a wound dressing, a pharmaceutical composition, or a component of a medical device. In certain embodiments, the composition is in a liquid state at a temperature below about 25°C and in a gel state at a temperature above about 30°C.

[0018] In some embodiments, the composition further comprises at least one additional therapeutic agent. In certain embodiments, the at least one additional therapeutic agent is an antimicrobial agent, an anti-inflammatory agent, a growth factor, or a combination thereof.

[0019] In various aspects, provided herein is a method of treating a wound in a subject in need thereof, comprising administering to the wound a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component (e.g., PEDOT-S) incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the composition undergoes a sol-gel transition upon contact with the wound at a physiological temperature to form a hydrogel at the wound site.

[0020] In some embodiments, provided herein are methods of treating a wound in a subject in need thereof, comprising: administering to the wound a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l-sulfonic acid) (PEDOT-S) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the composition undergoes a sol-gel transition upon contact with the wound at a physiological temperature to form a hydrogel at the wound site.

[0021] In some embodiments, the wound is a skin wound. In certain embodiments, the wound is selected from the group consisting of a surgical wound, a traumatic wound, a burn wound, a chronic wound, and a diabetic ulcer. In some embodiments, the PEDOT component is PEDOT-S. In some embodiments, the PEDOT component is PEDOT:PSS. In some embodiments, the composition is administered topically to the wound. In certain embodiments, the composition is administered by injection to the wound site. In some embodiments, the hydrogel composition further exhibits antimicrobial activity at the wound site. In certain embodiments, the antimicrobial activity comprises inhibition of growth of Staphylococcus aureus.Attorney Docket No. NWEST-44869.601

[0022] Client Ref. No. NU2025-017-02 In some embodiments, the composition maintains at least about 70% viability of mammalian cells at the wound site. In some embodiments, the composition promotes cell migration at the wound site. In certain embodiments, the PEDOT component is present at a concentration derived from a PEDOT solution having a PEDOT concentration of from about 2 mg / mL to about 20 mg / mL. In some embodiments, the method further comprises administering at least one additional therapeutic agent to the wound.

[0023] In certain aspects, provided herein is a method of inhibiting growth of bacteria on a surface, comprising contacting the surface with a composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the composition inhibits growth of at least one bacterial species.

[0024] In some embodiments, provided herein are methods of inhibiting growth of bacteria on a surface, comprising: contacting the surface with a composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component; and a poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l -sulfonic acid) (PEDOT-S) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the composition inhibits growth of at least one bacterial species.

[0025] In some embodiments, provided herein are methods of promoting tissue repair or regeneration in a subject in need thereof, comprising: administering to a tissue site a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component; and a poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l-sulfonic acid) (PEDOT-S) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the composition undergoes a sol-gel transition at the tissue site at a physiological temperature.

[0026] In various aspects, provided herein is a method of promoting tissue repair or regeneration in a subject in need thereof, comprising administering to a tissue site a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component (e.g., PEDOT-S)Attorney Docket No. NWEST-44869.601

[0027] Client Ref. No. NU2025-017-02 incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the composition undergoes a sol-gel transition at the tissue site at a physiological temperature. In some embodiments, the tissue is selected from the group consisting of skin, tendon, ligament, and muscle. In certain embodiments, the tissue comprises nerve tissue.

[0028] In some embodiments, provided herein are methods of preparing a thermoresponsive hydrogel composition, comprising: (a) providing a poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l -sulfonic acid) (PEDOT-S) solution; and (b) combining the PEDOT-S solution with poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to form a PEDOT-PPCN composite hydrogel.

[0029] In some embodiments, provided herein are methods of preparing a thermoresponsive hydrogel composition, comprising: (a) synthesizing poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) by: (i) combining citric acid, polyethylene glycol, and glycerol 1,3-diglycerolate diacrylate (GDD) under polycondensation conditions to form a PPCacrylate prepolymer; and (ii) copolymerizing the PPCacrylate prepolymer with N-isopropylacrylamide (NIPAAm) via free radical polymerization to form PPCN; (b) providing a poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l -sulfonic acid) (PEDOT-S) solution; and (c) combining the PPCN and the PEDOT solution to form a PEDOT-PPCN composite hydrogel.

[0030] In certain aspects, provided herein is a method of preparing a thermoresponsive hydrogel composition, comprising: (a) providing a poly(3,4-ethylenedioxythiophene) (PEDOT) solution (e.g., a PEDOT-S solution); and (b) combining the PEDOT solution with poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to form a PEDOT-PPCN composite hydrogel.

[0031] In various aspects, provided herein is a method of preparing a thermoresponsive hydrogel composition, comprising: (a) synthesizing poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) by (i) combining citric acid, polyethylene glycol, and glycerol 1.3-diglycerolate diacrylate (GDD) under polycondensation conditions to form a PPCacrylate prepolymer, and (ii) copolymerizing the PPCacrylate prepolymer with N-isopropylacrylamide (NIPAAm) via free radical polymerization to form PPCN; (b) providing a poly(3,4-ethylenedioxythiophene) (PEDOT) solution; and (c) combining the PPCN and the PEDOT solution (e.g., PEDOT-S) to form a PEDOT-PPCN composite hydrogel. In some embodiments of the methods of preparing a thermoresponsive hydrogel composition, the PEDOT solutionAttorney Docket No. NWEST-44869.601

[0032] Client Ref. No. NU2025-017-02 comprises PEDOT:PSS. In some embodiments, the PEDOT solution comprises PEDOT-S. In certain embodiments, the PEDOT solution has a PEDOT concentration of about 2 mg / mL. In certain embodiments, the PEDOT solution has a PEDOT concentration of about 20 mg / mL. In some embodiments, the PEDOT solution is combined with the PPCN at a volume ratio of PEDOT solution to total solvent of from about 0.1% to about 100% (v / v). In certain embodiments, the PPCN is present at a concentration of about 100 mg / mL. In some embodiments, the method further comprises allowing the PEDOT-PPCN composite hydrogel to undergo gelation at a temperature of from about 25 °C to about 42°C. In some embodiments, the method further comprises applying the PEDOT-PPCN composite hydrogel to a substrate to form a wound dressing.

[0033] In certain embodiments, the polycondensation step is conducted at about 140°C with stirring at about 300 rpm for about 45 minutes. In certain embodiments, the free radical polymerization step is conducted in 1,4-dioxane at about 65 °C using azobisisobutyronitrile (AIBN) as a free radical initiator. In some embodiments, the polyethylene glycol is PEG-400.

[0034] In certain aspects, provided herein is a method of preparing a thermoresponsive hydrogel composition, comprising: (a) synthesizing self-doped poly(3,4-ethylenedioxythiophene) (PEDOT-S) by oxidative polymerization of an EDOT-S monomer; and (b) combining the PEDOT-S with poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to form a PEDOT-S-PPCN composite hydrogel.

[0035] In some embodiments, the oxidative polymerization comprises combining the EDOT-S monomer with Na2S2Os and FeCL in an aqueous solution. In certain embodiments, the EDOT-S monomer is present at about 0.61 mmol, the Na2S20s is present at about 1.22 mmol, and the FeCL is present at about 0.031 mmol. In some embodiments, the method further comprises dialyzing the PEDOT-S against water using a membrane having a molecular weight cutoff of about 1 kDa.

[0036] In certain aspects, provided herein is a wound dressing comprising a substrate and a thermoresponsive hydrogel composition disposed on or within the substrate, the hydrogel composition comprising a PEDOT-PPCN composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the hydrogel composition undergoes a sol-gel transition at a temperature between about 25°C and about 42°C.Attorney Docket No. NWEST-44869.601

[0037] Client Ref. No. NU2025-017-02 In some embodiments, provided herein are wound dressings comprising: a substrate; and a thermoresponsive hydrogel composition disposed on or within the substrate, the hydrogel composition comprising a PEDOT-PPCN composite hydrogel comprising a poly(4-(2.3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l -sulfonic acid) (PEDOT-S) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the hydrogel composition undergoes a sol-gel transition at a temperature between about 25°C and about 42°C.

[0038] In some embodiments, the substrate is selected from the group consisting of a gauze, a foam, a film, a mesh, a hydrocolloid, and a nonwoven fabric. In some embodiments, the PEDOT component is PEDOT-S. In some embodiments, the PEDOT component is PEDOT:PSS. In certain embodiments, the hydrogel composition exhibits antimicrobial activity against at least one bacterial species. In certain embodiments, the hydrogel composition maintains at least about 70% viability of mammalian cells contacted by the composition after 24 hours.

[0039] In various aspects, provided herein is a medical device comprising a thermoresponsive hydrogel composition, the hydrogel composition comprising a PEDOT-PPCN composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component.

[0040] In some embodiments, the medical device is a wound dressing, a tissue scaffold, a drug delivery device, or a bioelectronic interface. In some embodiments, the hydrogel composition undergoes a sol-gel transition at a temperature between about 25°C and about 42°C.

