Aqueous foam compositions and methods of making and using thereof

Abstract

Described herein are flowable, aqueous foams for the treatment of wounds. These foams can comprise a continuous aqueous phase comprising water, a biocompatible foam-forming agent, and an active agent; and bubbles comprising an expansion gas dispersed within the continuous phase. In some cases, the foam composition exhibits a complete breakdown time of from 1 minute to 12 hours at 25 ºC and 1 atm. Also described herein are methods of treating wounds using these foams as well as aqueous foam precursor compositions suitable for generating these foams.

Description

[0001] Attorney Docket No. 10975-078W01

[0002] AQUEOUS FOAM COMPOSITIONS AND METHODS OF MAKING AND USING THEREOF

[0003] CROSS-REFERENCE TO REEATED APPLICATIONS

[0004] This application claims benefit of priority of U.S. Provisional Application 63 / 682,552, filed August 13, 2024, which is hereby incorporated by reference in its entirety.

[0005] BACKGROUND

[0006] Wound care remains a critical aspect of clinical and home-based medical treatment. Effective management of both acute and chronic wounds — including surgical incisions, bums, ulcers, and traumatic injuries — typically focuses on physical protection of the wound site as well as the timely and controlled delivery of therapeutic agents to promote healing and prevent infection.

[0007] Traditional wound dressings such as gauze, hydrogels, hydrocolloids, and films offer various benefits but often fall short in achieving sustained drug delivery, conformability to complex wound geometries, and moisture balance. While some modem dressings incorporate antimicrobial agents or growth factors, these are typically limited by short-duration activity, uneven distribution of the active compounds, or instability during storage and use.

[0008] There remains a need for improved foam compositions that are biocompatible, adaptable to various wound types, and capable of delivering therapeutic agents in a controlled and sustained manner. Ideally, such compositions would be easy to apply, conform to irregular wound surfaces, and provide extended release of dmgs such as antibiotics, analgesics, antiinflammatory agents, or growth factors.

[0009] SUMMARY

[0010] Flowable aqueous foams are a promising platform for wound care and drug delivery. These systems include a continuous aqueous phase comprising water, a foam-forming agent (e.g., a polymer or surfactant), and an active agent; and a discontinuous gas phase dispersed within the aqueous phase. These foams are conformable, lightweight stmctures that can flow into and fill wounds of varying shapes and depths. Upon application, such foams can provide a moist environment, promote oxygen exchange, and allow for the localized administration of active agents (e.g., active pharmaceutical ingredients (APIs)), including antibiotics, analgesics, and Attorney Docket No. 10975-078W01 immunomodulatory agents, across the wound bed. Importantly, the compositions that can conform to irregular wound beds, and deliver therapeutic agents in a stable, sustained, and effective manner.

[0011] For example, provided herein are flowable aqueous foam compositions that comprise a continuous aqueous phase comprising water, a biocompatible foam-forming agent, and an active agent; and bubbles comprising an expansion gas dispersed within the continuous phase. In some cases, the foam composition exhibits a complete breakdown time of from 1 minute to 12 hours at 25 °C and 1 atm.

[0012] In some embodiments, the aqueous foam composition exhibits a viscosity of from 1,000 cP to 200,000 cP at 25°C and 1 atm, such as a viscosity of from 10,000 cP to 200,000 cP, from 25,000 cP to 200,000 cP, or from 50,000 cP to 200,000 cP at 25°C and 1 atm.

[0013] In some embodiments, the aqueous foam exhibits an average initial bubble size of from 100 microns to 1000 microns, as determined by image analysis.

[0014] In some embodiments, the aqueous foam exhibits an average bubble size at volumetric loss onset of from 800 microns to 3500 microns, as determined by image analysis.

[0015] In some embodiments, the aqueous foam exhibits a time to breakdown onset of from 30 seconds to 8 hours at 25°C and 1 atm, such as from 1 minute to 5 hours, from 1 minute to 2 hours, from 1 minute to 1 hour, from 1 minute to 45 minutes, from 1 minute to 20 minutes, or from 20 minutes to 40 minutes at 25°C and 1 atm.

[0016] In some embodiments, the aqueous foam exhibits a complete breakdown time of from 5 minutes to 5 hours at 25°C and 1 atm, such as from 5 minutes to 2 hours, or from 2 hours to 4 hours at 25°C and 1 atm.

[0017] In some embodiments, the aqueous foam composition is sterile.

[0018] In some embodiments, the aqueous foam composition exhibits a density of from 2 Ibs / gal to 8 Ibs / gal.

[0019] In some embodiments, the aqueous foam composition exhibits a foam quality of at least 40%, such as a foam quality of from 60% to 95%.

[0020] In some embodiments, the aqueous foam composition exhibits non-Newtonian shearthinning behavior.

[0021] In some embodiments, the aqueous foam composition exhibits a viscoelastic crossover modulus of from 1 Pa to 30,000 Pa at 25°C and 1 atm.

[0022] In some embodiments, the foam-forming agent comprises a polymeric foam forming Attorney Docket No. 10975-078W01 agent, such as a biopolymeric foam-forming agent.

[0023] In some embodiments, the foam-forming agent comprises a polysaccharide (e.g., alginate, chitosan, agarose, carrageenan, a cellulosic polymer such as carboxymethyl cellulose (CMC), hyaluronic acid, an alkyl polyglycoside, or a combination thereof), a protein (e.g., collagen, gelatin, whey protein, ovalbumin, conalbumin, globulins, ovomucin, or a combination thereof), a synthetic polymer (e.g., polyvinyl alcohol, polyvinyl acetate, a polyalkylene oxide (e.g., a crosslinked polyethylene glycol), a polyester (e.g., polylactic acid, polyglycolic acid, polycaprolactone)), or a combination thereof.

[0024] In some embodiments, the foam-forming agent comprises a surfactant, such as a nonionic surfactant, an anionic surfactant, a zwitterionic surfactant, or a combination thereof. In certain embodiments, the surfactant comprises a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or a combination thereof; an alkyl polyglycoside; sodium lauryl sulfate (SLS); sodium cocoyl isethionate (SCI); potassium lauryl sulfate; a glycoside saponin, such as a glycoside saponin extracted from Quillaja saponaria. a glycoside saponin extracted from soapwort (Saponaria officinalis), a glycoside saponin extracted from senega root (Polygala senega), a glycoside saponin extracted from sarsaparilla (Smilax ornataf, cocamidopropyl betaine; or a combination thereof.

[0025] In some embodiments, the foam-forming agent comprises a poloxamer, such as Poloxamer 407 (PEOioiPPOsePEOioi), Poloxamer 188 (PEO75PPO29PEO75), Poloxamer 338 (PEO141PPO44PEO141), Poloxamer 124 (PEO12PPO20PEO12), Poloxamer 237 (PEO64PPO37PEO64), and mixtures thereof; carboxymethyl cellulose (CMC); methyl cellulose, chitosan; alginate; a polyvinyl alcohol; a gelatin, such as gelatin methacryloyl; a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); or any combination thereof.

[0026] In some embodiments, the foam-forming agent is present in an amount of from 0. 1% by weight to 10% by weight, based on the total weight of the aqueous foam precursor composition, such as from 0.5% by weight to 7% by weight, from 0.5% by weight to 5% by weight, from 0.5% by weight to 4% by weight, or from 1% by weight to 3% by weight. Attorney Docket No. 10975-078W01

[0027] In some embodiments, the active agent comprises a therapeutic agent, a prophylactic agent, a diagnostic agent, or a combination thereof. In some embodiments, the active agent comprises an antimicrobial agent, an analgesic agent, a hemostatic agent, a growth factor, an immunomodulatory agent, an orthobiologic agent, an extracellular vesicle, an exosome agent, a senolytic agent, or a combination thereof.

[0028] In some embodiments, the active agent comprises (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immunomodulatory agent, wound healing agent, an analgesic agent; or a combination thereof.

[0029] In some embodiments, the active agent comprises (1) an antimicrobial agent; (2) an analgesic agent; and optionally (3) an immunomodulatory agent, wound healing agent, a hemostatic agent, or a combination thereof.

[0030] In some embodiments, the antimicrobial agent comprises an antibacterial agent. In some embodiments, the antimicrobial agent is chosen from an aminoglycoside (e.g., tobramycin, neomycin), a peptide antibiotic (vancomycin, bacitracin), a beta-lactam antibiotic (e.g., ceftazidime, ceftriaxone, cefazolin), a Polymyxins (polymyxin B, colistin), or combinations thereof. In certain embodiments, the antimicrobial agent can comprise a combination of an antibacterial agent that is active against Gram-positive bacteria and an antibacterial agent that is active against Gram-positive bacteria. In other embodiments, the antimicrobial agent comprises an antifungal agent.

[0031] In some embodiments, the hemostatic agent is chosen from an antifibrinolytic (e.g., tranexamic Acid (TXA)), a coagulation factor or analog thereof (e.g., recombinant factor Vila (rFVIIa), prothrombin complex concentrates (PCCs), fibrinogen concentrates, desmopressin), or combinations thereof.

[0032] In some embodiments, the immunomodulatory' agent is chosen from a Toll-like Receptor (TLR) agonist (e.g., Polyinosinic-polycytidylic acid (poly(I:C)), a CpG oligonucleotide), a cytosolic receptor agonist (e.g., 2'3'-cyclic di-GMP (c-di-GMP), ADU-S100 (MIW815), DMXAA (Vadimezan)), or combinations thereof.

[0033] In some embodiments, the wound healing agent is chosen from a wound healing macrophage (M<b) activator, a fibroblast growth factor (FGF), an epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), or a combination thereof.

[0034] In some embodiments, the analgesic agent is chosen from a local anesthetic (an amide) Attorney Docket No. 10975-078W01 such as lidocaine, bupivacaine, mepivacaine, or ropivacaine; a non-steroidal anti-inflammatory drug (an NSAID) such as diclofenac or ketoprofen; an opioids such as morphine or fentanyl; or a combination thereof.

[0035] In certain embodiments, the foam composition comprises: a continuous aqueous phase comprising water, from 0.1% by weight to 10% by weight of a biopolymer foam -forming agent, based on the total weight of the foam composition, and an active agent; and bubbles comprising an expansion gas dispersed within the continuous phase; wherein the active agent comprises (a) (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immunomodulatory agent, wound healing agent, an analgesic agent; a combination thereof; (b) (1) an antimicrobial agent; (2) an analgesic agent; and optionally (3) an immunomodulatory agent, wound healing agent, a hemostatic agent, or a combination thereof; or (c) an antimicrobial agent alone.

[0036] In some embodiments, the active agent is present in an amount of from 0.001% by weight to 25% by weight, based on the total weight of the aqueous foam composition.

[0037] In some embodiments, the aqueous foam composition further comprises one or more additional components chosen from a viscosity-modifying polymer, a foam stabilizer, a pH modifying agent (e.g., an acid, an alkali agent, or a combination thereof), a chelating agent (e.g., EDTA or a salt thereof), a preservative, a colorant, a sorbent, a co-solvent, or any combination thereof.

[0038] In certain embodiments, the aqueous foam composition further comprises a foam stabilizer. In certain embodiments, the foam stabilizer is selected from a crosslinker, a particulate stabilizer, or any combination thereof. In certain embodiments, the foam stabilizer comprises a crosslinker selected from a borate crosslinking agent, a Ca crosslinking agent, a Zr crosslinking agent, a Ti crosslinking agent, an Al crosslinking agent, an organic crosslinker (e.g., malonate, polyethyleneimine), or any combination thereof.

[0039] In some embodiments, the aqueous foam composition further comprises a viscositymodifying polymer. In certain embodiments, the viscosity-modifying polymer comprises a water-soluble polymer, such as a biopolymer. In certain embodiments, the viscosity-modifying polymer is chosen from xanthan, guar, a scleroglucan, a schizophyllan, hydroxyethyl cellulose (HEC), or any combination thereof.

[0040] The foam compositions described herein can be applied to wounds to treat the wound, treat or prevent an infection, to improve wound healing, or a combination thereof. Accordingly, provided herein are methods of treating a wound that comprise applying a foam composition Attorney Docket No. 10975-078W01 described herein to a wound.

[0041] In some embodiments, the method further comprises generating the aqueous foam composition from an aqueous foam precursor composition and an expansion gas.

[0042] In some embodiments, generating the aqueous based foam comprises: shearing the aqueous foam precursor composition in the presence of the expansion gas; injecting the expansion gas into the aqueous foam precursor composition; or any combination thereof.

[0043] In some embodiments, the expansion gas comprises nitrogen, CO2, air, nitrous oxide, propane, butane, or any combination thereof.

[0044] In some embodiments, the aqueous foam composition exhibits a volumetric expansion ratio of from 1 to 10 upon generation of the aqueous foam from the aqueous foam precursor composition.

[0045] Also described herein are aqueous foam precursor compositions that can be combined with an expansion gas to form a flowable aqueous foam. For example, provided herein are sterile aqueous foam precursor compositions that comprise water; from 0. 1% to 10% by weight of a biocompatible polymeric foam-forming agent; and an active agent.

[0046] In some embodiments, the water can be present in an amount of from 5% by weight to 98% by weight, based on the total weight of the aqueous foam precursor composition. In certain embodiments, the aqueous foam precursor composition is a concentrate, and the water is present in an amount of from 5% by weight to 40% by weight, based on the total weight of the aqueous foam precursor composition. In other embodiments, the water is present in an amount of from 60% by weight to 98% by weight, based on the total weight of the aqueous foam precursor composition

[0047] In some embodiments, the foam-forming agent comprises a biopolymeric foam-forming agent.