[0041] In certain aspects, provided herein is a kit comprising: (a) poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN); (b) a poly(3,4-ethylenedioxythiophene) (PEDOT) solution; and (c) instructions for combining (a) and (b) to form a thermoresponsive PEDOT-PPCN composite hydrogel.

[0042] In some embodiments, the PEDOT solution comprises PEDOT-S at a concentration of from about 2 mg / mL to about 20 mg / mL. In certain embodiments, the PEDOT solution comprises PEDOT:PSS at a concentration of about 2 mg / mL. In some embodiments, the kit further comprises a wound dressing substrate. In some embodiments, the kit further comprises at least one additional therapeutic agent.

[0043] In various aspects, provided herein is a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-Attorney Docket No. NWEST-44869.601

[0044] Client Ref. No. NU2025-017-02 ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, for use in therapy.

[0045] In some embodiments, the therapy is wound treatment. In some embodiments, the therapy is inhibiting microbial growth at a wound site. In certain embodiments, the therapy is tissue repair or regeneration. In some embodiments, the PEDOT component is PEDOT-S. In some embodiments, the PEDOT component is PEDOT:PSS.

[0046] In certain embodiments, the composition undergoes a sol-gel transition at a temperature between about 25°C and about 42°C. In some embodiments, the composition maintains at least about 70% viability of mammalian cells contacted by the composition after 24 hours. In some embodiments, the composition further comprises at least one additional therapeutic agent. In certain embodiments, the microbial growth comprises growth of Staphylococcus aureus. In certain embodiments, the tissue is selected from the group consisting of skin, tendon, ligament, muscle, and nerve tissue.

[0047] BREIF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts the PEDOT-PPCN composite hydrogel synthesis and characterization. (A) Schematic illustrating the hydrogel’s role in enhancing cell migration at the injury site to accelerate wound healing. (B) Diagram of the PEDOT-PPCN structure, showing the PPCN polymer matrix and incorporated PEDOT component (PEDOT:PSS or PEDOT-S-H), with PEDOT-PPCN composite formation facilitated by electrostatic interactions. (C) Representative images of the PEDOT-PPCN hydrogels in a liquid state (top) and a gelled state (bottom), at concentrations of 0.1%, 1%, 10%, 50%, and 100% (v / v) PEDOT, for both PEDOT-S and PEDOT:PSS formulations at two PEDOT concentrations.

[0048] FIG. 2 depicts characterization data demonstrating that PEDOT-PPCN preserves favorable characteristics of PPCN. (A) Rheological analysis of PEDOT-PPCN hydrogels incorporating PEDOT:PSS (left panel) and PEDOT-S at 20 mg / mL (right panel), showing storage modulus (G') and loss modulus (G") as a function of temperature (15-45°C). Gelation temperatures remain within physiologically relevant ranges across all tested PEDOT concentrations (0.1%, 1%, 10%, 50%, 100% v / v). (B) Cell viability assay results for L929 fibroblast cells after 24 hours of contact with PEDOT-PPCN hydrogels, assessed by Alamar Blue assay. PEDOT:PSS (left panel): concentrations above 1% (v / v) resulted in less than 50% cell viability. PEDOT-S at 20 mg / mL (right panel): cell viability was maintained at least 70% acrossAttorney Docket No. NWEST-44869.601

[0049] Client Ref. No. NU2025-017-02 all tested concentrations. (C) Antimicrobial assay results against Staphylococcus aureus. Colonyforming unit (CFU) plates for PEDOT-S (top row) and PEDOT:PSS (bottom row), with nontreated (NT), penicillin- streptomycin (PS), and PPCN-only controls, showing increasing antimicrobial activity with higher PEDOT concentrations for both PEDOT variants.

[0050] FIG. 3 shows EIS measurements for PEDOT-PPCN. Among the tested formulations, the 10% and 100% PEDOT-S PPCN hydrogels demonstrated the highest conductivity. While understanding the mechanism is not necessary to practice the present invention, this may be attributed to molecular interactions and bond shifts observed in the 50% formulation, as indicated by the FTIR spectrum.

[0051] FIG. 4 shows Characterization of PEDOT-S incorporated into PPCN. (A) FTIR spectra of PPCN hydrogels containing varying concentrations of PEDOT-S, top - i)10% and ii) 100%; bottom - iii) 50% ). (B) Rheological properties of the PEDOT-S-PPCN hydrogels. (C) Free radical scavenging activity of the different hydrogel formulations.

[0052] DEFINITIONS

[0053] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, some preferred methods, compositions, devices, and materials are described herein. However, before the present materials and methods are described, it is to be understood that this invention is not limited to the particular molecules, compositions, methodologies or protocols herein described, as these may vary in accordance with routine experimentation and optimization. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only and is not intended to limit the scope of the embodiments described herein.

[0054] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. However, in case of conflict, the present specification, including definitions, will control. Accordingly, in the context of the embodiments described herein, the following definitions apply.

[0055] As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a component” is a reference to one or more components and equivalents thereof known to those skilled in the art, and so forth.Attorney Docket No. NWEST-44869.601

[0056] Client Ref. No. NU2025-017-02 As used herein, the term “and / or” includes any and all combinations of listed items, including any of the listed items individually. For example, “A, B, and / or C” encompasses A, B, C. AB, AC. BC, and ABC, each of which is to be considered separately described by the statement “A, B, and / or C.”

[0057] As used herein, "about" when modifying a numerical value means within 10% of the stated value, unless the context indicates a different degree of variance. For example, “about 25°C” encompasses a temperature range from 22.5°C to 27.5°C. Throughout this specification, specific numerical values and ranges are provided. It is to be understood that these values and ranges are approximations and that the word "about" may be inferred even if not expressly stated, unless the context clearly dictates otherwise.

[0058] All ranges disclosed herein encompass every sub-range and value within the stated range. For example, a range of "from about 25°C to about 42°C" includes, e.g., from about 25°C to about 30°C, from about 30°C to about 37°C, from about 35°C to about 42°C, about 37°C, and all intermediate values and sub-ranges.

[0059] As used herein, the term “comprise” and linguistic variations thereof denote the presence of recited feature(s), element(s), method step(s), etc. without the exclusion of the presence of additional feature(s), element(s), method step(s), etc. Conversely, the term “consisting of’ and linguistic variations thereof, denotes the presence of recited feature(s), element(s), method step(s), etc. and excludes any unrecited feature(s), element(s), method step(s), etc., except for ordinarily-associated impurities. The phrase “consisting essentially of’ denotes the recited feature(s), element(s), method step(s), etc. and any additional feature(s), element(s), method step(s), etc. that do not materially affect the basic nature of the composition, system, or method. Many embodiments herein are described using open “comprising” language. Such embodiments encompass multiple closed “consisting of’ and / or “consisting essentially of’ embodiments, which may alternatively be claimed or described using such language.

[0060] “Kit,” as used herein, refers an assemblage of separate components, etlements, composition etc. together for a singular purpose. A kit may be a packaged combination of components, for example, together with instructions for combining and / or using the components. The components of a kit may be provided in separate containers within a single package, or in separate packages that are provided together. Instructions may be provided in printed form, inAttorney Docket No. NWEST-44869.601

[0061] Client Ref. No. NU2025-017-02 electronic form, by reference to a publicly accessible resource (e.g., a website or package insert), or may be absent.

[0062] “PPCN” or “poly(polyethylene glycol citrate-co-N-isopropylacrylamide),” as used herein, refers to a thermoresponsive, biodegradable polymer synthesized by sequential polycondensation and free radical polymerization of citric acid, polyethylene glycol (e.g., PEG 400), glycerol 1.3-diglycerolate diacrylate (GDD), and N-isopropylacrylamide (NIPAAm).

[0063] PPCN is characterized by a lower critical solution temperature (LCST) that enables it to exist as a liquid below the LCST and as a gel above the LCST. In some embodiments, the polycondensation step produces a PPCacrylate prepolymer from citric acid, polyethylene glycol, and GDD, and the prepolymer is subsequently copolymerized with NIPAAm via free radical polymerization to yield PPCN.

[0064] “PEDOT” or “poly(3,4-ethylenedioxythiophene),” as used herein, refers to the conjugated polymer poly(3,4-ethylenedioxythiophene) and derivatives thereof. PEDOT encompasses both doped forms (e.g.. PEDOT:PSS) and self-doped forms (e.g.. PEDOT-S). Unless otherwise specified, “PEDOT” as used herein includes any PEDOT variant suitable for incorporation into a PPCN matrix to form a PEDOT-PPCN composite hydrogel.

[0065] “PEDOT:PSS” or “poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate),” as used herein, refers to a complex of the conjugated polymer PEDOT doped with the polyanion polystyrene sulfonate) (PSS). PEDOT:PSS is commercially available as an aqueous dispersion (e.g., from Heraeus under the trade name Clevios™). The PSS component serves as both a charge-balancing dopant and a dispersant that facilitates water solubility of the otherwise hydrophobic PEDOT.

[0066] “PEDOT-S” or “self-doped poly(3,4-ethylenedioxythiophene),” which is poly(4-(2,3-dihydrothieno[3,4-b][l,4]dioxin-2-yl)butane-l -sulfonic acid), as used herein, refers to a derivative of PEDOT in which sulfonate groups are covalently attached to the EDOT monomer backbone (as pendant groups), rather than being provided by an external dopant such as PSS. PEDOT-S is synthesized by oxidative polymerization of a sulfonated EDOT monomer (“LOOTS’’). The pendant sulfonate groups provide self-doping and water solubility without the need for an external polyelectrolyte dopant.

[0067] “PPCacrylate prepolymer,” as used herein, refers to the intermediate product formed by the polycondensation of citric acid, polyethylene glycol (e.g., PEG 400), and glycerol 1,3-Attorney Docket No. NWEST-44869.601

[0068] Client Ref. No. NU2025-017-02 diglycerolate diacrylate (GDD). The PPCacrylate prepolymer contains acrylate functionality that enables subsequent free radical copolymerization with NIPAAm to form PPCN.

[0069] “N-isopropylacrylamide” or “NIPAAm” or “NIPAAM,” as used herein, refers to the monomer N-isopropylacrylamide (CAS No. 2210-25-5), which is used as a comonomer in the synthesis of PPCN. NIPAAm imparts thermoresponsive behavior to polymers incorporating it.

[0070] “PEDOT-PPCN” or “PEDOT-PPCN composite hydrogel,” as used herein, refers to a composite hydrogel formed by incorporating a PEDOT component (including PEDOT:PSS, PEDOT-S, or other PEDOT derivatives) into a PPCN matrix. The PEDOT and PPCN components in the PEDOT-PPCN composite are associated through non-covalent interactions.

[0071] “Composite” or “composite hydrogel,” as used herein, refers to a material formed by combining two or more distinct components such that the resulting material possesses properties attributable to the combination that are not exhibited by either component alone. As used herein, a “PEDOT-PPCN composite hydrogel” refers to a hydrogel material comprising a PEDOT component associated with a PPCN matrix. The association between the PEDOT and PPCN components may be through any non-covalent interaction, including electrostatic interactions, hydrogen bonding, van der Waals interactions, or combinations thereof. As used herein, a “composite” is distinguished from a mere physical mixture (i.e., a simple blend in which the components do not interact) and from a covalent copolymer (i.e., a polymer in which the components are joined by covalent bonds). Exemplary, evidence that a PEDOT-PPCN composite has been formed includes, but is not limited to, retention of thermoresponsive behavior of the PPCN component in the presence of the PEDOT component, uniform visual appearance of the composite, and / or the composite exhibiting functional properties (such as antimicrobial activity) not exhibited by the PPCN component alone.

[0072] “Hydrogel,” as used herein, refers to a three-dimensional network of hydrophilic polymers that can absorb and retain a significant amount of water while maintaining a distinct three-dimensional structure. In the context of this disclosure, a hydrogel refers to the gel state of a thermoresponsive composition that has undergone a sol-gel transition.

[0073] “Antimicrobial activity,” as used herein, refers to a measurable reduction in the viability or growth of at least one microbial species when contacted with a composition described herein, as compared to an untreated control under comparable conditions. Antimicrobial activity may be assessed by any suitable method known in the art, including, but not limited to, colony-formingAttorney Docket No. NWEST-44869.601

[0074] Client Ref. No. NU2025-017-02 unit (CFU) enumeration, minimum inhibitory concentration (MIC) assays, zone of inhibition assays, or optical density measurements. As used herein, a composition “exhibits antimicrobial activity” if it produces a statistically significant reduction in CFU or other measure of microbial viability relative to an untreated or vehicle-treated control.

[0075] “Biocompatible,” as used herein, refers to a material or composition that does not elicit a substantial cytotoxic response when contacted with living mammalian cells under standard in vitro culture conditions. In some embodiments, a composition is considered biocompatible if it maintains at least about 70% viability of mammalian cells contacted by the composition after 24 hours, as measured by a standard cell viability assay such as the Alamar Blue assay, the MTT assay, or the Live / Dead assay. The term “biocompatible” as used herein does not require the absence of any immune or inflammatory response in vivo, but rather indicates that the composition is suitable for use in contact with living tissue.

[0076] “Biodegradable,” as used herein, refers to a material that is capable of being broken down into simpler chemical species by biological processes, including hydrolysis, enzymatic degradation, or cellular metabolism. A biodegradable polymer, as used herein, includes polymers that degrade under physiological conditions (e.g., in aqueous environments at about 37°C and physiological pH) over a period ranging from days to months.

[0077] “Thermoresponsive as used herein, refers to a material or composition that exhibits a reversible change in physical state (e.g., a sol-gel transition) in response to a change in temperature. A thermoresponsive composition as described herein exists as a liquid (sol) at temperatures below its LCST and transitions to a gel at temperatures above its LCST. In some embodiments, a thermoresponsive composition described herein undergoes a sol-gel transition at a temperature between about 25°C and about 42°C.

[0078] “Sol-gel transition,” as used herein, refers to the reversible phase change of a thermoresponsive composition from a liquid state (“sol”) to a gel state (“gel”) in response to a change in temperature. For PPCN-based compositions, the sol-gel transition occurs when the temperature is raised above the LCST. The sol-gel transition may be characterized by oscillatory rheology, wherein the transition is defined as the temperature at which the storage modulus (G') exceeds the loss modulus (G").

[0079] “Lower critical solution temperature” or “LCST,” as used herein, refers to the temperature below which a thermoresponsive polymer is miscible with its solvent (e.g., water) inAttorney Docket No. NWEST-44869.601

[0080] Client Ref. No. NU2025-017-02 all proportions, and above which phase separation occurs, resulting in gelation. For PPCN-based compositions, the LCST is the temperature at which the storage modulus (G') begins to increase relative to the loss modulus (G"). as determined by oscillatory rheology under defined conditions.

[0081] “Physiological temperature,” as used herein, refers to a temperature within the range encountered in a living mammalian body, generally from about 35°C to about 40°C. In typical usage herein, physiological temperature refers to approximately 37°C, which is the normal core body temperature of a human subject.

[0082] “Subject,” as used herein, refers to a mammal, including a human, a non-human primate, a rodent, a canine, a feline, a bovine, an ovine, an equine, or a porcine subject. In some embodiments, the subject is a human. In some embodiments, the subject is “in need thereof,” meaning the subject has a condition (e.g., a wound, a tissue injury, an infection) for which treatment with the compositions or methods described herein is indicated.

[0083] “Therapeutic agent,” as used herein, refers to any substance that produces a therapeutic or prophylactic effect when administered to a subject. Therapeutic agents include, but are not limited to, antimicrobial agents (e.g., antibiotics, antifungals), anti-inflammatory agents (e.g., corticosteroids, non-steroidal anti-inflammatory drugs), growth factors (e.g., EGF, PDGF, VEGF, FGF), analgesics, and small molecule drugs.

[0084] “Pharmaceutical composition,” as used herein, refers to a composition comprising a PEDOT-PPCN composite hydrogel together with at least one pharmaceutically acceptable carrier, diluent, or excipient. A pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0085] “Pharmaceutically acceptable carrier,” “diluent,” or “excipient,” as used herein, refers to a substance that is not a therapeutic agent itself and is used as a carrier, diluent, or vehicle for delivery of a therapeutic composition to a subject, or is added to a composition to improve its handling, storage, or administration characteristics. Pharmaceutically acceptable carriers include, but are not limited to, water, saline, buffered solutions, glycerol, and other biocompatible solvents or excipients.

[0086] “Wound,” as used herein, refers to any disruption of the integrity of skin or other tissue resulting from injury, surgery, disease, or other cause. Wounds include, but are not limited to,Attorney Docket No. NWEST-44869.601

[0087] Client Ref. No. NU2025-017-02 surgical wounds, traumatic wounds (e.g., lacerations, abrasions, puncture wounds), burn wounds, chronic wounds (e.g., venous ulcers, pressure ulcers), and diabetic ulcers.

[0088] “Wound dressing,” as used herein, refers to an article of manufacture designed to be placed on or over a wound to promote healing, protect the wound from contamination, or deliver therapeutic agents to the wound site. A wound dressing as described herein comprises a substrate and a thermoresponsive hydrogel composition disposed on or within the substrate.

[0089] “Substrate,” as used herein, for example, in the context of a wound dressing, refers to a physical support material on or within which a hydrogel composition is disposed. Substrates include, but are not limited to, gauze, foam, film, mesh, hydrocolloid, and nonwoven fabric. The substrate provides structural support for the hydrogel composition and may facilitate handling and application of the wound dressing to a wound site. A substrate may also encompass other non-dressing materials upon which a composition herein may be applied.