[0048] In some embodiments, the foam-forming agent comprises a polysaccharide (e.g., alginate, chitosan, agarose, carrageenan, a cellulosic polymer such as carboxymethyl cellulose (CMC), hyaluronic acid, an alkyl polyglycoside, or a combination thereof), a protein (e.g., collagen, gelatin, whey protein, ovalbumin, conalbumin, globulins, ovomucin, or a combination thereof), a synthetic polymer (e.g., polyvinyl alcohol, polyvinyl acetate, a polyalkylene oxide (e.g., a crosslinked polyethylene glycol), a polyester (e.g., polylactic acid, polyglycolic acid, polycaprolactone)), or a combination thereof.

[0049] In some embodiments, the foam-forming agent comprises a surfactant, such as a non- Attorney Docket No. 10975-078W01 ionic surfactant, an anionic surfactant, a zwitterionic surfactant, or a combination thereof. In certain embodiments, the surfactant comprises a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or a combination thereof; an alkyl polyglycoside; sodium lauryl sulfate (SLS); sodium cocoyl isethionate (SCI); potassium lauryl sulfate; a glycoside saponin, such as a glycoside saponin extracted from Quillaja saponaria. a glycoside saponin extracted from soapwort (Saponaria officinalis), a glycoside saponin extracted from senega root (Polygala senega), a glycoside saponin extracted from sarsaparilla (Smilax ornataf, cocamidopropyl betaine; or a combination thereof.

[0050] In some embodiments, the foam-forming agent comprises a poloxamer, such as Poloxamer 407 (PEOioiPPOsePEOioi), Poloxamer 188 (PEO75PPO29PEO75), Poloxamer 338 (PEO141PPO44PEO141), Poloxamer 124 (PEO12PPO20PEO12), Poloxamer 237 (PEO64PPO37PEO64), and mixtures thereof; carboxymethyl cellulose (CMC); methyl cellulose, chitosan; alginate; a polyvinyl alcohol; a gelatin, such as gelatin methacryloyl; a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); or any combination thereof.

[0051] In some embodiments, the foam-forming agent is present in an amount of from 0. 1% by weight to 10% by weight, based on the total weight of the aqueous foam precursor composition, such as from 0.5% by weight to 7% by weight, from 0.5% by weight to 5% by weight, from 0.5% by weight to 4% by weight, or from 1% by weight to 3% by weight.

[0052] In some embodiments, the active agent comprises a therapeutic agent, a prophylactic agent, a diagnostic agent, or a combination thereof. In some embodiments, the active agent comprises an antimicrobial agent, an analgesic agent, a hemostatic agent, a growth factor, an immunomodulatory agent, an orthobiologic agent, an extracellular vesicle, an exosome agent, a senolytic agent, or a combination thereof.

[0053] In some embodiments, the active agent comprises (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immunomodulatory agent, wound healing agent, an analgesic agent; or a combination thereof.

[0054] In some embodiments, the active agent comprises (1) an antimicrobial agent; (2) an Attorney Docket No. 10975-078W01 analgesic agent; and optionally (3) an immunomodulatory agent, wound healing agent, a hemostatic agent, or a combination thereof.

[0055] In some embodiments, the antimicrobial agent comprises an antibacterial agent. In some embodiments, the antimicrobial agent is chosen from an aminoglycoside (e.g., tobramycin, neomycin), a peptide antibiotic (vancomycin, bacitracin), a beta-lactam antibiotic (e.g., ceftazidime, ceftriaxone, cefazolin), a Polymyxins (polymyxin B, colistin), or combinations thereof. In certain embodiments, the antimicrobial agent can comprise a combination of an antibacterial agent that is active against Gram-positive bacteria and an antibacterial agent that is active against Gram-positive bacteria. In other embodiments, the antimicrobial agent comprises an antifungal agent.

[0056] In some embodiments, the hemostatic agent is chosen from an antifibrinolytic (e.g., tranexamic Acid (TXA)), a coagulation factor or analog thereof (e.g., recombinant factor Vila (rFVIIa), prothrombin complex concentrates (PCCs), fibrinogen concentrates, desmopressin), or combinations thereof.

[0057] In some embodiments, the immunomodulatory agent is chosen from a Toll-like Receptor (TLR) agonist (e.g., Polyinosinic-polycytidylic acid (poly(I:C)), a CpG oligonucleotide), a cytosolic receptor agonist (e.g., 2'3'-cyclic di-GMP (c-di-GMP), ADU-S100 (MIW815), DMXAA (Vadimezan)), or combinations thereof.

[0058] In some embodiments, the wound healing agent is chosen from a wound healing macrophage (M<b) activator, a fibroblast growth factor (FGF), an epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), or a combination thereof.

[0059] In some embodiments, the analgesic agent is chosen from a local anesthetic (an amide) such as lidocaine, bupivacaine, mepivacaine, or ropivacaine; a non-steroidal anti-inflammatory drug (an NSAID) such as diclofenac or ketoprofen; an opioids such as morphine or fentanyl; or a combination thereof.

[0060] In some embodiments, the active agent is present in an amount of from 0.001% by weight to 25% by weight, based on the total weight of the aqueous foam precursor composition.

[0061] In some embodiments, the aqueous foam precursor composition further comprises one or more additional components chosen from a viscosity-modifying polymer, a foam stabilizer, a pH modifying agent (e.g., an acid, an alkali agent, or a combination thereof), a chelating agent (e.g., EDTA or a salt thereof), a preservative, a colorant, a sorbent, a co-solvent, or any combination thereof. Attorney Docket No. 10975-078W01

[0062] In certain embodiments, the aqueous foam precursor composition further comprises a foam stabilizer. In certain embodiments, the foam stabilizer is selected from a crosslinker, a particulate stabilizer, or any combination thereof. In certain embodiments, the foam stabilizer comprises a crosslinker selected from a borate crosslinking agent, a Ca crosslinking agent, a Zr crosslinking agent, a Ti crosslinking agent, an Al crosslinking agent, an organic crosslinker (e.g., malonate, polyethyleneimine), or any combination thereof.

[0063] In some embodiments, the aqueous foam precursor composition further comprises a viscosity-modifying polymer. In certain embodiments, the viscosity-modifying polymer comprises a water-soluble polymer, such as a biopolymer. In certain embodiments, the viscosity-modifying polymer is chosen from xanthan, guar, a scleroglucan, a schizophyllan, hydroxyethyl cellulose (HEC), or any combination thereof.

[0064] Also described herein are foamable compositions that comprise an aqueous foam precursor composition described herein and a liquefied or a compressed gas propellant (e.g., nitrogen, CO2, air, nitrous oxide, propane, butane, or any combination thereof).

[0065] Additional advantages of the disclosed compositions, systems, and methods will be set forth in part in the description which follows, and in part will be obvious from the description. The advantages of the disclosed compositions, systems, and methods will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosed compositions, systems, and methods, as claimed.

[0066] The details of one of more embodiments of the invention are set forth in the accompanying drawings and description below. Other features, objects, and advantages of the invention will be apparent form the description and drawings, and from the claims.

[0067] BRIEF DESCRIPTION OF THE FIGURES

[0068] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects of the disclosure, and together with the description, serve to explain the principles of the disclosure.

[0069] Figure 1. Multifunctional Medical Foam (MF) to enhance acute wound management in situ. In one example, the MF composition includes a viscous biopolymer-based medical MF that can rapidly deliver the antibiotic vancomycin, the hemostatic agent tranexamic acid (TXA), and Attorney Docket No. 10975-078W01 a STING agonist (2'3'-cGAMP), and a wound healing macrophage (M<D) activator, directly to the surface of a wound having complex geometries.

[0070] Figure 2. Medical Foam (MF) Delivery. In one embodiment, the MF composition includes vancomycin, tranexamic acid (TXA), and STING agonists (2'3'-cGAMP) stored initially as dry powders. These agents are combined with a viscous biopolymer (e.g., carboxymethyl cellulose). This pre-foam mixture passes through a microfluidic nozzle, introducing a vapor phase (i.e., gas bubbles) to the MF composition and mixing the agents, forming a stable therapeutic foam. The MF composition is applied topically ensuring volumefilling delivery to the wound site.

[0071] Figure 3. Assessment of Carboxymethyl Cellulose (CMC) in a Mouse Closed Wound Model. (Panel A) Surgical introduction of CMC hydrogel into a closed wound in a mouse model rotator cuff partial transection model. (Panel B) Histological evaluation (H&E staining) of the wound site post-CMC application at 3 -weeks revealed negligible immunological response and no adverse tissue reactions. (Panel C) Comparative H&E-stained tissue section from an unaltered, healthy area of the same model, serving as a baseline for evaluation.

[0072] Figure 4. Evaluation of MF as an Effective Delivery System for Vancomycin. (Panel A) Application of MF loaded with vancomycin onto agar plates pre-inoculated with the bacterium Staphylococcus aureus. (Panel B) Observations at 24-hour post-application revealing significant bacterial eradication, indicating the successful delivery and antibacterial action of Vancomycin in a CMC foam

[0073] Figure 5. Visualization of Medical Foam's (MF’s) Hemostatic Properties. MF with TXA was applied on a smooth plate inclined at 30 degrees. The foam maintains structural and rheologic integrity and effectiveness in the presence of blood, as evidence by it not flowing down the inclined plate due to blood clotting.

[0074] Figures 6A-6D. 2’3’ cGAMP STING-agonism in immunomodulation and wound healing. (Figure 6A) Pathways activated following STING-agonism. (Figure 6B) STING-agonist stimulation of mesenchymal stromal cells (MSC) on cytokine secretion. (Figure 6C) Volcano plot of STING-treated (MSC) compared to untreated. (Figure 6D) List of differentially expressed genes, description, unadjusted p-value, and fold change of the top upregulated genes in differential analysis results from STING-agonist. Of note, CXCL10 and interferon related genes were upregulated in MSC stimulated with the STING agonist.

[0075] Figure 7. Medical Foam (MF) for Enhanced Wound Conformity. (Panels A, B) Attorney Docket No. 10975-078W01

[0076] Variations of the MF’s bubble diameter dictating the foam's viscosity tailored for clinical applications. (Panel C) Simulated wounds: unfdled (left) versus filled with MF (right) (Panel D) Cross-sectional view of a simulated wound demonstrates the comparative depth coverage of foam, putty, and dry powder. (Panel E) Visualization of a simulated penetrating wound in muscle tissue, highlighting the volumetric filling proficiency of the MF.

[0077] Figures 8A-8B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate; TWEEN® 20) in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of Polysorbate 20 was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 8A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 8B is a plot showing the bubble size and foam volume as a function of time.

[0078] Figures 9A-9B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight Poloxamer 407 (PLURONIC® F-127 (PF 127)) in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of Poloxamer 407 was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 9A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 9B is a plot showing the bubble size and foam volume as a function of time.

[0079] Figures 10A-10B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight polyvinyl alcohol in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of polyvinyl alcohol was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 10A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The Attorney Docket No. 10975-078W01 volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 1 OB is a plot showing the bubble size and foam volume as a function of time.

[0080] Figures 11A-11B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight polyethylene glycol (PEG) in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of polyethylene glycol was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 11A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 1 IB is a plot showing the bubble size and foam volume as a function of time.

[0081] Figures 12A-12B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight sodium alginate (NaAlg) in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of sodium alginate was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 12A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 12B is a plot showing the bubble size and foam volume as a function of time.

[0082] Figures 13A-13B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight methyl cellulose (MC) in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of MC was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 13A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 13B is a plot showing Attorney Docket No. 10975-078W01 the bubble size and foam volume as a function of time.

[0083] Figures 14A-14B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight gelatin methacryloyl (GelMa) in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of gelatin methacryloyl was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 14A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 14B is a plot showing the bubble size and foam volume as a function of time.

[0084] Figures 15A-15B. Characterization of the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight chitosan in water. Foam was generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of chitosan was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Figure 15A shows photographs of the resulting foam initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Figure 15B is a plot showing the bubble size and foam volume as a function of time.

[0085] DETAILED DESCRIPTION

[0086] The compositions, systems, and methods described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included herein.

[0087] Definitions

[0088] Before the present compositions, systems, and methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific synthetic methods or specific reagents, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Attorney Docket No. 10975-078W01

[0089] 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. Unless otherwise specified, all percentages are in weight percent and the pressure is in atmospheres.

[0090] The organic moieties mentioned when defining variable positions within the general formulae described herein (e.g., the term “halogen”) are collective terms for the individual substituents encompassed by the organic moiety. The prefix Cn-Cm preceding a group or moiety indicates, in each case, the possible number of carbon atoms in the group or moiety that follows.

[0091] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed at room temperature (e.g., ~20°C) and pressure (1 atm). Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0092] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included at room temperature (e.g., ~20°C) and pressure (1 atm).