[0090] “Medical device,” as used herein, refers to any instrument, apparatus, implement, machine, contrivance, implant, or other article that is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, or intended to affect the structure or function of the body. Medical devices include, but are not limited to, wound dressings, tissue scaffolds, surgical tools, drug delivery devices, bioelectronic interfaces, sensors, and electrode coatings.

[0091] “Administering” or “administration,” as used herein, refers to providing a composition to a subject or to a site (e.g., a wound site, a tissue site) by any suitable route. Administering includes, but is not limited to, topical application, injection (including subcutaneous, intradermal, and intramuscular injection), irrigation, instillation, and placement. Administering does not require that the composition be in any particular physical state at the time of delivery; for example, a thermoresponsive composition may be administered as a liquid and undergo gelation after administration. Administering may encompass both self-administration and administration to another, unless stated otherwise.

[0092] “Cell viability assay,” as used herein, refers to any quantitative or semi-quantitative assay that measures the proportion of living cells in a population after exposure to a test condition. Exemplary cell viability assays include, but are not limited to, the Alamar Blue (resazurin reduction) assay, the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, the MTS assay, the Live / Dead (calcein-AM / ethidium homodimer) assay, and trypan blue exclusion.Attorney Docket No. NWEST-44869.601

[0093] Client Ref. No. NU2025-017-02 “Fibroblast,” as used herein, refers to a connective tissue cell type that produces extracellular matrix components and plays a central role in wound healing. In some embodiments, fibroblasts used for biocompatibility testing include the L929 murine fibroblast cell line (ATCC CCL-1) or primary human dermal fibroblasts.

[0094] “Incorporated into,” as used herein, refers to a first component (e.g., PEDOT) being retained within a second component (e.g., a PPCN matrix) such that a composite material is formed. “Incorporated into” encompasses any means of combining components, including, but not limited to, dissolving one component into a solution containing the other component, mixing one component into a solution of the other, or co-formulating the components. The term does not require covalent bonding between the components.

[0095] DETAILED DESCRIPTION

[0096] The present disclosure relates generally to thermoresponsive composite hydrogel compositions comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component (e.g., PEDO-S) incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) matrix, and methods of making and using such compositions for wound treatment, tissue repair, antimicrobial, and other applications.

[0097] Citrate-based thermoresponsive polymers, such as poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN), have been developed for biomedical applications. PPCN is synthesized through sequential polycondensation and free radical polymerization of citric acid, polyethylene glycol, and N-isopropylacrylamide. Separately, conducting polymers such as poly(3,4-ethylenedioxythiophene) (PEDOT) and its derivatives have been investigated for bioelectronic applications, including neural electrodes, biosensors, and bioelectronic interfaces. PEDOT-based materials are valued for their electrical conductivity, chemical stability, and processability. However, PEDOT formulations have been associated with limited biocompatibility and biofunctionality, particularly at higher concentrations, which has constrained their use in direct tissue-contact applications.

[0098] In some embodiments, provided herein are thermoresponsive hydrogel compositions comprising a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component and a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into said PPCNAttorney Docket No. NWEST-44869.601

[0099] Client Ref. No. NU2025-017-02 component to form a PEDOT-PPCN composite hydrogel. The present disclosure is not limited to particular PEDOT-PPCN compositions.

[0100] In some embodiments, the PEDOT component of the PEDOT-PPCN composite hydrogel comprises PEDOT:PSS, PEDOT-S, or a combination thereof. In some embodiments, the PEDOT component is poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS).

[0101] PEDOT:PSS is a complex of the conjugated polymer PEDOT doped with the polyanion polystyrene sulfonate) (PSS). PEDOT:PSS is commercially available as an aqueous dispersion (e.g., Heraeus Clevios™) at various concentrations, including about 2 mg / mL. In some embodiments, the PEDOT component is a self-doped poly(3,4-ethylenedioxythiophene) (PEDOT-S). PEDOT-S is a derivative of PEDOT in which sulfonate groups are covalently attached as pendant groups to the EDOT monomer backbone, providing self-doping and water solubility without the need for an external polyelectrolyte dopant such as PSS. PEDOT-S may be synthesized by oxidative polymerization of a sulfonated EDOT monomer (EDOT-S). In some embodiments, the PEDOT component is present in a combination of PEDOT:PSS and PEDOT-S.

[0102] In certain aspects, the PEDOT-PPCN composite hydrogel has a concentration of about 0.2 mg / mL to about 200 mg / mL (e.g., 0.2 mg / mL, 0.5 mg / mL, 1 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 50 mg / mL, 100 mg / mL, 200mg / mL, or values or ranges therebetween) of PEDOT or PEDOT-S in the PPCN matrix. As used herein, the concentration of the PEDOT component in the PEDOT-PPCN composite hydrogel may be expressed as a percentage (v / v) of a PEDOT stock solution relative to the total solvent volume used to dissolve the PPCN component. For example, if 200 pL of a PEDOT stock solution is combined with 1800 pL of water for a total solvent volume of 2000 pL, and PPCN is dissolved in this combined solvent, the PEDOT component is present at 10% (v / v). The PEDOT stock solution itself has a defined PEDOT concentration (e.g., about 2 mg / mL or about 20 mg / mL); thus the final mass of PEDOT in the composition depends on both the % (v / v) of the PEDOT stock solution and the concentration of the stock solution. In some embodiments, the PEDOT component is present at a concentration derived from a PEDOT solution having a PEDOT concentration of from about 1 mg / mL to about 50 mg / mL, or about 2 mg / mL to about 20 mg / mL. In some embodiments, the PEDOT component is present in an amount of from about 0.1% to about 100% (v / v) of a PEDOT solution relative to a total solvent volume used to dissolve the PPCN component. InAttorney Docket No. NWEST-44869.601

[0103] Client Ref. No. NU2025-017-02 some embodiments, the PEDOT solution has a PEDOT concentration of about 0.2 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, or about 50 mg.mL.

[0104] In some embodiments, the PPCN component of the PEDOT-PPCN composite hydrogel comprises the reaction product of citric acid, polyethylene glycol, glycerol 1,3-diglycerolate diacrylate (GDD), and N-isopropylacrylamide (NIPAAm). In some embodiments, the citric acid, polyethylene glycol, and GDD are combined under polycondensation conditions to form a PPCacrylate prepolymer, and the citric acid, polyethylene glycol, and GDD are present in a molar ratio of COOH to OH groups of about 1:1.8:0.2. The PPCacrylate prepolymer is then copolymerized with NIPAAm at about a 1:1 molar ratio via free radical polymerization to form PPCN. In some embodiments, the polyethylene glycol is of any suitable molecular weight, such as polyethylene glycol-100 (PEG 100), polyethylene glycol-150 (PEG 150), polyethylene glycol-200 (PEG 200), polyethylene glycol-300 (PEG 300), polyethylene glycol-400 (PEG 400), polyethylene glycol-600 (PEG 600), polyethylene glycol-800 (PEG 800). polyethylene glycol-1000 (PEG 1000), etc. Poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) is primarily composed of citric acid, PEG (e.g., polyethylene glycol-400 (PEG 400)), and N-isopropylacrylamide (NIPAAM). It is synthesized through a two-step process: polycondensation followed by free radical polymerization. During the polycondensation step, citric acid (e.g., about 0.02 moles), PEG (e.g.. PEG 400) (e.g., about 0.04 moles), and Glycerol 1,3-diglycerolate diacrylate (GDD, e.g., about 0.1 moles) are combined at about 140°C and stirred at about 300 rpm for about 45 minutes. The final molar ratio of COOH to OH groups is about 1:1.8:0.2 (citric acid:PEG), forming the PPCacrylate prepolymer. In the subsequent free radical copolymerization, the PPCacrylate prepolymer is reacted with NIPAAM in about a 1 : 1 molar ratio, using Azobisisobutyronitrile (AIBN) as the initiator. The reaction is carried out in 1,4-dioxane as the solvent at about 65 °C under about 300 rpm stirring. The product is then precipitated dropwise into diethyl ether and dried under vacuum to yield PPCN. In some embodiments, the PPCN component is present at a concentration of about 10 mg / mL to 500 mg / mL (e.g., 10 mg / mL, 20 mg / mL, 50 mg / mL, 100 mg / mL, 200 mg / mL, 500 mg / mL, or values or ranges therebetween) in the PEDOT-PPCN composite hydrogel (e.g., about 200 mg / mL or about 200 mg PPCN per about 2 mL total solvent volume).Attorney Docket No. NWEST-44869.601

[0105] Client Ref. No. NU2025-017-02 In some embodiments, the PEDOT-PPCN composite hydrogel undergoes a sol-gel transition at a temperature between about 15°C and about 50°C (e.g., about 15°C, about 18°C, about 20°C, about 22°C, about 25°C, about 27°C. about 30°C. about 32°C, about 35°C, about 38°C, about 40°C, about 42°C, about 45°C, about 47°C, about 50°C„ or ranges or values therebetween). In some embodiments, the composition has a sol-gel transition temperature of from about 30°C to about 40°C. The sol-gel transition of the PEDOT-PPCN composite hydrogel is characterized by an increase in the storage modulus (G') relative to the loss modulus (G") as measured by oscillatory rheology. In some embodiments, the PEDOT-PPCN composite hydrogel is in a liquid state at a temperature below about 25 °C and in a gel state at a temperature above about 30°C. The thermoresponsive behavior of the PEDOT-PPCN composite hydrogel is attributable to the PPCN component, which exhibits a lower critical solution temperature (LCST). Incorporation of the PEDOT component into the PPCN matrix does not abolish or substantially shift the thermoresponsive gelation behavior of the PPCN, as demonstrated by the rheological data presented in herein.