[0093] Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed subject matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0094] It is understood that when combinations, subsets, groups, etc. of elements are disclosed (e.g., combinations of components in a composition, or combinations of steps in a method), that while specific reference of each of the various individual and collective combinations and permutations of these elements may not be explicitly disclosed, each is specifically contemplated and described herein. By way of example, if an item is described herein as including a component of type A, a component of type B, a component of type C, or any combination thereof, it is understood that this phrase describes all of the various individual and collective combinations and permutations of these components. For example, in some embodiments, the Attorney Docket No. 10975-078W01 item described by this phrase could include only a component of type A. In some embodiments, the item described by this phrase could include only a component of type B. In some embodiments, the item described by this phrase could include only a component of type C. In some embodiments, the item described by this phrase could include a component of type A and a component of type B. In some embodiments, the item described by this phrase could include a component of type A and a component of type C. In some embodiments, the item described by this phrase could include a component of type B and a component of type C. In some embodiments, the item described by this phrase could include a component of type A, a component of type B, and a component of type C. In some embodiments, the item described by this phrase could include two or more components of type A (e.g., Al and A2). In some embodiments, the item described by this phrase could include two or more components of type B (e.g., Bl and B2). In some embodiments, the item described by this phrase could include two or more components of type C (e.g., Cl and C2). In some embodiments, the item described by this phrase could include two or more of a first component (e.g., two or more components of type A (Al and A2)), optionally one or more of a second component (e.g., optionally one or more components of type B), and optionally one or more of a third component (e.g., optionally one or more components of type C). In some embodiments, the item described by this phrase could include two or more of a first component (e.g., two or more components of type B (B 1 and B2)), optionally one or more of a second component (e.g., optionally one or more components of type A), and optionally one or more of a third component (e.g., optionally one or more components of type C). In some embodiments, the item described by this phrase could include two or more of a first component (e.g., two or more components of type C (Cl and C2)), optionally one or more of a second component (e.g., optionally one or more components of type A), and optionally one or more of a third component (e.g., optionally one or more components of type B).

[0095] It is understood that throughout this specification the identifiers “first” and “second” are used solely to aid in distinguishing the various components and steps of the disclosed subject matter. The identifiers “first” and “second” are not intended to imply any particular order, amount, preference, or importance to the components or steps modified by these terms.

[0096] In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings.

[0097] As used in this specification and the following claims, the terms “comprise” (as well as forms, derivatives, or variations thereof, such as “comprising” and “comprises”) and “include” Attorney Docket No. 10975-078W01

[0098] (as well as forms, derivatives, or variations thereof, such as “including” and “includes”) are inclusive (i.e., open-ended) and do not exclude additional elements or steps. For example, the terms "comprise" and / or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. Accordingly, these terms are intended to not only cover the recited element(s) or step(s), but may also include other elements or steps not expressly recited. Furthermore, as used herein, the use of the terms “a” or “an” when used in conjunction with an element may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” Therefore, an element preceded by “a” or “an” does not, without more constraints, preclude the existence of additional identical elements.

[0099] The use of the term “about” applies to all numeric values, whether or not explicitly indicated. This term generally refers to a range of numbers that one of ordinary skill in the art would consider as a reasonable amount of deviation to the recited numeric values (i.e., having the equivalent function or result). For example, this term can be construed as including a deviation of ±10 percent of the given numeric value provided such a deviation does not alter the end function or result of the value. Therefore, a value of about 1% can be construed to be a range from 0.9% to 1.1%. Furthermore, a range may be construed to include the start and the end of the range. For example, a range of 10% to 20% (i.e., range of 10%-20%) can includes 10% and also includes 20%, and includes percentages in between 10% and 20%, unless explicitly stated otherwise herein.

[0100] “Exemplary” means “an example of’ and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes.

[0101] “Optional” or “optionally” means that the subsequently described event or circumstance occurs and instances where it does not.

[0102] As used herein, the term “consisting essentially of with regards to the herein disclosed compositions refers to compositions including less than 2% w / w, less than 1% w / w, less than 0.5% w / w, less than 0.1% w / w, less than 0.05% w / w or less than 0.01% w / w of ingredients other than those disclosed. Each possibility is a separate embodiment.

[0103] Reference will now be made in detail to specific aspects of the disclosed materials, compounds, compositions, articles, systems, and methods, examples of which are illustrated in Attorney Docket No. 10975-078W01 the accompanying examples and figures.

[0104] Foam Compositions

[0105] Provided herein are flowable aqueous foam compositions. The aqueous foam compositions can comprise a continuous aqueous phase comprising water, a biocompatible foam-forming agent, and an active agent; and bubbles comprising an expansion gas dispersed within the continuous phase.

[0106] In certain embodiments, the foam composition comprises a continuous aqueous phase comprising water, from 0.1% by weight to 10% by weight of a biopolymer foam -forming agent, based on the total weight of the foam composition, and an active agent; and bubbles comprising an expansion gas dispersed within the continuous phase; wherein the active agent comprises (a) (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immunomodulatory agent, wound healing agent, an analgesic agent; a combination thereof; (b) (1) an antimicrobial agent; (2) an analgesic agent; and optionally (3) an immunomodulatory' agent, wound healing agent, a hemostatic agent, or a combination thereof; or (c) an antimicrobial agent alone.

[0107] In some embodiments, the aqueous foam composition further comprises one or more additional components chosen from a viscosity-modifying polymer, a foam stabilizer, a pH modifying agent (e.g., an acid, an alkali agent, or a combination thereof), a chelating agent (e.g., EDTA or a salt thereof), a preservative, a colorant, a sorbent, a co-solvent, or any combination thereof.

[0108] The expansion gas can comprise any suitable gas or propellant. In some embodiments, the expansion gas comprises nitrogen, CO2, air, nitrous oxide, propane, butane, or any combination thereof.

[0109] In some embodiments, the aqueous foam composition exhibits a viscosity of at least 1,000 cP at 25°C and 1 atm (e.g., at least 5,000 cP, at least 10,000 cP, at least 25,000 cP, at least 50,000 cP, at least 100,000 cP, or at least 150,000 cP). In some embodiments, the aqueous foam composition exhibits a viscosity of 200,000 cP or less at 25°C and 1 atm (e.g., 150,000 cP or less, 100,000 cP or less, 50,000 cP or less, 25,000 cP or less, 10,000 cP or less, or 5,000 cP or less).

[0110] The aqueous foam composition can exhibit a viscosity ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the aqueous foam composition can exhibit a viscosity of from 1,000 cP to 200,000 Attorney Docket No. 10975-078W01 cP at 25°C and 1 atm, such as a viscosity of from 10,000 cP to 200,000 cP, from 25,000 cP to 200,000 cP, or from 50,000 cP to 200,000 cP at 25°C and 1 atm.

[0111] In some embodiments, the aqueous foam exhibits an average initial bubble size of at least 100 microns (e.g., at least 200 microns, at least 250 microns, at least 300 microns, at least 400 microns, at least 500 microns, at least 600 microns, at least 700 microns, at least 750 microns, at least 800 microns, or at least 900 microns) as determined by image analysis. In some embodiments, the aqueous foam exhibits an average initial bubble size of 1000 microns or less (e.g., 900 microns or less, 800 microns or less, 750 microns or less, 700 microns or less, 600 microns or less, 500 microns or less, 400 microns or less, 300 microns or less, 250 microns or less, or 200 microns or less) as determined by image analysis.

[0112] The aqueous foam can exhibit an average initial bubble size ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the aqueous foam exhibits an average initial bubble size of from 100 microns to 1000 microns, as determined by image analysis.

[0113] In some embodiments, the aqueous foam exhibits an average bubble size at volumetric loss onset of at least 800 microns (e.g., at least 900 microns, at least 1000 microns, at least 1250 microns, at least 1500 microns, at least 1750 microns, at least 2000 microns, at least 2500 microns, or at least 3000 microns) as determined by image analysis. In some embodiments, the aqueous foam exhibits an average bubble size at volumetric loss onset of 3500 microns or less (e.g., 3000 microns or less, 2500 microns or less, 2000 microns or less, 1750 microns or less, 1500 microns or less, 1250 microns or less, 1000 microns or less, or 900 microns or less) as determined by image analysis.

[0114] The aqueous foam can exhibit an average bubble size at volumetric loss onset ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the aqueous foam exhibits an average bubble size at volumetric loss onset of from 800 microns to 3500 microns, as determined by image analysis.

[0115] In some embodiments, the aqueous foam exhibits a time to breakdown onset of at least 30 seconds (e.g., at least 1 minute, at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, or at least 7 hours) at 25°C and 1 atm. In some embodiments, the aqueous foam exhibits a time to breakdown onset of 8 hours or less (e.g., 7 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or Attorney Docket No. 10975-078W01 less, 1 hour or less, 40 minutes or less, 30 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less, 5 minutes or less, or 1 minute or less) at 25°C and 1 atm.

[0116] The aqueous foam can exhibit a time to breakdown onset ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the aqueous foam exhibits a time to breakdown onset of from 30 seconds to 8 hours at 25°C and 1 atm, such as from 1 minute to 5 hours, from 1 minute to 2 hours, from 1 minute to 1 hour, from 1 minute to 45 minutes, from 1 minute to 20 minutes, or from 20 minutes to 40 minutes at 25°C and 1 atm.

[0117] In some embodiments, the aqueous foam exhibits a complete breakdown time of at least

[0118] 1 minute (e.g., at least 5 minutes, at least 15 minutes, at least 30 minutes, at least 1 hour, at least

[0119] 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, or at least 11 hours) at 25 °C and 1 atm. In some embodiments, the aqueous foam exhibits a complete breakdown time of 12 hours or less (e.g., 11 hours or less, 10 hours or less, 9 hours or less, 8 hours or less, 7 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, or 5 minutes or less) at 25 °C and 1 atm.

[0120] The aqueous foam can exhibit a complete breakdown time ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the aqueous foam composition exhibits a complete breakdown time of from 1 minute to 12 hours at 25 °C and 1 atm, such as from 5 minutes to 5 hours, from 5 minutes to 2 hours, or from 2 hours to 4 hours at 25°C and 1 atm.

[0121] In some embodiments, the aqueous foam composition is sterile.

[0122] In some embodiments, the aqueous foam composition exhibits a density of from 2 Ibs / gal to 8 Ibs / gal.

[0123] In some embodiments, the aqueous foam composition exhibits a foam quality of at least 40%, such as a foam quality of from 60% to 95%.

[0124] In some embodiments, the aqueous foam composition exhibits non-Newtonian shearthinning behavior.

[0125] In some embodiments, the aqueous foam composition exhibits a viscoelastic crossover modulus of from 1 Pa to 30,000 Pa at 25°C and 1 atm.

[0126] In some embodiments, the aqueous foam compositions described herein can exhibit a foam half-life (at 25°C and 1 atm) of 5 minutes or more (e.g., 10 minutes or more, 15 minutes or Attorney Docket No. 10975-078W01 more, 30 minutes or more, 1 hour or more, 2 hours or more, 4 hours or more, 6 hours or more, 8 hours or more, or 10 hours or more). In some embodiments, the aqueous foam precursor compositions described herein can exhibit a foam half-life (at 25°C and 1 atm) of 12 hours or less (e.g., 10 hours or less, 8 hours or less, 6 hours or less, 4 hours or less, 2 hours or less, 1 hours or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less).

[0127] The aqueous foam compositions described herein can exhibit a foam half-life (at 25°C and 1 atm) ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the aqueous foam compositions described herein can exhibit a foam half-life (at 25°C and 1 atm) of from 5 minutes to 12 hours (e.g., from 5 minutes to 6 hours, from 5 minutes to 4 hours, from 30 minutes to 12 hours, from 30 minutes to 6 hours, or from 30 minutes to 4 hours).

[0128] Foam Precursor Compositions

[0129] Also described herein are aqueous foam precursor compositions. The aqueous foam precursor compositions can comprise an aqueous solution which can form an aqueous-based foam upon combination with an expansion gas. In some embodiments, the aqueous foam precursor compositions described herein can be sterile so as to form sterile foams when foamed via entrainment of an expansion gas.

[0130] In some embodiments, the aqueous foam precursor compositions described herein can comprise water; from 0. 1% to 10% by weight of a biocompatible polymeric foam -forming agent; and an active agent. In some embodiments, the aqueous foam precursor composition further comprises one or more additional components chosen from a viscosity-modifying polymer, a foam stabilizer, a pH modifying agent (e.g., an acid, an alkali agent, or a combination thereof), a chelating agent (e.g., EDTA or a salt thereof), a preservative, a colorant, a sorbent, a co-solvent, or any combination thereof.

[0131] In some embodiments, the water is present in an amount of from 5% by weight to 98% by weight, based on the total weight of the aqueous foam precursor composition. In some embodiments, the aqueous foam precursor composition is a concentrate, and the water is present in an amount of from 5% by weight to 40% by weight, based on the total weight of the aqueous foam precursor composition. In some of these embodiments, the concentrate can be diluted, for example, by mixing with water or a suitable co-solvent, prior to foam formation. In other embodiments, the water can be present in an amount of from 60% by weight to 98% by weight, based on the total weight of the aqueous foam precursor composition. In some embodiments, the Attorney Docket No. 10975-078W01 aqueous foam precursor composition can be used to form an aqueous-based foam without dilution.

[0132] In some embodiments, the aqueous foam precursor compositions described herein can be packaged as a foamable composition in a container (e.g., a pressurized container, such as a spray can) in combination with a liquefied or a compressed gas propellant.

[0133] Methods of Making and Methods of Use

[0134] The foam compositions described herein can be applied to wounds to treat the wound, treat or prevent an infection, to improve wound healing, or a combination thereof. Accordingly, provided herein are methods of treating a wound that comprise applying a foam composition described herein to a wound.

[0135] As used herein the expression “wound” may include an injury to living tissue may be caused by a cut, blow, or other impact, typically one in which the skin is cut or broken. A wound may be a chronic or acute injury. Acute wounds occur as a result of surgery or trauma. They move through the stages of healing within a predicted timeframe. Chronic wounds typically begin as acute wounds. The acute wound can become a chronic wound when it does not follow the healing stages resulting in a lengthened recovery. It is believed that the transition from acute to chronic wound can be due to a patient being immunocompromised.