[0106] In some embodiments, the PEDOT-PPCN composite hydrogel exhibits antimicrobial activity against at least one bacterial species (Staphylococcus aureus). In some embodiments, the bacterial species is Staphylococcus aureus. In some embodiments, the PEDOT-PPCN composite hydrogel exhibits antimicrobial activity against various Gram-positive bacteria, such as, but not limited to Streptococcus pyogenes, Enterococcus faecalis, Staphylococcus epidermidis, Cutibacterium acnes, Bacillus subtilis, Clostridium difficile, Listeria monocytogenes, Corynebacterium diphtheriae, etc. In some embodiments, the PEDOT-PPCN composite hydrogel exhibits antimicrobial activity against various Gram-negative bacteria, such as, but not limited to Salmonella enterica, Shigella spp., Campylobacter jejuni, Vibrio cholerae, Helicobacter pylori, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae, Proteus mirabilis, Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis, Legionella pneumophila, etc. As demonstrated in FIG. 2C, both PEDOT-S-PPCN and PEDOT:PSS-PPCN composite hydrogels exhibited antimicrobial activity against S. aureus, with increasing antimicrobial activity observed at higher PEDOT concentrations.

[0107] In some embodiments, the PEDOT-PPCN composite hydrogel maintains at least about 70% (e.g., 70%, 75%, 80%, 85%, 90%, 95%, 99%, or ranges therebetween) viability ofAttorney Docket No. NWEST-44869.601

[0108] Client Ref. No. NU2025-017-02 mammalian cells contacted by the composition after 24 hours as measured by a cell viability assay. In some embodiments, the mammalian cells are fibroblasts (e.g., L929 fibroblasts). As demonstrated in FIG. 2B, PEDOT-S-PPCN composite hydrogels maintained cell viability of at least about 70% across all tested concentrations (0.1% to 100% v / v of 20 mg / mL PEDOT-S stock solution) when tested against L929 murine fibroblast cells using the Alamar Blue assay after 24 hours. In contrast, PEDOT:PSS-PPCN composite hydrogels at concentrations above 1% (v / v) resulted in less than 50% cell viability under the same conditions.

[0109] In some embodiments, the PPCN component of the PEDOT-PPCN composite hydrogel is biodegradable. In some embodiments, the PPCN component exhibits intrinsic antioxidant properties, including free radical scavenging activity and metal ion chelation activity..

[0110] The PEDOT-PPCN composite hydrogel is formed by incorporating the PEDOT component into the PPCN matrix.

[0111] In some embodiments, the PEDOT-PPCN composite hydrogel is provided as a pharmaceutical composition further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the PEDOT-PPCN composite hydrogel is formulated as a wound dressing, a pharmaceutical composition, or a component of a medical device.

[0112] In some embodiments, the PEDOT-PPCN composite hydrogel further comprises at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent is an antimicrobial agent, an anti-inflammatory agent, a growth factor, or a combination thereof.

[0113] Exemplary antimicrobial agents include, but are not limited to, antibiotics (e.g., penicillin, streptomycin, gentamicin, vancomycin, mupirocin), antifungal agents (e.g.. nystatin, fluconazole), and silver-based antimicrobials (e.g., silver sulfadiazine, silver nanoparticles). Exemplary anti-inflammatory agents include, but are not limited to, corticosteroids (e.g., hydrocortisone, dexamethasone), non-steroidal anti-inflammatory drugs (e.g., ibuprofen), and anti-inflammatory peptides. Exemplary growth factors include, but are not limited to, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-0).

[0114] In some embodiments, provided herein is a method of treating a wound in a subject in need thereof, comprising administering to the wound a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, wherein the composition undergoes a sol-gelAttorney Docket No. NWEST-44869.601

[0115] Client Ref. No. NU2025-017-02 transition upon contact with the wound at a physiological temperature to form a hydrogel at the wound site.

[0116] In some embodiments, the wound is a skin wound. In some embodiments, the wound is selected from the group consisting of a surgical wound, a traumatic wound, a burn wound, a chronic wound, and a diabetic ulcer.

[0117] In some embodiments, the composition is administered topically to the wound. In some embodiments, the composition is administered by injection to the wound site. Because the PEDOT-PPCN composite hydrogel is in a liquid state below its LCST, the composition can be applied by injection through a needle or cannula and will undergo gelation in situ at the wound site upon reaching physiological temperature.

[0118] In some embodiments, the hydrogel composition further exhibits antimicrobial activity at the wound site. In some embodiments, the antimicrobial activity comprises inhibition of growth of Staphylococcus aureus.

[0119] In some embodiments, the composition maintains at least about 70% (e.g„ 70%. 75%, 80%, 85%, 90%, 95%, 99%, or ranges therebetween) viability of mammalian cells at the wound site, hi some embodiments, the composition promotes cell migration at the wound site.

[0120] In some embodiments, methods further comprise administering at least one additional therapeutic agent to the wound.

[0121] In some embodiments, provided herein is a method of inhibiting growth of bacteria on a surface, comprising contacting the surface with a composition comprising a PEDOT-PPCN composite hydrogel, wherein the composition inhibits growth of at least one bacterial species.

[0122] In some embodiments, provided herein is a method of promoting tissue repair or regeneration in a subject in need thereof, comprising administering to a tissue site a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, wherein the composition undergoes a sol-gel transition at the tissue site at a physiological temperature. In some embodiments, the tissue is selected from the group consisting of skin, tendon, ligament, and muscle. In some embodiments, the tissue comprises nerve tissue.

[0123] In some embodiments, provided herein is a method of preparing a thermoresponsive hydrogel composition, comprising: (a) providing a poly(3,4-ethylenedioxythiophene) (PEDOT) solution; and (b) combining the PEDOT solution with poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to form a PEDOT-PPCN composite hydrogel. In someAttorney Docket No. NWEST-44869.601

[0124] Client Ref. No. NU2025-017-02 embodiments, the method further comprises synthesizing PPCN by: (i) combining citric acid, polyethylene glycol, and glycerol 1,3 -diglycerolate diacrylate (GDD) under polycondensation conditions to form a PPCacrylate prepolymer; and (ii) copolymerizing the PPCacrylate prepolymer with N-isopropylacrylamide (NIPAAm) via free radical polymerization to form PPCN. In some embodiments, step (a)(i) is conducted at about 140°C with stirring at about 300 rpm for about 45 minutes. In some embodiments, step (a)(ii) is conducted in 1,4-dioxane at about 65°C using azobisisobutyronitrile (AIBN) as a free radical initiator. In some embodiments, the polyethylene glycol is PEG-400.

[0125] In some embodiments, provided herein is a method of preparing a thermoresponsive hydrogel composition comprising: (a) synthesizing self-doped poly(3,4-ethylenedioxythiophene) (PEDOT-S) by oxidative polymerization of an EDOT-S monomer; and (b) combining the PEDOT-S with PPCN to form a PEDOT-S-PPCN composite hydrogel. In some embodiments, the oxidative polymerization comprises combining the EDOT-S monomer with NaaSaOx and FeCE in an aqueous solution. In some embodiments, the EDOT-S monomer is present at about 0.61 mmol, the Na2S20s is present at about 1.22 mmol, and the FeCE is present at about 0.031 mmol.

[0126] For PEDOT-S synthesis, EDOT-S (e.g., about 0.61 mmol) is dissolved in about 3 mL of MilliQ water, and a mixture of Na2S20s (e.g., about 1.22 mmol) and FeCE (e.g., about 0.031 mmol) dissolved in about 3 mL of MilliQ water is added dropwise. After about 3 hours of stirring, the resulting solution is precipitated in acetone and centrifuged at about 3500 rpm for about 5 minutes. The polymer is then dialyzed against MilliQ water for about 2 days using a membrane having a molecular weight cutoff of about 1 kDa.

[0127] In some embodiments, a PEDOT solution comprises PEDOT:PSS. In some embodiments, the PEDOT solution comprises PEDOT-S. In some embodiments, the PEDOT solution has a PEDOT concentration of about 2 mg / mL. In some embodiments, the PEDOT solution has a PEDOT concentration of about 20 mg / mL. In some embodiments, the PEDOT solution is combined with the PPCN at a volume ratio of PEDOT solution to total solvent of from about 0.1% to about 100% (v / v). In some embodiments, the PPCN is present at a concentration of about 100 mg / mL.