[0136] Chronic wounds may include for example: venous ulcers (such as those that occur in the legs), which account for the majority of chronic wounds and mostly affect the elderly, diabetic ulcers (for example, foot or ankle ulcers), peripheral arterial disease, pressure ulcers, or epidermolysis bullosa (EB).

[0137] Examples of other wounds include, but are not limited to, abdominal wounds or other large or incisional wounds (either as a result of surgery, trauma, stemiotomies, fasciotomies, or other conditions), dehisced wounds, acute wounds, chronic wounds, subacute and dehisced wounds, traumatic wounds (such as from orthopedic trauma), flaps and skin grafts, lacerations, abrasions, contusions, bums, diabetic ulcers, pressure ulcers, stoma, surgical wounds, trauma and venous ulcers, broken bones or the like.

[0138] Wounds may also include a deep tissue injury. Deep tissue injury is a term proposed by the National Pressure Ulcer Advisory Panel (NPUAP) to describe a unique form of pressure ulcers. These ulcers have been described by clinicians for many years with terms such as purple pressure ulcers, ulcers that are likely to deteriorate and bruises on bony prominences.

[0139] The wound may comprise an acute or chronic wound. The wound may be present in any Attorney Docket No. 10975-078W01 subject. "Subjects" (or "patients") to be treated with the methods and compositions described herein include both human subjects and animal subjects (particularly other mammalian subjects such as dogs, cats, horses, monkeys, etc.) for veterinary purposes. Human subjects are particularly preferred. The subjects may be male or female and may be any age, including neonate, infant, juvenile, adolescent, adult, and geriatric subjects.

[0140] In some embodiments, the method further comprises generating the aqueous foam composition from an aqueous foam precursor composition and an expansion gas. The aqueous foam composition can be generated from the aqueous foam precursor composition using any suitable means, such as a foam generator. The foam generator can comprise any suitable apparatus known conventionally for generating foams. In some examples, the foam generator can include an in-line mixer and a mesh screen configured in series. The in-line mixer can be, for example, a static mixer, which can receive and mix the aqueous foam precursor solution and the expansion gas, and mix the two. The mixture can then pass through one or more mesh screens positioned downstream of the fluid outlet of the in-line mixer. The resulting assembly can effectively shear the aqueous foam precursor in the presence of the expansion gas to form an aqueous-based foam. If desired, the dimensions (e.g., the mesh size) of the one or more mesh screens can be varied to influence characteristics of the foam produced by the foam generator. Alternatively, the foam generator can comprise one or more nozzles or ports which inject the expansion gas into the aqueous foam precursor to form a foam. Alternatively, the foam generator can comprise a dynamic mixer to mechanically agitate (e.g., a mechanically stir, shake, vortex, sonicate, and the like) the aqueous foam precursor in the presence of the expansion gas to form a foam.

[0141] In some embodiments, generating the aqueous foam composition can comprise: shearing the aqueous foam precursor composition in the presence of the expansion gas; injecting the expansion gas into the aqueous foam precursor composition; or any combination thereof.

[0142] In some embodiments, the expansion gas comprises nitrogen, CO2, air, nitrous oxide, propane, butane, or any combination thereof.

[0143] In some embodiments, the aqueous foam composition exhibits a volumetric expansion ratio of at least 1 (e.g., at least 1.5, at least 2, at least 2.5, at least 3, at least 3.5, at least 4, at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, at least 7.5, at least 8, at least 8.5, at least 9, or at least 9.5) upon generation of the aqueous foam from the aqueous foam precursor composition. In some embodiments, the aqueous foam composition exhibits a volumetric Attorney Docket No. 10975-078W01 expansion ratio of 10 or less (e.g., 9.5 or less, 9 or less, 8.5 or less, 8 or less, 7.5 or less, 7 or less, 6.5 or less, 6 or less, 5.5 or less, 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, or 1.5 or less) upon generation of the aqueous foam from the aqueous foam precursor composition.

[0144] The aqueous foam composition exhibits a volumetric expansion ratio ranging from any of the minimum values described above to any of the maximum values described above upon generation of the aqueous foam from the aqueous foam precursor composition. For example, in some embodiments, the aqueous foam composition exhibits a volumetric expansion ratio of from 1 to 10 upon generation of the aqueous foam from the aqueous foam precursor composition.

[0145] Foam-Forming Agents

[0146] The aqueous foam compositions and aqueous foam precursor compositions described herein can include one or more foam -forming agents. As used herein, the phrase “foamforming agent” is meant to include foam producing agents and compounds that are able to generate a foamable composition when admixed with a liquid or gel composition. The foamable composition generates a foam when combined with an expansion gas within a dispensing device or upon dispensing from a dispensing device. Examples of foam-forming agents include polymers (including biopolymers and synthetic polymers), surfactants, cholesteryl esters, fatty acid, phospholipids, carbohydrates, proteins, and even certain hydrophobic solvents.

[0147] In some embodiments, the foam-forming agent comprises a polymeric foam forming agent, such as a biopolymeric foam-forming agent. Examples of polymeric foam-forming agents include polysaccharides (e.g., alginate, chitosan, agarose, carrageenan, a cellulosic polymer such as carboxymethyl cellulose (CMC), hyaluronic acid, an alkyl polyglycoside, or a combination thereof), proteins (e.g., collagen, gelatin, whey protein, ovalbumin, conalbumin, globulins, ovomucin, or a combination thereof), synthetic polymers (e.g., polyvinyl alcohol, polyvinyl acetate, a polyalkylene oxide (e.g., a crosslinked polyethylene glycol), a polyester (e.g., polylactic acid, polyglycolic acid, polycaprolactone)), chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), and combinations thereof (e.g., copolymers and blends thereof).

[0148] In some embodiments, the foam-forming agent comprises a poloxamer. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (polyethylene Attorney Docket No. 10975-078W01 oxide)).

[0149] In some embodiments, the foam-forming agent comprises a poloxamer, such as Poloxamer 407 (PEOioiPPOsePEOioi), Poloxamer 188 (PEO75PPO29PEO75), Poloxamer 338 (PEO141PPO44PEO141), Poloxamer 124 (PEO12PPO20PEO12), Poloxamer 237 (PEO64PPO37PEO64), and mixtures thereof; carboxymethyl cellulose (CMC); methyl cellulose, chitosan; alginate; a polyvinyl alcohol; a gelatin, such as gelatin methacryloyl; a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); or any combination thereof.

[0150] In some examples, the foam-forming agent comprises one or more surfactants. Suitable surfactants can include natural and synthetic ionic or non-ionic surfactants. In some embodiments, the foam-forming agent can comprise an anionic surfactant, a non-ionic surfactant, or any combination thereof. Suitable surfactants (and combinations of surfactants) are known in the art as discussed in more detail below.

[0151] In some examples, suitable anionic surfactants include a hydrophobic tail that comprises from 6 to 60 carbon atoms. In some embodiments, the anionic surfactant can include a hydrophobic tail that comprises at least 6 carbon atoms (e.g., at least 7 carbon atoms, at least 8 carbon atoms, at least 9 carbon atoms, at least 10 carbon atoms, at least 11 carbon atoms, at least 12 carbon atoms, at least 13 carbon atoms, at least 14 carbon atoms, at least 15 carbon atoms, at least 16 carbon atoms, at least 17 carbon atoms, at least 18 carbon atoms, at least 19 carbon atoms, at least 20 carbon atoms, at least 21 carbon atoms, at least 22 carbon atoms, at least 23 carbon atoms, at least 24 carbon atoms, at least 25 carbon atoms, at least 26 carbon atoms, at least 27 carbon atoms, at least 28 carbon atoms, at least 29 carbon atoms, at least 30 carbon atoms, at least 31 carbon atoms, at least 32 carbon atoms, at least 33 carbon atoms, at least 34 carbon atoms, at least 35 carbon atoms, at least 36 carbon atoms, at least 37 carbon atoms, at least 38 carbon atoms, at least 39 carbon atoms, at least 40 carbon atoms, at least 41 carbon atoms, at least 42 carbon atoms, at least 43 carbon atoms, at least 44 carbon atoms, at least 45 carbon atoms, at least 46 carbon atoms, at least 47 carbon atoms, at least 48 carbon atoms, at least 49 carbon atoms, at least 50 carbon atoms, at least 51 carbon atoms, at least 52 carbon atoms, at least 53 carbon atoms, at least 54 carbon atoms, at least 55 carbon atoms, at least 56 carbon atoms, at least 57 carbon atoms, at least 58 carbon atoms, or at least 59 carbon atoms). In Attorney Docket No. 10975-078W01 some embodiments, the anionic surfactant can include a hydrophobic tail that comprises 60 carbon atoms or less (e.g., 59 carbon atoms or less, 58 carbon atoms or less, 57 carbon atoms or less, 56 carbon atoms or less, 55 carbon atoms or less, 54 carbon atoms or less, 53 carbon atoms or less, 52 carbon atoms or less, 51 carbon atoms or less, 50 carbon atoms or less, 49 carbon atoms or less, 48 carbon atoms or less, 47 carbon atoms or less, 46 carbon atoms or less, 45 carbon atoms or less, 44 carbon atoms or less, 43 carbon atoms or less, 42 carbon atoms or less, 41 carbon atoms or less, 40 carbon atoms or less, 39 carbon atoms or less, 38 carbon atoms or less, 37 carbon atoms or less, 36 carbon atoms or less, 35 carbon atoms or less, 34 carbon atoms or less, 33 carbon atoms or less, 32 carbon atoms or less, 31 carbon atoms or less, 30 carbon atoms or less, 29 carbon atoms or less, 28 carbon atoms or less, 27 carbon atoms or less, 26 carbon atoms or less, 25 carbon atoms or less, 24 carbon atoms or less, 23 carbon atoms or less, 22 carbon atoms or less, 21 carbon atoms or less, 20 carbon atoms or less, 19 carbon atoms or less, 18 carbon atoms or less, 17 carbon atoms or less, 16 carbon atoms or less, 15 carbon atoms or less, 14 carbon atoms or less, 13 carbon atoms or less, 12 carbon atoms or less, 11 carbon atoms or less, 10 carbon atoms or less, 9 carbon atoms or less, 8 carbon atoms or less, or 7 carbon atoms or less).

[0152] The anionic surfactant can include a hydrophobic tail that comprises a number of carbon atoms ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the anionic surfactant can comprise a hydrophobic tail comprising from 6 to 15, from 16 to 30, from 31 to 45, from 46 to 60, from 6 to 25, from 26 to 60, from 6 to 30, from 31 to 60, from 6 to 32, from 33 to 60, from 6 to 12, from 13 to 22, from 23 to 32, from 33 to 42, from 43 to 52, from 53 to 60, from 6 to 10, from 10 to 15, from 16 to 25, from 26 to 35, or from 36 to 45 carbon atoms. The hydrophobic (lipophilic) carbon tail may be a straight chain, branched chain, and / or may comprise cyclic structures. The hydrophobic carbon tail may comprise single bonds, double bonds, triple bonds, or any combination thereof. In some embodiments, the anionic surfactant can include a branched hydrophobic tail derived from Guerbet alcohols. The hydrophilic portion of the anionic surfactant can comprise, for example, one or more sulfate moieties (e.g., one, two, or three sulfate moieties), one or more sulfonate moieties (e.g., one, two, or three sulfonate moieties), one or more sulfosuccinate moieties (e.g., one, two, or three sulfosuccinate moieties), one or more carboxylate moieties (e.g., one, two, or three carboxylate moieties), or any combination thereof.

[0153] In some embodiments, the anionic surfactant can comprise, for example a sulfonate, a Attorney Docket No. 10975-078W01 disulfonate, a poly sulfonate, a sulfate, a disulfate, a polysulfate, a sulfosuccinate, a disulfosuccinate, a poly sulfosuccinate, a carboxylate, a dicarboxylate, a poly carboxylate, or any combination thereof. In some examples, the anionic surfactant can comprise an internal olefin sulfonate (IOS), an isomerized olefin sulfonate, an alfa olefin sulfonate (AOS), an alkyl aryl sulfonate (AAS), a xylene sulfonate, an alkane sulfonate, a petroleum sulfonate, an alkyl diphenyl oxide (di)sulfonate, an alcohol sulfate, an alkoxy sulfate, an alkoxy sulfonate, an alkoxy carboxylate, an alcohol phosphate, or an alkoxy phosphate. In some embodiments, the anionic surfactant can comprise an alkoxy carboxylate surfactant, an alkoxy sulfate surfactant, an alkoxy sulfonate surfactant, an alkyl sulfonate surfactant, an aryl sulfonate surfactant, or an olefin sulfonate surfactant. In some embodiments, the anionic surfactant can comprise an olefin sulfonate surfactant. In some embodiments, the anionic surfactant can comprise a C14-C16 olefin sulfonate surfactant. In some embodiments, the anionic surfactant can comprise an isomerized C14-C16 olefin sulfonate surfactant.

[0154] An "alkoxy carboxylate surfactant" or "alkoxy carboxylate" refers to a compound having an alkyl or aryl attached to one or more alkoxylene groups (typically -CH2-CH(ethyl)-O-, -CH2- CH(methyl)-O-, or -CH2-CH2-O-) which, in turn is attached to -COO" or acid or salt thereof including metal cations such as sodium. In embodiments, the alkoxy carboxylate surfactant can be defined by the formulae below: wherein R1is substituted or unsubstituted C6-C36 alkyl or substituted or unsubstituted aryl; R2is, independently for each occurrence within the compound, hydrogen or unsubstituted C1-C6 alkyl; R3is independently hydrogen or unsubstituted C1-C6 alkyl, n is an integer from 0 to 175, z is an integer from 1 to 6 and M+is a monovalent, divalent or trivalent cation. In some of these embodiments, R1can be an unsubstituted linear or branched C6-C36 alkyl.

[0155] In certain embodiments, the alkoxy carboxylate can be a C6-C32:PO(0-65):EO(0-100)- carboxylate (i.e., a C6-C32 hydrophobic tail, such as a branched or unbranched C6-C32 alkyl group, attached to from 0 to 65 propyleneoxy groups (-CH2-CH(methyl)-O- linkers), attached in turn to from 0 to 100 ethyleneoxy groups (-CH2-CH2-O- linkers), attached in turn to -COO" or an acid or salt thereof including metal cations such as sodium). In certain embodiments, the alkoxy carboxylate can be a branched or unbranched C6-C30:PO(30-40):EO(25-35)-carboxylate. Attorney Docket No. 10975-078W01

[0156] In certain embodiments, the alkoxy carboxylate can be a branched or unbranched C6- C12:PO(30-40):EO(25-35)-carboxylate. In certain embodiments, the alkoxy carboxylate can be a branched or unbranched C6-C30:EO(8-30)-carboxylate.

[0157] An “alkoxy sulfate surfactant” or “alkoxy sulfate” refers to a surfactant having an alkyl or aryl attached to one or more alkoxylene groups (typically -CH2-CH(ethyl)-O-, -CH2- CH(methyl)-O-, or -CH2-CH2-O-) which, in turn is attached to -SCh’ or acid or salt thereof including metal cations such as sodium. In some embodiment, the alkoxy sulfate surfactant has the formula R-(BO)e-(PO)f-(EO)g-SO3‘ or acid or salt (including metal cations such as sodium) thereof, wherein R is C6-C32 alkyl, BO is -CH2-CH(ethyl)-O-, PO is -CH2-CH(methyl)-O-, and EO is -CH2-CH2-O-. The symbols e, f and g are integers from 0 to 50 wherein at least one is not zero.

[0158] In embodiments, the alkoxy sulfate surfactant can be an aryl alkoxy sulfate surfactant. The aryl alkoxy surfactant can be an alkoxy surfactant having an aryl attached to one or more alkoxylene groups (typically -CH2-CH(ethyl)-O-, -CH2-CH(methyl)-O-, or -CH2-CH2-O-) which, in turn is attached to -SOs" or acid or salt thereof including metal cations such as sodium.

[0159] An “alkyl sulfonate surfactant” or “alkyl sulfonate” refers to a compound that includes an alkyl group (e.g., a branched or unbranched C6-C32 alkyl group) attached to -SO.f or acid or salt thereof including metal cations such as sodium.

[0160] An “aryl sulfate surfactant” or “aryl sulfate” refers to a compound having an aryl group attached to -O-SCh" or acid or salt thereof including metal cations such as sodium. An “aryl sulfonate surfactant” or “aryl sulfonate” refers to a compound having an aryl group attached to - SO3- or acid or salt thereof including metal cations such as sodium. In some cases, the aryl group can be substituted, for example, with an alkyl group (an alkyl aryl sulfonate).

[0161] An “internal olefin sulfonate,” “isomerized olefin sulfonate,” or “IOS” refers to an unsaturated hydrocarbon compound comprising at least one carbon-carbon double bond and at least one SOs" group, or a salt thereof. As used herein, a “C20-C28 internal olefin sulfonate,” “a C20-C28 isomerized olefin sulfonate,” or “C20-C28 IOS” refers to an IOS, or a mixture of IOSS with an average carbon number of 20 to 28, or of 23 to 25. The C20-C28 IOS may comprise at least 80% of IOS with carbon numbers of 20 to 28, at least 90% of IOS with carbon numbers of 20 to 28, or at least 99% of IOS with carbon numbers of 20 to 28. As used herein, a “C15- C18 internal olefin sulfonate,” “C15-C18 isomerized olefin sulfonate,” or “C15-C18 IOS” refers to an IOS or a mixture of IOSs with an average carbon number of 15 to 18, or of 16 to 17. The Attorney Docket No. 10975-078W01

[0162] C15-C18 IOS may comprise at least 80% of IOS with carbon numbers of 15 to 18, at least 90% of IOS with carbon numbers of 15 to 18, or at least 99% of IOS with carbon numbers of 15 to 18. The internal olefin sulfonates or isomerized olefin sulfonates may be alpha olefin sulfonates, such as an isomerized alpha olefin sulfonate. The internal olefin sulfonates or isomerized olefin sulfonates may also comprise branching. In certain embodiments, C15-18 IOS may be added to the single-phase liquid surfactant package when the LPS injection fluid is intended for use in high temperature unconventional subterranean formations, such as formations above 130°F (approximately 55 °C). The IOS may be at least 20% branching, 30% branching, 40% branching, 50% branching, 60% branching, or 65% branching. In some embodiments, the branching is between 20-98%, 30-90%, 40-80%, or around 65%. Examples of internal olefin sulfonates and the methods to make them are found in U.S. Pat. No. 5,488,148, U.S. Patent Application Publication 2009 / 0112014, and SPE 129766, all incorporated herein by reference.

[0163] In embodiments, the anionic surfactant can be a disulfonate, alkyldiphenyloxide disulfonate, mono alkyldiphenyloxide disulfonate, di alkyldiphenyloxide disulfonate, or a di alkyldiphenyloxide monosulfonate, where the alkyl group can be a C6-C36 linear or branched alkyl group. In embodiments, the anionic surfactant can be an alkylbenzene sulfonate or a dibenzene disufonate. In embodiments, the anionic surfactant can be benzenesulfonic acid, decyl(sulfophenoxy)-disodium salt; linear or branched C6-C36 alkyl:PO(0-65):EO(0-100) sulfate; or linear or branched C6-C36 alkyl:PO(0-65):EO(0-100) carboxylate. In embodiments, the anionic surfactant is an isomerized olefin sulfonate (C6-C30), internal olefin sulfonate (C6- C30) or internal olefin disulfonate (C6-C30). In some embodiments, the anionic surfactant is a Guerbet-PO(0-65)-EO(0-100) sulfate (Guerbet portion can be C6-C36). In some embodiments, the anionic surfactant is a Guerbet-PO(0-65)-EO(0-100) carboxylate (Guerbet portion can be C6- C36). In some embodiments, the anionic surfactant is alkyl PO(0-65) and EO(O-IOO) sulfonate: where the alkyl group is linear or branched C6-C36. In some embodiments, the anionic surfactant is a sulfosuccinate, such as a dialkylsulfosuccinate. In some embodiments, the anionic surfactant is an alkyl aryl sulfonate (AAS) (e.g. an alkyl benzene sulfonate (ABS)), a C10-C30 internal olefin sulfate (IOS), a petroleum sulfonate, or an alkyl diphenyl oxide (di)sulfonate.

[0164] In some examples, the anionic surfactant can comprise a surfactant defined by the formula below:

[0165] R1— R2— R3wherein R1comprises a branched or unbranched, saturated or unsaturated, cyclic or non-cyclic, Attorney Docket No. 10975-078W01 hydrophobic carbon chain having 6-32 carbon atoms and an oxygen atom linking R1and R2; R2comprises an alkoxylated chain comprising at least one oxide group selected from the group consisting of ethylene oxide, propylene oxide, butylene oxide, and combinations thereof; and R3comprises a branched or unbranched hydrocarbon chain comprising 2-12 carbon atoms and from 2 to 5 carboxylate groups.

[0166] In some examples, the anionic surfactant can comprise a surfactant defined by the formula below: wherein R4is a branched or unbranched, saturated or unsaturated, cyclic or non-cyclic, hydrophobic carbon chain having 6-32 carbon atoms; and M represents a counterion (e.g., Na+, K+). In some embodiments, R4is a branched or unbranched, saturated or unsaturated, cyclic or non-cyclic, hydrophobic carbon chain having 6-16 carbon atoms.

[0167] Suitable non-ionic surfactants include compounds that can be added to increase wettability. In embodiments, the hydrophilic-lipophilic balance (HLB) of the non-ionic surfactant is greater than 10 (e.g., greater than 9, greater than 8, or greater than 7). In some embodiments, the HLB of the non-ionic surfactant is from 7 to 10.

[0168] The non-ionic surfactant can comprise a hydrophobic tail comprising from 6 to 60 carbon atoms. In some embodiments, the non-ionic surfactant can include a hydrophobic tail that comprises at least 6 carbon atoms (e.g., at least 7 carbon atoms, at least 8 carbon atoms, at least 9 carbon atoms, at least 10 carbon atoms, at least 11 carbon atoms, at least 12 carbon atoms, at least 13 carbon atoms, at least 14 carbon atoms, at least 15 carbon atoms, at least 16 carbon atoms, at least 17 carbon atoms, at least 18 carbon atoms, at least 19 carbon atoms, at least 20 carbon atoms, at least 21 carbon atoms, at least 22 carbon atoms, at least 23 carbon atoms, at least 24 carbon atoms, at least 25 carbon atoms, at least 26 carbon atoms, at least 27 carbon atoms, at least 28 carbon atoms, at least 29 carbon atoms, at least 30 carbon atoms, at least 31 carbon atoms, at least 32 carbon atoms, at least 33 carbon atoms, at least 34 carbon atoms, at least 35 carbon atoms, at least 36 carbon atoms, at least 37 carbon atoms, at least 38 carbon atoms, at least 39 carbon atoms, at least 40 carbon atoms, at least 41 carbon atoms, at least 42 carbon atoms, at least 43 carbon atoms, at least 44 carbon atoms, at least 45 carbon atoms, at least 46 carbon atoms, at least 47 carbon atoms, at least 48 carbon atoms, at least 49 carbon Attorney Docket No. 10975-078W01 atoms, at least 50 carbon atoms, at least 51 carbon atoms, at least 52 carbon atoms, at least 53 carbon atoms, at least 54 carbon atoms, at least 55 carbon atoms, at least 56 carbon atoms, at least 57 carbon atoms, at least 58 carbon atoms, or at least 59 carbon atoms). In some embodiments, the non-ionic surfactant can include a hydrophobic tail that comprises 60 carbon atoms or less (e.g., 59 carbon atoms or less, 58 carbon atoms or less, 57 carbon atoms or less, 56 carbon atoms or less, 55 carbon atoms or less, 54 carbon atoms or less, 53 carbon atoms or less, 52 carbon atoms or less, 51 carbon atoms or less, 50 carbon atoms or less, 49 carbon atoms or less, 48 carbon atoms or less, 47 carbon atoms or less, 46 carbon atoms or less, 45 carbon atoms or less, 44 carbon atoms or less, 43 carbon atoms or less, 42 carbon atoms or less, 41 carbon atoms or less, 40 carbon atoms or less, 39 carbon atoms or less, 38 carbon atoms or less, 37 carbon atoms or less, 36 carbon atoms or less, 35 carbon atoms or less, 34 carbon atoms or less, 33 carbon atoms or less, 32 carbon atoms or less, 31 carbon atoms or less, 30 carbon atoms or less, 29 carbon atoms or less, 28 carbon atoms or less, 27 carbon atoms or less, 26 carbon atoms or less, 25 carbon atoms or less, 24 carbon atoms or less, 23 carbon atoms or less, 22 carbon atoms or less, 21 carbon atoms or less, 20 carbon atoms or less, 19 carbon atoms or less, 18 carbon atoms or less, 17 carbon atoms or less, 16 carbon atoms or less, 15 carbon atoms or less, 14 carbon atoms or less, 13 carbon atoms or less, 12 carbon atoms or less, 11 carbon atoms or less, 10 carbon atoms or less, 9 carbon atoms or less, 8 carbon atoms or less, or 7 carbon atoms or less).

[0169] The non-ionic surfactant can include a hydrophobic tail that comprises a number of carbon atoms ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the non-ionic surfactant can comprise a hydrophobic tail comprising from 6 to 15, from 16 to 30, from 31 to 45, from 46 to 60, from 6 to 25, from 26 to 60, from 6 to 30, from 31 to 60, from 6 to 32, from 33 to 60, from 6 to 12, from 13 to 22, from 23 to 32, from 33 to 42, from 43 to 52, from 53 to 60, from 6 to 10, from 10 to 15, from 16 to 25, from 26 to 35, or from 36 to 45 carbon atoms. In some cases, the hydrophobic tail may be a straight chain, branched chain, and / or may comprise cyclic structures. The hydrophobic carbon tail may comprise single bonds, double bonds, triple bonds, or any combination thereof. In some cases, the hydrophobic tail can comprise an alkyl group, with or without an aromatic ring (e.g., a phenyl ring) attached to it. In some embodiments, the hydrophobic tail can comprise a branched hydrophobic tail derived from Guerbet alcohols.