[0128] In some embodiments, methods further comprises allowing the PEDOT-PPCN composite hydrogel to undergo gelation at a temperature of from about 25 °C to about 42°C.Attorney Docket No. NWEST-44869.601

[0129] Client Ref. No. NU2025-017-02 In some embodiments, the method further comprises applying the PEDOT-PPCN composite hydrogel to a substrate to form a wound dressing.

[0130] The PEDOT-PPCN composite hydrogels may be formulated at various PEDOT concentrations. The following exemplary formulations use about 200 mg PPCN in a total volume of about 2 mL: For PEDOT:PSS at about 2 mg / mL stock concentration: 100% (v / v): about 200 mg PPCN in about 2 mL PEDOT:PSS solution; 50% (v / v): about 200 mg PPCN in about 1 mL PEDOT:PSS solution + about 1 mL MilliQ water; 10% (v / v): about 200 mg PPCN in about 200 pL PEDOT:PSS solution + about 1800 pL MilliQ water; 1% (v / v): about 200 mg PPCN in about 20 pL PEDOT:PSS solution + about 1980 pL MilliQ water; 0.1% (v / v): about 200 mg PPCN in about 2 pL PEDOT:PSS solution + about 1998 pL MilliQ water. For PEDOT-S at about 2 mg / mL stock concentration: 100% (v / v): about 200 mg PPCN in about 2 mL PEDOT-S solution; 50% (v / v): about 200 mg PPCN in about 1 mL PEDOT-S solution + about 1 mL MilliQ water; 10% (v / v): about 200 mg PPCN in about 200 pL PEDOT-S solution + about 1800 pL MilliQ water: 1% (v / v): about 200 mg PPCN in about 20 pL PEDOT-S solution + about 1.98 mL MilliQ water; 0.1% (v / v): about 200 mg PPCN in about 2 pL PEDOT-S solution + about 1998 pL MilliQ water. For PEDOT-S at about 20 mg / mL stock concentration: 100% (v / v): about 200 mg PPCN in about 2 mL PEDOT-S solution; 50% (v / v): about 200 mg PPCN in about 1 mL PEDOT-S solution + about 1 mL MilliQ water; 10% (v / v): about 200 mg PPCN in about 200 pL PEDOT-S solution + about 1800 pL MilliQ water; 1% (v / v): about 200 mg PPCN in about 20 pL PEDOT-S solution + about 1.98 mL MilliQ water; 0.1% (v / v): about 200 mg PPCN in about 2 pL PEDOT-S solution + about 1998 pL MilliQ water. For PEDOT:PSS, the material was purchased commercially (e.g., from Heraeus) at a concentration of about 2 mg / mL.

[0131] In some embodiments, provided herein is a wound dressing comprising a substrate and a thermoresponsive hydrogel composition disposed on or within the substrate, the hydrogel composition comprising a PEDOT-PPCN composite hydrogel, wherein the hydrogel composition undergoes a sol-gel transition, e.g., at a temperature between about 25 °C and about 42°C. In some embodiments, the substrate is selected from the group consisting of a gauze, a foam, a film, a mesh, a hydrocolloid, and a nonwoven fabric. The PEDOT-PPCN composite hydrogel may be disposed on the substrate by coating, impregnation, lamination, or other suitable method.Attorney Docket No. NWEST-44869.601

[0132] Client Ref. No. NU2025-017-02 In some embodiments, provided herein is a medical device comprising a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel. In some embodiments, the medical device is a wound dressing, a tissue scaffold, a drug delivery device, or a bioelectronic interface.

[0133] In some embodiments, provided herein is a kit comprising: (a) poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN); (b) a poly(3.4-ethylenedioxythiophene) (PEDOT) solution; and (c) instructions for combining (a) and (b) to form a thermoresponsive PEDOT-PPCN composite hydrogel. In some embodiments, the kit further comprises a wound dressing substrate. In some embodiments, the kit further comprises at least one additional therapeutic agent.

[0134] In some embodiments, the PEDOT-PPCN composite hydrogel compositions described herein are for use in therapy. In some embodiments, the therapy is wound treatment. In some embodiments, the therapy is inhibiting microbial growth at a wound site. In some embodiments, the therapy is tissue repair or regeneration. In some embodiments, the tissue is selected from the group consisting of skin, tendon, ligament, muscle, and nerve tissue.

[0135] It is to be understood that the embodiments described herein are not mutually exclusive and that features from different embodiments may be combined.

[0136] EXPERIMENTAL

[0137] Example 1: Synthesis of PPCN

[0138] Poly (poly ethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) was synthesized as follows. PPCN is primarily composed of citric acid, polyethylene glycol-400 (PEG 400), and N-isopropylacrylamide (NIP A AM). It is synthesized through a two-step process: polycondensation followed by a free radical polymerization.

[0139] During the polycondensation step, citric acid (about 0.02 moles), PEG 400 (about 0.04 moles), and Glycerol 1,3-diglycerolate diacrylate (GDD, about 0.1 moles) were combined at about 140°C and stirred at about 300 rpm for about 45 minutes. The final molar ratio of COOH to OH groups was about 1:1.8:0.2 (citric acid:PEG), forming the PPCacrylate prepolymer.

[0140] In the subsequent free radical copolymerization, the PPCacrylate prepolymer was reacted with NIPAAM in about a 1:1 molar ratio, using Azobisisobutyronitrile (AIBN) as the initiator. The reaction was carried out in 1,4-dioxane as the solvent at about 65°C under about 300 rpmAttorney Docket No. NWEST-44869.601

[0141] Client Ref. No. NU2025-017-02 stirring. The product was then precipitated dropwise into diethyl ether and dried under vacuum to yield PPCN.

[0142] Example 2: Synthesis of PEDOT-S

[0143] Self-doped poly(3,4-ethylenedioxythiophene) (PEDOT-S) was synthesized by oxidative polymerization as follows. EDOT-S (about 0.61 mmol) was dissolved in about 3 mL of MilliQ water, and a mixture of Na2S20s (about 1.22 mmol) and FeCL (about 0.031 mmol) dissolved in about 3 mL of MilliQ water was added dropwise. After about 3 hours of stirring, the resulting solution was precipitated in acetone and centrifuged at about 3500 rpm for about 5 minutes. The polymer was then dialyzed against MilliQ water for about 2 days using a 1 kDa membrane.

[0144] Example 3: Formulation of PEDOT-PPCN Composite Hydrogels

[0145] Poly (poly ethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) was synthesized as described in Example 1 and mixed with two forms of poly (3, 4-ethylenedioxy thiophene) (PEDOT): PEDOT-S and PEDOT:PSS. PEDOT:PSS (Heraeus) was used at a concentration of about 2 mg / mL, while PEDOT-S, synthesized as described in Example 2, was added at concentrations of about 2 mg / mL and about 20 mg / mL. These concentrations were used to create different PEDOT-PPCN composites, resulting in final PEDOT compositions of 100%, 50%, 10%, 1%, and 0.1% (v / v) in PPCN. The resulting composite is a thermoresponsive conductive material.

[0146] The different concentrations of PEDOT-PPCN were formulated in the following manner (using about 2 mL as an example):

[0147] PEDOTzPSS [. about 2 mg / mL]

[0148] % (v / v) PPCN (mg) PEDOT:PSS Solution MilliQ Water

[0149] 100% about 200 about 2 mL

[0150] 50% about 200 about 1 mL about 1 mL

[0151] 10% about 200 about 200 pL about 1800 pL

[0152] 1% about 200 about 20 pL about 1980 pL

[0153]

[0154] Attorney Docket No. NWEST-44869.601

[0155] Client Ref. No. NU2025-017-02 0.1% about 200 about 2 pL about 1998 pL

[0156]

[0157]

[0158] PEDOT-S [about 2 mg / mL]

[0159] % (v / v) ! PPCN (mg) i PEDOT-S Solution MilliQ Water

[0160] 100% about 200 about 2 mL

[0161] 50% about 200 about 1 mL about 1 mL

[0162] 10% about 200 about 200 pL about 1800 pL

[0163] 1% about 200 about 20 pL about 1.98 mL

[0164] 0.1% about 200 ^ about 2 pL about 1998 pL

[0165]

[0166] PEDOT-S [about 20 mg / mL]

[0167] % (v / v) ; PPCN (mg) PEDOT-S Solution MilliQ Water

[0168] 100% about 200 about 2 mL

[0169] 50% about 200 about 1 mL about 1 mL

[0170] 10% about 200 about 200 pL about 1800 pL

[0171] 1% about 200 about 20 pL about 1.98 mL

[0172] 0.1% about 200 about 2 pL about 1998 pL

[0173]

[0174] Example 4: Rheological Characterization of PEDOT-PPCN Hydrogels

[0175] The viscoelastic properties of PEDOT-PPCN hydrogels were investigated using a Discovery Hybrid DHR-3 rheometer (TA Instruments, New Castle, DE). Analysis was conducted at a frequency of about 1.5 Hz, a heating rate of about 2°C min-1, an about 1.5% strain, and an about 50 rad s ' angular frequency in the temperature range of about 15-45°C. The rheometer measured changes in the storage modulus (G') and loss modulus (G") of PEDOT-PPCN solutions as a function of temperature.

[0176] As shown in FIG. 2A, rheological analysis of PEDOT-PPCN hydrogels incorporating PEDOT:PSS (left panel) and PEDOT-S at 20 mg / mL (right panel) demonstrated that gelationAttorney Docket No. NWEST-44869.601

[0177] Client Ref. No. NU2025-017-02 temperatures remained within physiologically relevant ranges across all tested PEDOT concentrations (0.1%, 1%, 10%, 50%, and 100% v / v). The storage modulus (G') increased relative to the loss modulus (G") at temperatures consistent with a sol-gel transition between about 25 °C and about 42°C, confirming that incorporation of the PEDOT component into the PPCN matrix did not abolish the thermoresponsive gelation behavior of PPCN.

[0178] Example 5: Cell Viability Assessment of PEDOT-PPCN Hydrogels

[0179] Cytocompatibility of PEDOT-PPCN was analyzed as follows. Cells (L929 murine fibroblasts) were seeded in 24-well tissue culture plates at a density of about 5 x 104cells per well and incubated at about 37°C overnight. The cells were treated with PEDOT-PPCN solution (about 100 pL per well) and the composition was allowed to gel. Cell viability was assessed after about 24 hours of culture using the Alamar Blue assay and normalized to the non-treated condition.

[0180] As shown in FIG. 2B, cell viability results for L929 fibroblast cells after 24 hours of contact with PEDOT-PPCN hydrogels demonstrated differential biocompatibility between PEDOT:PSS and PEDOT-S formulations. For PEDOT:PSS-PPCN hydrogels (left panel), concentrations above 1% (v / v) resulted in less than 50% cell viability. In contrast, for PEDOT-S-PPCN hydrogels at 20 mg / mL (right panel), cell viability was maintained at least about 70% across all tested concentrations (0.1% to 100% v / v).

[0181] Example 6: Antimicrobial Activity of PEDOT-PPCN Hydrogels

[0182] Antimicrobial properties of PEDOT-PPCN were analyzed against S. aureus as follows. About 100 pL of PEDOT-PPCN was added into a 96-well plate and gelled for about 30 minutes. Subsequently, about 100 pL of bacteria (about 105CFU mL ' ) were added to each well. After overnight incubation, the bacterial suspension was collected and serially diluted to about IxlO2, about IxlO3, about IxlO4, and about 1x10s. The diluted samples were then added to LB agar plates (containing about 15 mL of LB agar in 10 mm Petri dishes). After another overnight incubation, digital images of each agar plate were taken and the colony-forming units (CFU) were counted. The incubation was conducted at about 37°C overnight. Penicillin-streptomycin was used as a positive control.Attorney Docket No. NWEST-44869.601

[0183] Client Ref. No. NU2025-017-02 As shown in FIG. 2C, antimicrobial assay results against Staphylococcus aureus demonstrated that both PEDOT-S-PPCN (top row) and PEDOT:PSS-PPCN (bottom row) hydrogels exhibited antimicrobial activity, with increasing antimicrobial activity observed at higher PEDOT concentrations. Non-treated (NT), penicillin-streptomycin (PS), and PPCN-only controls were included for comparison.

[0184] Example 7: Exemplary Preparation of a PEDOT-PPCN Wound Dressing

[0185] A PEDOT-PPCN wound dressing is prepared as follows. A PEDOT-S-PPCN composite hydrogel is formulated as described in Example 4, using PEDOT-S at about 20 mg / mL and about 10% (v / v) PEDOT-S solution. The liquid PEDOT-S-PPCN composition (at a temperature below about 25°C) is applied to a substrate (e.g., a sterile gauze, foam, or nonwoven fabric) by coating or impregnation. The resulting wound dressing is stored at a temperature below the LCST of the composition (e.g., at about 4°C to about 20°C) to maintain the composition in a liquid or semiliquid state on the substrate. Upon application to a wound site at physiological temperature (e.g., about 37°C), the composition undergoes a sol-gel transition and forms a hydrogel at the wound site, conforming to the wound geometry.

[0186] Example 8: Exemplary Method of Treating a Wound Using PEDOT-PPCN Composite Hydrogel

[0187] A wound on a subject in need thereof is treated as follows. A PEDOT-S-PPCN composite hydrogel is formulated as described in Example 4 (e.g., using PEDOT-S at about 20 mg / mL and about 10% v / v PEDOT-S solution in about 100 mg / mL PPCN). The composition is maintained in a liquid state at a temperature below its LCST (e.g., at room temperature or below). The liquid composition is administered to the wound by topical application directly to the wound surface, or by injection to the wound site using a syringe. Upon contact with the wound at physiological temperature (e.g., about 37°C), the composition undergoes a sol-gel transition and forms a conformal hydrogel at the wound site. The hydrogel provides antimicrobial activity against bacteria (e.g., Staphylococcus aureus) at the wound site while maintaining biocompatibility with mammalian cells at the wound site (e.g., at least about 70% viability of fibroblasts after 24 hours).Attorney Docket No. NWEST-44869.601

[0188] Client Ref. No. NU2025-017-02 REFERENCES

[0189] The following references are herein incorporated by reference in their entireties.

[0190] Yang et al.. "A Thermoresponsive Biodegradable Polymer with Intrinsic Antioxidant Properties," Biomacromolecules, 2014, DOI: 10.1021 / bm5010004.

[0191] Montione et al., "Poly(3,4-ethylenedioxythiophene) (PEDOT) Derivatives: Innovative Conductive Polymers for Bioelectronics," Polymers (Basel). 2017 Aug 11;9(8):354. doi:

[0192] 10.3390 / polym9080354

Claims

Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-02 CLAIMS1. A thermoresponsive hydrogel composition comprising:a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component; and a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into said PPCN component to form a PEDOT-PPCN composite hydrogel.

2. The composition of claim 1, wherein the composition undergoes a sol-gel transition at a temperature between about 25 °C and about 42°C.

3. The composition of claim 1, wherein said PEDOT component comprises PEDOT:PSS, PEDOT- S, or a combination thereof.

4. The composition of claim 1, wherein said PEDOT component is PEDOT- S, which is poly(4-(2,3-dihydrothieno[3,4-b] [ 1 ,4]dioxin-2-yl)butane- 1 -sulfonic acid).

5. The composition of claim 1, wherein said PEDOT component is poly(3,4-ethylenedioxy thiophene): poly (styrene sulfonate) (PEDOT:PSS).

6. The composition of claim 1, wherein the PEDOT component is present at a concentration derived from a PEDOT solution having a PEDOT concentration of from about 2 mg / mL to about 20 mg / mL.

7. The composition of claim 1, wherein the PEDOT component is present in an amount of from about 0.1% to about 100% (v / v) of a PEDOT solution relative to a total solvent volume used to dissolve the PPCN component.

8. The composition of claim 6, wherein the PEDOT solution has a PEDOT component concentration of about 2 mg / mL.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-02 9. The composition of claim 6, wherein the PEDOT solution has a PEDOT concentration of about 20 mg / mL.

10. The composition of claim 1, wherein the PPCN component comprises the reaction product of citric acid, polyethylene glycol, glycerol 1,3-diglycerolate diacrylate (GDD), and N-isopropylacrylamide (NIPAAm).

11. The composition of claim 10. wherein the citric acid, polyethylene glycol, and GDD are combined under polycondensation conditions to form a PPCacrylate prepolymer, and wherein the citric acid, polyethylene glycol, and GDD are present in a molar ratio of COOH to OH groups of about 1:1.8:0.2, and the PPCacrylate prepolymer is copolymerized with NIPAAm at about a 1 : 1 molar ratio.

12. The composition of claim 10. wherein the polyethylene glycol is polyethylene glycol-400 (PEG 400).

13. The composition of claim 1, wherein the PPCN component is present at a concentration of about 100 mg / mL.

14. The composition of claim 1, wherein the composition has a sol-gel transition temperature of from about 30°C to about 40°C.

15. The composition of claim 1, wherein the composition exhibits antimicrobial activity against at least one Gram-positive bacterial species.

16. The composition of claim 15, wherein the Gram-positive bacterial species is Staphylococcus aureus.

17. The composition of claim 1, wherein the composition maintains at least about 70% viability of mammalian cells contacted by the composition after 24 hours as measured by a cell viability assay.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-0218. The composition of claim 17, wherein the mammalian cells are fibroblasts.

19. The composition of claim 1, wherein the PPCN component is biodegradable.

20. The composition of claim 1, wherein the PPCN component exhibits intrinsic antioxidant properties.

21. The composition of claim 1, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

22. The composition of claim 1, wherein the composition is formulated as a wound dressing, a pharmaceutical composition, or a component of a medical device.