[0170] Example non-ionic surfactants include alkyl aryl alkoxy alcohols, alkyl alkoxy alcohols, Attorney Docket No. 10975-078W01 or any combination thereof. In embodiments, the non-ionic surfactant may be a mix of surfactants with different length lipophilic tail chain lengths. For example, the non-ionic surfactant may be C9-C 11 :9EO, which indicates a mixture of non-ionic surfactants that have a lipophilic tail length of 9 carbon to 11 carbon, which is followed by a chain of 9 EOs. The hydrophilic moiety is an alkyleneoxy chain (e.g., an ethoxy (EO), butoxy (BO) and / or propoxy (PO) chain with two or more repeating units of EO, BO, and / or PO). In some embodiments, 1- 100 repeating units of EO are present. In some embodiments, 0-65 repeating units of PO are present. In some embodiments, 0-25 repeating units of BO are present. For example, the non- ionic surfactant could comprise 10EO:5PO or 5EO. In embodiments, the non-ionic surfactant may be a mix of surfactants with different length lipophilic tail chain lengths. For example, the non-ionic surfactant may be C9-C11:PO9:EO2, which indicates a mixture of non-ionic surfactants that have a lipophilic tail length of 9 carbon to 11 carbon, which is followed by a chain of 9 POs and 2 EOs. In specific embodiments, the non-ionic surfactant is linear C9- C1 E9EO. In some embodiments, the non-ionic surfactant is a Guerbet PO(0-65) and EO(O-IOO) (Guerbet can be C6-C36); or alkyl PO(0-65) and EO(O-IOO): where the alkyl group is linear or branched C1-C36. In some examples, the non-ionic surfactant can comprise a branched or unbranched C6-C32:PO(0-65):EO(0-100) (e.g., a branched or unbranched C6-C30:PO(30- 40):EO(25-35), a branched or unbranched C6-C12:PO(30-40):EO(25-35), a branched or unbranched C6-30:EO(8-30), or any combination thereof). In some embodiments, the non-ionic surfactant is one or more alkyl polyglucosides.

[0171] Examples of suitable primary foaming surfactants are disclosed, for example, in U.S. Patent Nos. 3,811,504, 3,811,505, 3,811,507, 3,890,239, 4,463,806, 6,022,843, 6,225,267, 7,629,299, 7,770,641, 9,976,072, 8,211, 837, 9,422,469, 9,605,198, and 9,617,464; WIPO Patent Application Nos. WO / 2008 / 079855, WO / 2012 / 027757 and WO / 2011 / 094442; as well as U.S. Patent Application Nos. 2005 / 0199395, 2006 / 0185845, 2006 / 0189486, 2009 / 0270281, 2011 / 0046024, 2011 / 0100402, 2011 / 0190175, 2007 / 0191633, 2010 / 004843. 2011 / 0201531, 2011 / 0190174, 2011 / 0071057, 2011 / 0059873, 2011 / 0059872, 2011 / 0048721, 2010 / 0319920, 2010 / 0292110, and 2017 / 0198202, each of which is hereby incorporated by reference herein in its entirety for its description of example surfactants.

[0172] Suitable surfactants can also comprise one or more cationic surfactants. Example cationic surfactants include surfactant analogous to those described above, except bearing primary, secondary, or tertiary amines, or quaternary ammonium cations, as a hydrophilic head Attorney Docket No. 10975-078W01 group. Suitable surfactants can also comprise one or more zwitterionic surfactants. "Zwitterionic" or "zwitterion" as used herein refers to a neutral molecule with a positive (or cationic) and a negative (or anionic) electrical charge at different locations within the same molecule. Example zwitterionic surfactants include betains and sultains

[0173] In some examples, the one or more surfactants can comprise sodium lauryl sulfate (SLS). SLS is commonly used in industrial cleaning products and detergents, SLS is known for its strong foaming properties.

[0174] In some examples, the one or more surfactants can comprise cocamidopropyl betaine: This surfactant is often used in cleaning formulations and can enhance foam stability while being milder on surfaces.

[0175] In some examples, the one or more surfactants can comprise an Alkyl Polyglucoside (APG). Derived from renewable resources, these non-ionic surfactants are effective in various cleaning applications, including household and industrial cleaners, and provide good foaming.

[0176] In some examples, the one or more surfactants can comprise a Quillajci Saponcirici extract. Known for its natural foaming properties, this extract is used in firefighting foams and as a foaming agent in various industrial applications.

[0177] In some examples, the one or more surfactants can comprise sodium cocoyl isethionate (SCI). While often found in personal care products, SCI is also effective in industrial cleaning formulations due to its excellent foaming and mildness.

[0178] In some examples, the one or more surfactants can comprise potassium lauryl sulfate. Similar to SLS, this surfactant is used in various cleaning products and is known for its ability to produce stable foam.

[0179] In some embodiments, the one or more surfactants can comprise a non-ionic surfactant.

[0180] In some examples, the one or more surfactants can comprise a polysorbate-type nonionic surfactant formed by the ethoxylation of sorbitan monolaurate. Examples of polysorbates include polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or a combination thereof.

[0181] In some embodiments, the one or more surfactants can comprise an alkyl polyglycoside.

[0182] In some embodiments, the one or more surfactants can comprise one or more anionic surfactants. Attorney Docket No. 10975-078W01

[0183] In some embodiments, the one or more surfactants can comprise a sulfate surfactant, a sulfonate surfactant, a carboxylate surfactant, or a combination thereof.

[0184] In some embodiments, the one or more surfactants can comprise sodium lauryl sulfate (SLS), sodium cocoyl isethionate (SCI), potassium lauryl sulfate, or a combination thereof.

[0185] In some embodiments, the one or more surfactants can comprise a glycoside saponin, such as a glycoside saponin extracted from Quillaja saponaria. a glycoside saponin extracted from soapwort (Saponaria officinalis), a glycoside saponin extracted from senega root (Polygala senega), a glycoside saponin extracted from sarsaparilla (Smilax ornata).

[0186] In some embodiments, the one or more surfactants can comprise one or more zwitterionic surfactants, such as cocamidopropyl betaine.

[0187] In some embodiments, the foam-forming agent comprises a surfactant, such as a nonionic surfactant, an anionic surfactant, a zwitterionic surfactant, or a combination thereof. In certain embodiments, the surfactant comprises a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or a combination thereof; an alkyl polyglycoside; sodium lauryl sulfate (SLS); sodium cocoyl isethionate (SCI); potassium lauryl sulfate; a glycoside saponin, such as a glycoside saponin extracted from Quillaja saponaria, a glycoside saponin extracted from soapwort (Saponaria officinalis), a glycoside saponin extracted from senega root (Polygala senega), a glycoside saponin extracted from sarsaparilla (Smilax ornata),' cocamidopropyl betaine; or a combination thereof.

[0188] In some examples, the foam-forming agent comprises a hydrophobic solvent, petrolatum, paraffin wax, a fatty alcohol, a fatty acid, a wax, shea butter, or a combination thereof.

[0189] In some embodiments, the foam-forming agent(s) can be present in an amount of at least 0.1% by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., at least 0.5% by weight, at least 1% by weight, at least 1.5% by weight, at least 2% by weight, at least 2.5% by weight, at least 3% by weight, at least 4% by weight, at least 5% by weight, at least 6% by weight, at least 7% by weight, at least 8% by weight, or at least 9% by weight). In some embodiments, the foam-forming agent(s) can be present in an amount of 10% by weight or less, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, 5% by weight or less, 4% by weight or less, Attorney Docket No. 10975-078W01

[0190] 3% by weight or less, 2.5% by weight or less, 2% by weight or less, 1.5% by weight or less, 1% by weight or less, or 0.5% by weight or less).

[0191] The foam-forming agent(s) can be present in an amount ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the foam -forming agent(s) can be present in an amount of from 0.1% by weight to 10% by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition, such as from 0.5% by weight to 7% by weight, from 0.5% by weight to 5% by weight, from 0.5% by weight to 4% by weight, or from 1% by weight to 3% by weight.

[0192] Active Agents

[0193] The aqueous foam compositions and aqueous foam precursor compositions described herein can include one or more active agents. Examples of suitable active agents include active agents that are conventionally applied to treat wounds or as part of wound care, including anti- infective agents, anti-inflammatory agents, analgesics, immunomodulatory agents, and agents to stimulate wound healing.

[0194] In some embodiments, the active agent comprises a therapeutic agent, a prophylactic agent, a diagnostic agent, or a combination thereof. In some embodiments, the active agent comprises an antimicrobial agent, an analgesic agent, a hemostatic agent, a growth factor, an immunomodulatory agent, an orthobiologic agent, an extracellular vesicle, an exosome agent, a senolytic agent, or a combination thereof.

[0195] In some embodiments, the active agent comprises (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immunomodulatory agent, wound healing agent, an analgesic agent; or a combination thereof.

[0196] In some embodiments, the active agent comprises (1) an antimicrobial agent; (2) an analgesic agent; and optionally (3) an immunomodulatory agent, wound healing agent, a hemostatic agent, or a combination thereof.

[0197] In some embodiments, the active agent comprises one or more antimicrobial agents alone.

[0198] The term “antimicrobial agent” refers to a bioactive molecule that kills or inhibits the growth or replication of bacteria, fungi, algae, or other pathogenic organisms. A wide variety of antimicrobial agents are known in the art, and are described, for example, in U.S. Patent Publication No. 2006 / 0078604 (Kanios et al.), which is incorporated herein by reference in its Attorney Docket No. 10975-078W01 entirety.

[0199] In some embodiments, the antimicrobial agent comprises an antibacterial agent. Examples of antibacterial agents (antibiotics) include Aminoglycosides such as Amikacin, Apramycin, Arbekacin, Bambermycins, Butirosin, Dibekacin, Dihdrostreptomycin, Fortimicin(s), Gentamicin, Ispamicin, Kanamycin, Micronomicin, Neomycin, Neomycin Undecylenate, Netilmicin, Paromomycin, Ribostamycin, Sisomicin, Spectinomycin, Streptomycin, Streptonicozid and Tobramycin; Amphenicols such as Azidamfenicol, Chloramphenicol, Chloramphenicol Palmitate, Chloramphenicol Pantothenate, Florfenicol and Thiamphenicol; Ansamycins such as Rifamide, Rifampin, Rifamycin and Rifaximin; P-Lactams, including: Carbapenems such as Imipenem; Cephalosporins such as Cefactor, Cefadroxil, Cefamandole, Cefatrizine, Cefazedone, Cefazolin, Cefixime, Cefmenoxime, Cefodizime, Cefonicid, Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Cefpimizole, Cefpirimide, Cefpodoxime Proxetil, Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefuzonam, Cephacetrile Sodium, Cephalexin, Cephaloglycin, Cephaloridine, Cephalosporin, Cephalothin, Cephapirin Sodium, Cephradine and Pivcefalexin; Cephamycins such as Cefbuperazone, Cefmetazole, Cefininox, Cefetan and Cefoxitin; Monobactams such as Aztreonam, Carumonam and Tigemonam; Oxacephems such as Flomoxef and Moxolactam; Penicillins such as Amidinocillin, Amdinocillin Pivoxil, Amoxicillin, Ampicillan, Apalcillin, Aspoxicillin, Azidocillan, Azlocillan, Bacampicillin, Benzylpenicillinic Acid, Benzylpenicillin Sodium, Carbenicillin, Carfecillin Sodium, Carindacillin, Clometocillin, Cioxacillin, Cyclacillin, Dicloxacillin, Diphenicillin Sodium, Epicillin, Fenbenicillin, Floxicillin, Hetacillin, Lenampicillin, Metampicillin, Methicillin Sodium, Mezlocillin, Nafcillin Sodium, Oxacillin, Penamecillin, Penethamate Hydriodide, Penicillin G Benethamine, Penicillin G Benzathine, Penicillin G Benzhydrylamine, Penicillin G Calcium, Penicillin G Hydrabamine, Penicillin G Potassium, Penicillin G Procaine, Penicillen N, Penicillin 0, Penicillin V, Penicillin V Benzathine, Penicillin V Hydrabamine, Penimepicycline, Phenethicillin Potassium, Piperacillin, Pivapicillin, Propicillin, Quinacillin, Sulbenicillin, Talampicillin, Temocillin and Ticarcillin; Lincosamides such as Clindamycin and Lincomycin; Macrolides such as Azithromycin, Carbomycin, Clarithromycin, Erythromycin, Erythromycin Acistrate, Erythromycin Estolate, Erythromycin Glucoheptonate, Erythromycin Lactobionate, Erythromycin Propionate, Erythromycin Stearate, Josamycin, Leucomycins, Midecamycins, Miokamycin, Oleandomycin, Primycin, Rokitamycin, Rosaramicin, Roxithromycin, Spiramycin Attorney Docket No. 10975-078W01 and Troleandomycin; Polypeptides such as Amphomycin, Bacitracin, Capreomycin, Colistin, Enduracidin, Enviomycin, Fusafungine, Gramicidin(s), Gramicidin S, Mikamycin, Polymyxin, Polymyxin B-Methanesulfonic Acid, Pristinamycin, Ristocetin, Teicoplanin, Thiostrepton, Tuberactinomycin, Tyrocidine, Tyrothricin, Vancomycin, Viomycin, Viomycin Pantothenate, Virginiamycin and Zinc Bacitracin; Tetracyclines such as Apicycline, Chlortetracycline, Clomocycline, Demeclocycline, Doxycycline, Guamecycline, Lymecycline, Meclocycline, Methacycline, Minocycline, Oxytetracycline, Penimepicycline, Pipacycline, Rolitetracycline, Sancycline, Senociclin and Tetracycline; 2,4-Diaminopyrimidines such as Brodimoprim, Tetroxoprim and Trimethoprim; Nitrofurans such as Furaltadone, Furazolium Chloride, Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Nifurprazine, Nifurtoinol and Nitrofurantoin; Quinolones and Analogs such as Amifloxacin, Cinoxacin, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Flumequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin, Pipemidic Acid, Piromidic Acid, Rosoxacin, Temafloxacin and Tosufloxacin; Sulfonamides such as Acetyl Sulfamethoxypyrazine, Acetyl Sulfisoxazole, Azosulfamide, Benzylsulfamide, Chloramine-B, Chloramine-T, Dichloramine T, Formosulfathiazole, N2Formylsulfisomidine, N2-a-D-Glucosylsulfanilamide, Mafenide, 4'- (Methylsulfamoyl)sulfanilanilide, p-Nitrosulfathiazole, Noprylsulfamide, Phthalylsulfacetamide, Phthalylsulfathiazole, Salazosulfadimidine, Succinylsulfathiazole, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine, Sulfadiazine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic Acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Sulfamethoxazole, Sulfamethoxypyridazine, Sulfametrole, Sulfamidochrysoidine, Sulfamoxole, Sulfanilamide, Sulfanilamidomethanesulfonic Acid Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, N4-Sulfanilylsulfanilamide, Sulfanilylurea, N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sulfaproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sulfasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomidine and Sulfisoxazole; Sulfones such as Acedapsone, Acediasulfone, Acetosulfone Sodium, Dapsone, Diathymosulfone, Glucosulfone Sodium, Solasulfone, Succisulfone, Sulfanilic Acid, p-Sulfanilylbenzylamine, p,p'-Sulfonyldianiline-N,N' digalactoside, Sulfoxone Sodium and Thiazolsulfone; and others such as Clofoctol, Hexedine, Methenamine, Methenamine Anhydromethylene-citrate, Methenamine Hippurate, Methenamine Mandelate, Methenamine Sulfosalicylate, Nitroxoline and Xibomol, Anticholinergics such as Attorney Docket No. 10975-078W01

[0200] Adiphenine Hydrochloride, Alverine, Ambutonomium Bromide, Aminopentamide, Amixetrine, Amprotropine Phosphate, Anisotropine Methylbromide, Apoatropine, Atropine, Atropine N- Oxide, Benactyzine, Benapryzine, Benzetimide, Benzilonium Bromide, Benztropine Mesylate, Bevonium Methyl Sulfate, Biperiden, Butropium Bromide, N-Butylscopolammonium Bromide, Buzepide, Camylofine, Caramiphen Hydrochloride, Chlorbenzoxamine, Chlorphenoxamine, Cimetropium Bromide, Clidinium Bromide, Cyclodrine, Cyclonium Iodide, Cycrimine Hydrochloride, Deptropine, Dexetimide, Dibutoline Sulfate, Dicyclomine Hydrochloride, Diethazine, Difemerine, Dihexyverine, Diphemanil Methylsulfate, N-(l,2- Diphenylethyl)nicotinamide, Dipiproverine, Diponium Bromide, Emepronium Bromide, Endobenzyline Bromide, Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Etomidoline, Eucatropine, Fenpiverinium Bromide, Fentonium Bromide, Flutropium Bromide, Glycopyrrolate, Heteronium Bromide, Hexocyclium Methyl Sulfate, Homatropine, Hyoscyamine, Ipratropium Bromide, Isopropamide, Levomepate, Mecloxamine, Mepenzolate Bromide, Metcaraphen, Methantheline Bromide, Methixene, Methscopolamine Bromide, Octamylamine, Chloride, Oxyphencyclimine, Oxyphenonium Bromide, Pentapiperide, Penthienate Bromide, Phencarbamide, Phenglutarimide, Pipenzolate Bromide, Piperidolate, Piperilate, Poldine Methysulfate, Pridinol, Prifmium Bromide, Procyclidine, Propantheline Bromide, Propenzolate, Propyromazine, Scopolamine, Scopolamine N-Oxide, Stilonium Iodide, Stramonium, Sultroponium, Thihexinol, Thiphenamil, Tiemonium Iodide, Timepidium Bromide, Tiquizium Bromide, Tridihexethyl Iodide, Trihexyphenidyl Hydrochloride, Tropacine, Tropenzile, Tropicamide, Trospium Chloride, Valethamate Bromide and Xenytropium Bromide, and other antibiotics such as Cycloserine, Mupirocin and Tuberin.

[0201] In some embodiments, the antimicrobial agent comprises an antifungal agent. Examples of antifungal agents include Polyenes such as Amphotericin-B, Candicidin, Dermostatin, Filipin, Fungichromin, Hachimycin, Hamycin, Lucensomycin, Mepartricin, Natamycin, Nystatin, Pecilocin and Perimycin; Allylamines such as Naftifme and Terbinafme; Imidazoles such as Bifonazole, Butoconazole, Chlordantoin, Chlormidazole, Cloconazole, Clotrimazole, Econazole, Enilconazole, Fenticonazole, Isoconazole, Ketoconazole, Miconazole, Omoconazole, Oxiconazole, Nitrate, Sulconazole and Tioconazole; Triazoles such as Fluconazole, Itraconazole and Terconazole; and others such as Azaserine, Griseofulvin, Oligomycins, Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tubercidin, Viridin, Acrisorcin, Amorolfme, Biphenamine, Bromosalicylchloranilide, Buclosamide, Calcium Propionate, Chlophenesin, Ciclopirox, Attorney Docket No. 10975-078W01

[0202] Cloxyquin, Coparaffinate, Diamthazole, Dihydrochloride, Exalamide, Flucytosine, Halethazole, Hexetidine, Loflucarban, Nifuratel, Potassium Iodide, Propionic Acid, Pyrithione, Salicylanilide, Sodium Propionate, Sulbentine, Tenonitrozole, Tolciclate, Tolindate, Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and Zinc Propionate.

[0203] In some embodiments, the antimicrobial agent is chosen from an aminoglycoside (e.g., tobramycin, neomycin), a peptide antibiotic (vancomycin, bacitracin), a beta-lactam antibiotic (e.g., ceftazidime, ceftriaxone, cefazolin), a Polymyxins (polymyxin B, colistin), or combinations thereof. In certain embodiments, the antimicrobial agent can comprise a combination of an antibacterial agent that is active against Gram-positive bacteria and an antibacterial agent that is active against Gram-positive bacteria. In other embodiments, the antimicrobial agent comprises an antifungal agent.

[0204] In some embodiments, the hemostatic agent is chosen from an antifibrinolytic (e.g., tranexamic Acid (TXA)), a coagulation factor or analog thereof (e.g., recombinant factor Vila (rFVIIa), prothrombin complex concentrates (PCCs), fibrinogen concentrates, desmopressin), or combinations thereof.

[0205] Examples of immunomodulatory agents include Amiprilose, Bucillamine, Ditiocarb Sodium, Inosine Pranobex, Interferon-y, Interleukin-2, Lentinan, Muroctasin, Platonin, Procodazole, Tetramisole, Thymomodulin, Thymopentin Ubenimex, Azathioprine, Cyclosporins and Mizoribine. In some embodiments, the immunomodulatory agent is chosen from a Toll -like Receptor (TLR) agonist (e.g., Polyinosinic-polycytidylic acid (poly(EC)), a CpG oligonucleotide), a cytosolic receptor agonist (e.g., 2'3'-cyclic di-GMP (c-di-GMP), ADU-S100 (MIW815), DMXAA (Vadimezan)), or combinations thereof.

[0206] In some embodiments, the wound healing agent is chosen from a wound healing macrophage (Mfl>) activator, a fibroblast growth factor (FGF), an epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), or a combination thereof.

[0207] Examples of analgesic agents include Chlorobutanol, Clove, Eugenol, Alfentanil, Allylprodine, Alphaprodine, Anileridine, Benzylmorphine, Bezitramide, Buprenorphine, Butorphanol, Clonitazene, Codeine, Codeine Methyl Bromide, Codeine Phosphate, Codeine Sulfate, Desomorphine, Dextromoramide, Dezocine, Diampromide, Dihydrocodeine, Dihydrocodeinone Enol Acetate, Dihydromorphine, Dimenoxadol, Dimepheptanol, Dimethylthiambutene, Dioxaphetyl Butyrate, Dipipanone, Eptazocine, Ethoheptazine, Ethyhnethlythiambutene, Ethylmorphine, Etonitazene, Fentanyl, Hydrocodone, Hydrocodone Attorney Docket No. 10975-078W01

[0208] Bitartrate, Hydromorphone, Hydroxypethidine, Isomethadone, Ketobemidone, Levorphanol, Lofentanil, Meperidine, Meptazinol, Metazocine, Methadone Hydrochloride, Metopon, Morphine, Morphine Derivatives, Myrophine, Nalbuphine, Narceine, Nicomorphine, Norlevorphanol, Normethadone, Normorphine, Norpipanone, Opium, Oxycodone, Oxymorphone, Papaveretum, Pentazocine, Phenadoxone, Phenazocine, Pheoperidine, Piminodine, Piritramide, Proheptazine, Promedol, Properidine, Propiram, Propoxyphene, Sufentanil, Tilidine, Acetaminophen, Acetaminosalol, Acetanilide, Acetylsalicylsalicylic Acid, Alclofenac, Alminoprofen, Aloxiprin, Aluminum Bis(acetylsalicylate), Aminochlorthenoxazin, 2-Amino-4-picoline, Aminopropylon, Aminopyrine, Ammonium Salicylate, Antipyrine, Antipyrine Salicylate, Antrafenine, Apazone, Aspirin, Benorylate, Benoxaprofen, Benzpiperylon, Benzydamine, p-Bromoacetanilide, 5 -Bromosalicylic Acid Acetate, Bucetin, Bufexamac, Bumadizon, Butacetin, Calcium Acetylsalicylate, Carbamazepine, Carbetidine, Carbiphene, Carsalam, Chloralantipyrine, Chlorthenoxazin(e), Choline Salicylate, Cinchophen, Ciramadol, Clometacin, Cropropamide, Crotethamide, Dexoxadrol, Difenamizole, Diflunisal, Dihydroxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone, Emorfazone, Enfenamic Acid, Epirizole, Etersalate, Ethenzamide, Ethoxazene, Etodolac, Felbinac, Fenoprofen, Floctafenine, Flufenamic Acid, Fluoresone, Flupirtine, Fluproquazone, Flurbiprofen, Fosfosal, Gentisic Acid, Glafenine, Ibufenac, Imidazole Salicylate, Indomethacin, Indoprofen, Isofezolac, Isoladol, Isonixin, Ketoprofen, Ketorolac, p-Lactophenetide, Lefetamine, Loxoprofen, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Methotrimeprazine, Metofoline, Miroprofen, Morazone, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5' Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Phenacetin, Phenazopyridine Hydrochloride, Phenocoll, Phenopyrazone, Phenyl Acetylsalicylate, Phenyl Salicylate, Phenyramidol, Pipebuzone, Piperylone, Prodilidine, Propacetamol, Propyphenazone, Proxazole, Quinine Salicylate, Ramifenazone, Rimazolium Metilsulfate, Salacetamide, Salicin, Salicylamide, Salicylamide O-Acetic Acid, Salicylsulfuric Acid, Salsalte, Salverine, Simetride, Sodium Salicylate, Sulfamipyrine, Suprofen, Talniflumate, Tenoxicam, Terofenamate, Tetradrine, Tinoridine, Tolfenamic Acid, Tolpronine, Tramadol, Viminol, Xenbucin, Zomepirac, Aminoarylcarboxylic acid derivatives such as Enfenamic Acid, Etofenamate, Flufenamic Acid, Isonixin, Meclofenamic Acid, Mefanamic Acid, Niflumic Acid, Talniflumate, Terofenamate and Tolfenamic Acid; Arylacetic acid derivatives such as Acemetacin, Alclofenac, Amfenac, Bufexamac, Cinmetacin, Clopirac, Diclofenac Sodium, Etodolac, Felbinac, Fenclofenac, Attorney Docket No. 10975-078W01

[0209] Fenclorac, Fenclozic Acid, Fentiazac, Glucametacin, Ibufenac, Indomethacin, Isofezolac, Isoxepac, Lonazolac, Metiazinic Acid, Oxametacine, Proglumetacin, Sulindac, Tiaramide, Tolmetin and Zomepirac; Arylbutyric acid derivatives such as Bumadizon, Butibufen, Fenbufen and Xenbucin; Arylcarboxylic acids such as Clidanac, Ketorolac and Tinoridine; Arylpropionic acid derivatives such as Alminoprofen, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Pranoprofen, Protizinic Acid, Suprofen and Tiaprofenic Acid; Pyrazoles such as Difenamizole and Epirizole; Pyrazolones such as Apazone, Benzpiperylon, Feprazone, Mofebutazone, Morazone, Oxyphenbutazone, Phenybutazone, Pipebuzone, Propyphenazone, Ramifenazone, Suxibuzone and Thiazolinobutazone; Salicylic acid derivatives such as Acetaminosalol, Aspirin, Benorylate, Bromosaligenin, Calcium Acetylsalicylate, Diflunisal, Etersalate, Fendosal, Gentisic Acid, Glycol Salicylate, Imidazole Salicylate, Lysine Acetylsalicylate, Mesalamine, Morpholine Salicylate, 1 -Naphthyl Salicylate, Olsalazine, Parsalmide, Phenyl Acetylsalicylate, Phenyl Salicylate, Salacetamide, Salicylamine O-Acetic Acid, Salicylsulfuric Acid, Salsalate and Sulfasalazine; Thiazinecarboxamides such as Droxicam, Isoxicam, Piroxicam and Tenoxicam; and others such as s-Acctamidocaproic Acid, S-Adenosylmethionine, 3-Amino-4- hydroxybutyric Acid, Amixetrine, Bendazac, Benzydamine, Bucolome, Difenpiramide, Ditazol, Emorfazone, Guaiazulene, Nabumetone, Nimesulide, Orgotein, Oxaceprol, Paranyline, Perisoxal, Pifoxime, Proquazone, Proxazole and Tenidap.