23. The composition of claim 1, wherein the composition is in a liquid state at a temperature below about 25 °C and in a gel state at a temperature above about 30°C.

24. The composition of claim 1, further comprising at least one additional therapeutic agent.

25. The composition of claim 24, wherein the at least one additional therapeutic agent is an antimicrobial agent, an anti-inflammatory agent, a growth factor, or a combination thereof.

26. A method of treating a wound in a subject in need thereof, comprising:administering to the wound a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component,wherein the composition undergoes a sol-gel transition upon contact with the wound at a physiological temperature to form a hydrogel at the wound site.

27. The method of claim 26, wherein the wound is a skin wound.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-0228. The method of claim 26, wherein the wound is selected from the group consisting of a surgical wound, a traumatic wound, a burn wound, a chronic wound, and a diabetic ulcer.

29. The method of claim 26, wherein the PEDOT component is PEDOT-S, which is poly(4-(2,3-dihydrothieno[3,4-b] [ 1 ,4]dioxin-2-yl)butane- 1 -sulfonic acid).

30. The method of claim 26, wherein the PEDOT component is PEDOT:PSS.

31. The method of claim 26, wherein the composition is administered topically to the wound.

32. The method of claim 26, wherein the composition is administered by injection to the wound site.

33. The method of claim 26, wherein the hydrogel composition further exhibits antimicrobial activity at the wound site.

34. The method of claim 33, wherein the antimicrobial activity comprises inhibition of growth of Staphylococcus aureus.

35. The method of claim 26, wherein the composition maintains at least about 70% viability of mammalian cells at the wound site.

36. The method of claim 26, wherein the composition promotes cell migration at the wound site.

37. The method of claim 26, wherein the PEDOT component is present at a concentration derived from a PEDOT solution having a PEDOT concentration of from about 2 mg / mL to about 20 mg / mL.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-02 38. The method of claim 26, further comprising administering at least one additional therapeutic agent to the wound.

39. A method of inhibiting growth of bacteria on a surface, comprising:contacting the surface with a composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, wherein the composition inhibits growth of at least one bacterial species.

40. A method of promoting tissue repair or regeneration in a subject in need thereof, comprising:administering to a tissue site a thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component,wherein the composition undergoes a sol-gel transition at the tissue site at a physiological temperature.

41. The method of claim 40, wherein the tissue is selected from the group consisting of skin, tendon, ligament, and muscle.

42. The method of claim 40, wherein the tissue comprises nerve tissue.

43. A method of preparing a thermoresponsive hydrogel composition, comprising:(a) providing a poly(3,4-ethylenedioxythiophene) (PEDOT) solution; and(b) combining the PEDOT solution with poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to form a PEDOT-PPCN composite hydrogel.

44. A method of preparing a thermoresponsive hydrogel composition, comprising:(a) synthesizing poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) by:Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-02 (i) combining citric acid, polyethylene glycol, and glycerol 1,3-diglycerolate diacrylate (GDD) under polycondensation conditions to form a PPCacrylate prepolymer; and(ii) copolymerizing the PPCacrylate prepolymer with N-isopropylacrylamide (NIPAAm) via free radical polymerization to form PPCN;(b) providing a poly(3,4-ethylenedioxythiophene) (PEDOT) solution; and(c) combining the PPCN and the PEDOT solution to form a PEDOT-PPCN composite hydrogel.

45. The method of claim 43 or 44, wherein the PEDOT solution comprises PEDOT:PSS.

46. The method of claim 43 or 44, wherein the PEDOT solution comprises PEDOT- S.

47. The method of claim 43 or 44, wherein the PEDOT solution has a PEDOT concentration of about 2 mg / mL.

48. The method of claim 43 or 44, wherein the PEDOT solution has a PEDOT concentration of about 20 mg / mL.

49. The method of claim 43 or 44, wherein the PEDOT solution is combined with the PPCN at a volume ratio of PEDOT solution to total solvent of from about 0.1% to about 100% (v / v).

50. The method of claim 43 or 44, wherein the PPCN is present at a concentration of about 100 mg / mL.

51. The method of claim 43 or 44, further comprising allowing the PEDOT-PPCN composite hydrogel to undergo gelation at a temperature of from about 25°C to about 42°C.

52. The method of claim 43 or 44, further comprising applying the PEDOT-PPCN composite hydrogel to a substrate to form a wound dressing.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-02 53. The method of claim 44, wherein step (a)(i) is conducted at about 140°C with stirring at about 300 rpm for about 45 minutes.

54. The method of claim 44, wherein step (a)(ii) is conducted in 1,4-dioxane at about 65°C using azobisisobutyronitrile (AIBN) as a free radical initiator.

55. The method of claim 44, wherein the polyethylene glycol is PEG-400.

56. A method of preparing a thermoresponsive hydrogel composition, comprising:(a) synthesizing self-doped poly (3, 4-ethylenedioxy thiophene) (PEDOT-S) by oxidative polymerization of an EDOT-S monomer;(b) combining the PEDOT-S with poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to form a PEDOT-S-PPCN composite hydrogel.

57. The method of claim 56, wherein the oxidative polymerization comprises combining the EDOT-S monomer with Na2S20s and FeCE in an aqueous solution.

58. The method of claim 57, wherein the EDOT-S monomer is present at about 0.61 mmol, the Na2S20s is present at about 1.22 mmol, and the FeCE is present at about 0.031 mmol.

59. The method of claim 56, further comprising dialyzing the PEDOT-S against water using a membrane having a molecular weight cutoff of about 1 kDa.

60. A wound dressing comprising:a substrate; anda thermoresponsive hydrogel composition disposed on or within the substrate, the hydrogel composition comprising a PEDOT-PPCN composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component,wherein the hydrogel composition undergoes a sol-gel transition at a temperature between about 25°C and about 42°C.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-0261. The wound dressing of claim 60, wherein the substrate is selected from the group consisting of a gauze, a foam, a film, a mesh, a hydrocolloid, and a nonwoven fabric.

62. The wound dressing of claim 60, wherein the PEDOT component is PEDOT-S.

63. The wound dressing of claim 60, wherein the PEDOT component is PEDOT:PSS.

64. The wound dressing of claim 60, wherein the hydrogel composition exhibits antimicrobial activity against at least one bacterial species.

65. The wound dressing of claim 60, wherein the hydrogel composition maintains at least about 70% viability of mammalian cells contacted by the composition after 24 hours.

66. A medical device comprising a thermoresponsive hydrogel composition, the hydrogel composition comprising a PEDOT-PPCN composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component.

67. The medical device of claim 66, wherein the medical device is a wound dressing, a tissue scaffold, a drug delivery device, or a bioelectronic interface.

68. The medical device of claim 66, wherein the hydrogel composition undergoes a sol-gel transition at a temperature between about 25°C and about 42°C.

69. A kit comprising:(a) poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN);(b) a poly(3,4-ethylenedioxythiophene) (PEDOT) solution; and(c) instructions for combining (a) and (b) to form a thermoresponsive PEDOT-PPCN composite hydrogel.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-02 70. The kit of claim 69, wherein the PEDOT solution comprises PEDOT-S at a concentration of from about 2 mg / mL to about 20 mg / mL.

71. The kit of claim 69, wherein the PEDOT solution comprises PEDOT:PSS at a concentration of about 2 mg / mL.

72. The kit of claim 69, further comprising a wound dressing substrate.

73. The kit of claim 69, further comprising at least one additional therapeutic agent.

74. A thermoresponsive hydrogel composition comprising a PEDOT-PPCN composite hydrogel, the composite hydrogel comprising a poly(3,4-ethylenedioxythiophene) (PEDOT) component incorporated into a poly (poly ethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) component, for use in therapy.

75. The composition for use according to claim 74, wherein the therapy is wound treatment.

76. The composition for use according to claim 74, wherein the therapy is inhibiting microbial growth at a wound site.

77. The composition for use according to claim 74, wherein the therapy is tissue repair or regeneration.

78. The composition for use according to claim 74, wherein the PEDOT component is PEDOT-S.

79. The composition for use according to claim 74, wherein the PEDOT component is PEDOT:PSS.

80. The composition for use according to claim 74, wherein the composition undergoes a solgel transition at a temperature between about 25°C and about 42°C.Attorney Docket No. NWEST-44869.601Client Ref. No. NU2025-017-0281. The composition for use according to claim 74, wherein the composition maintains at least about 70% viability of mammalian cells contacted by the composition after 24 hours.

82. The composition for use according to claim 74, wherein the composition further comprises at least one additional therapeutic agent.

83. The composition for use according to claim 76, wherein the microbial growth comprises growth of Staphylococcus aureus.

84. The composition for use according to claim 77, wherein the tissue is selected from the group consisting of skin, tendon, ligament, muscle, and nerve tissue.

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