[0210] In some embodiments, the analgesic agent is chosen from a local anesthetic (an amide) such as lidocaine, bupivacaine, mepivacaine, or ropivacaine; a non-steroidal anti-inflammatory drug (an NSAID) such as diclofenac or ketoprofen; an opioids such as morphine or fentanyl; or a combination thereof.

[0211] In some embodiments, the active agent is present in an amount of from 0.001% by weight to 25% by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition.

[0212] Additional Components

[0213] As discussed above, in some embodiments, the aqueous foams and aqueous foam precursor compositions described herein can further comprise one or more additional components, including a viscosity-modifying polymer, a foam stabilizer, a pH modifying agent (e.g., an acid, an alkali agent, or a combination thereof), a chelating agent (e.g., EDTA or a salt Attorney Docket No. 10975-078W01 thereof), a preservative, a sorbent, a colorant, a co-solvent, or any combination thereof.

[0214] Viscosity-Modifying Polymers

[0215] The aqueous foams and aqueous foam precursor compositions can comprise any suitable viscosity-modifying polymer. The viscosity-modifying polymer can comprise a synthetic polymer, a naturally occurring polymer (a biopolymer), or any combination thereof.

[0216] In some examples, the viscosity-modifying polymer can comprise a synthetic polymer. Examples of suitable synthetic polymers include polyacrylamides, such as partially hydrolyzed polyacrylamides (HPAMs or PHPAs), and hydrophobically-modified associative polymers (APs). Other examples include co-polymers of polyacrylamide (PAM) and one or both of 2- acrylamido 2-methylpropane sulfonic acid (and / or sodium salt) commonly referred to as AMPS (also more generally known as acrylamido tertiobutyl sulfonic acid or ATBS), N-vinyl pyrrolidone (NVP), and the NVP-based synthetic may be single-, co-, or ter-polymers. In one embodiment, the synthetic polymer is polyacrylic acid (PAA). In one embodiment, the synthetic polymer is polyvinyl alcohol (PVA). Copolymers may be made of any combination or mixture above, for example, a combination of NVP and ATBS.

[0217] In some examples, the viscosity-modifying polymer can comprise a synthetic polymer, such as hydrolyzed polyacrylamide (HP AM), N-vinylpyrrolidone (NVP), acrylamide tertiary butyl sulfonic acid (ATBS), 2-acrylamido-2 -methylpropane sulfonic acid (AMPS), or any combination thereof. In some examples, the viscosity-modifying polymer can comprise a blend of a biopolymer and a synthetic polymer.

[0218] In some examples, the viscosity-modifying polymer can comprise a biopolymer, such as a triple-helix forming biopolymer. In some examples, the viscosity-modifying polymer comprises a polysaccharide. In some examples, the viscosity-modifying polymer can be selected from the group consisting of xanthan, guar, a scleroglucan, a schizophyllan, hydroxyethyl cellulose (HEC), or any combination thereof.

[0219] The viscosity-modifying polymer can, for example, be present in an amount of 0.01% or more by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., 0.05% or more, 0.1% or more, 0.15% or more, 0.2% or more, 0.25% or more, 0.3% or more, 0.35% or more, 0.4% or more, 0.45% or more, 0.5% or more, 0.55% or more, 0.6% or more, 0.65% or more, 0.7% or more, 0.75% or more, 0.8% or more, 0.85% or more, or 0.9% or more). In some examples, the viscosity-modifying polymer can be present in an amount of 1% or less by weight, based on the total weight of the aqueous foam Attorney Docket No. 10975-078W01 composition or aqueous foam precursor composition (e.g., 0.95% or less, 0.9% or less, 0.85% or less, 0.8% or less, 0.75% or less, 0.7% or less, 0.65% or less, 0.6% or less, 0.55% or less, 0.5% or less, 0.45% or less, 0.4% or less, 0.35% or less, 0.3% or less, 0.25% or less, 0.2% or less, 0.15% or less, or 0.1% or less).

[0220] The amount of the viscosity-modifying polymer present can range from any of the minimum values described above to any of the maximum values described above. For example, the viscosity-modifying polymer can be present in an amount of from 0.01% to 1% by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., from 0.01% to 0.5%, from 0.5% to 1%, from 0.01% to 0.2%, from 0.2% to 0.4%, from 0.4% to 0.6%, from 0.6% to 0.8%, from 0.8% to 1%, from 0.01% to 0.9%, from 0.1% to 1%, from 0.1% to 0.9%, or from 0.01% to 0.75%).

[0221] Foam Stabilizers

[0222] In some embodiments, the aqueous foam compositions and aqueous foam precursor compositions described herien can further comprise a foam stabilizer. Examples of foam stabilizers can include, for example, fluorosurfactants, crosslinkers, particulate stabilizers, or any combination thereof.

[0223] In some embodiments, the aqueous foam precursor composition can comprise a fluorosurfactant. Fluorosurfactants are surfactants that include at least one fluorine atom. Examples of fluorosurfactants include perfluoroalkylethyl phosphates, perfluoroalkylethyl betaines, fluoroaliphatic amine oxides, fluoroaliphatic sodium sulfosuccinates, fluoroaliphatic stearate esters, fluoroaliphatic phosphate esters, fluoroaliphatic quaternaries, fluoroaliphatic polyoxyethylenes, and the like, and mixtures thereof.

[0224] In some examples, the fluorosurfactant can comprise a charged species, i.e. the fluorosurfactant can be an anionic, cationic, or zwitterionic fluorosurfactant. Examples of fluorosurfactants containing a charged species include perfluoroalkylethyl phosphates, perfluoroalkylethyl betaines, fluoroaliphatic amine oxides, fluoroaliphatic sodium sulfosuccinates, fluoroaliphatic phosphate esters, and fluoroaliphatic quaternaries. Specific examples of fluorosurfactants include DEA-C8-18 perfluoroalkylethyl phosphate, TEA-C8-18 perfluoroalkylethyl phosphate, NHr — C8-18 perfluoroalkylethyl phosphate, and C8-18 perfluoroalkylethyl betaine.

[0225] In some embodiments, the fluorosurfactant can be a compound the formula [F3CF2C — (CF2CF2)X — CH2CH2 — O — P2O31 | R11 where | R11 includes DEA, TEA, NH4, or betaine, and Attorney Docket No. 10975-078W01 where x is an integer from about 4 to about 18.

[0226] In some embodiments, the fluorosurfactant can comprise a fluoroaliphatic sulfosuccinate, a fluoroaliphatic sulfonate, an ethoxylated fluorinated alcohol, or any combination thereof.

[0227] In some embodiments, the aqueous foam precursor composition can comprise a crosslinker. Example crosslinkers are known in the art and can be selected based on a number of factors including the identity of the viscosity-modifying polymer. Examples of suitable crosslinking agents include borate crosslinking agents, Zr crosslinking agents, Ti crosslinking agents, Al crosslinking agents, organic crosslinkers (e.g., malonate, polyethyleneimine), and combinations thereof.

[0228] In some embodiments, the aqueous foam precursor compositions can comprise a particulate stabilizer (e.g., nanoparticles or microparticles). Examples of suitable nanoparticles and microparticles are known in the art, and include, for example, nickel oxide, alumina, silica (surface -modified), a silicate, iron oxide (Fc.iO-i). titanium oxide, impregnated nickel on alumina, synthetic clay, natural clay, iron zinc sulfide, magnetite, iron octanoate, or any combination thereof. In some examples, the foamed composition can further include a particulate stabilizer comprising a synthetic clay, a natural clay, or any combination thereof, such as attapulgite, bentonite, or any combination thereof. Other examples of suitable nanoparticles are described, for example, in U.S. Patent No. 10,266,750, which is hereby incorporated by reference in its entirety.

[0229] In some examples, the foamed composition can include a particulate stabilizer having an average particle size of 100 nanometers (nm) or more (e.g., 200 nm or more, 300 run or more, 400 nm or more, 500 nm or more, 750 nm or more, 1 micrometer (micron, pm) or more, 2 pm or more, 3 pm or more, 4 pm or more, 5 pm or more, 10 pm or more, 15 pm or more, or 20 pm or more). In some examples, the particulate stabilizer can have an average particle size of 25 pm or less (e.g., 20 pm or less, 15 pm or less, 10 pm or less, 5 pm or less, 4 pm or less, 3 pm or less, 2 pm or less, 1 pm or less, 750 nm or less, 500 nm or less, 400 nm or less, or 300 nm or less). The average particle size of the particulate stabilizer can range from any of the minimum values described above to any of the maximum values described above. For example, the particulate stabilizer can have an average particle size of from 100 nm to 25 pm (e.g., from 100 nm to 10 pm, from 100 nm to 5 pm, from 100 nm to 100 pm, from 100 pm to 500 pm, from 100 nm to 200 pm, from 100 nm to 150 pm, from 100 nm to 100 pm, from 100 nm to 50 pm, or from 100 nm to 10 pm). Attorney Docket No. 10975-078W01

[0230] The foam stabilizer can, for example, be present in an amount of 0.01% or more by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., 0.05% or more, 0.1% or more, 0.15% or more, 0.2% or more, 0.25% or more, 0.3% or more, 0.35% or more, 0.4% or more, 0.45% or more, 0.5% or more, 0.6% or more, 0.7% or more, 0.8% or more, 0.9% or more, l% or more, 1.25% or more, 1.5% or more, 1.75% or more, 2% or more, 2.5% or more, 3% or more, 3.5% or more, 4% or more, 4.5% or more, 5% or more, 5.5% or more, 6% or more, 6.5% or more, 7% or more, 7.5% or more, 8% or more, 8.5% or more, or 9% or more). In some examples, the foam stabilizer can be present in an amount of 10% or less by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., 9.5% or less, 9% or less, 8.5% or less, 8% or less, 7.5% or less, 7% or less, 6.5% or less, 6% or less, 5.5% or less, 5% or less, 4.5% or less, 4% or less, 3.5% or less, 3% or less, 2.5% or less, 2% or less, 1.75% or less, 1.5% or less, 1.25% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.45% or less, 0.4% or less, 0.35% or less, 0.3% or less, 0.25% or less, 0.2% or less, 0.15% or less, or 0.1% or less).

[0231] The amount of foam stabilizer present can range from any of the minimum values described above to any of the maximum values described above. For example, the foam stabilizer can be present in an amount of from 0.01% to 10% by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., from 0.01% to 5%, from 5% to 10%, from 0.01% to 2%, from 2% to 4%, from 4% to 6%, from 6% to 8%, from 8% to 10%, from 0.01% to 8%, from 0.01% to 6%, from 0.01% to 4%, from 0.01% to 1%, from 0.01% to 0.5%, or from 0.01% to 0.2%).

[0232] Sorbents

[0233] In some embodiments, the aqueous foam compositions and aqueous foam precursor compositions described herein can comprise a sorbent.

[0234] The sorbent can comprise a particulate sorbent that can absorb toxins, wound exudate, or other impurities that may be present within a wound bed. In some examples, the sorbent comprises carbon black, activated carbon, a molecular sieve, diatomaceous earth, graphite, charcoal, a porous polymer, or an AmiSorb particle.

[0235] In some embodiments, the sorbent can be present in an amount of at least 0. 1% by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., at least 0.5% by weight, at least 1% by weight, at least 1.5% by weight, at least 2% by weight, at least 2.5% by weight, at least 3% by weight, at least 4% by weight, at Attorney Docket No. 10975-078W01 least 5% by weight, at least 10% by weight, at least 15% by weight, or at least 20% by weight). In some embodiments, the sorbent can be present in an amount of 25% by weight or less, based on the total weight of the aqueous foam composition or aqueous foam precursor composition (e.g., 20% by weight or less, 15% by weight or less, 10% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight or less, 2.5% by weight or less, 2% by weight or less, 1.5% by weight or less, 1% by weight or less, or 0.5% by weight or less).

[0236] The sorbent can be present in an amount ranging from any of the minimum values described above to any of the maximum values described above. For example, in some embodiments, the sorbent can be present in an amount of from 0. 1% by weight to 25% by weight, based on the total weight of the aqueous foam composition or aqueous foam precursor composition.

[0237] Co- Solvents

[0238] In some examples, the aqueous foam compositions and aqueous foam precursor compositions can further comprise a co-solvent. Examples of co-solvents include, but are not limited to alcohols, such as lower carbon chain alcohols such as isopropyl alcohol, ethanol, n- propyl alcohol, n-butyl alcohol, sec-butyl alcohol, n-amyl alcohol, sec-amyl alcohol, n-hexyl alcohol, sec-hexyl alcohol and the like; alcohol ethers, polyalkylene alcohol ethers, polyalkylene glycols, poly(oxyalkylene)glycols, poly(oxyalkylene)glycol ethers, ethoxylated phenol, or any other common organic co-solvent or combinations of any two or more co-solvents. In one embodiment, the co-solvent can comprise alkyl ethoxylate (C1-C6)-XEO X=l-30 -linear or branched. In some embodiments, the co-solvent can comprise ethylene glycol butyl ether (EGBE), diethylene glycol monobutyl ether (DGBE), triethylene glycol monobutyl ether (TEGBE), ethylene glycol dibutyl ether (EGDE), polyethylene glycol monomethyl ether (mPEG), diethylene glycol, polyethylene glycol (PEG), or any combination thereof. In some embodiments, the co-solvent can comprise ethylene glycol butyl ether (EGBE) and diethylene glycol.

[0239] The present invention is not to be limited in scope by the specific embodiments described which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and accompanying drawings using no more than routine experimentation. Such modifications and equivalents are intended to Attorney Docket No. 10975-078W01 fall within the scope of the appended claims.

[0240] The examples below are intended to further illustrate certain aspects of the compositions and methods described herein and are not intended to limit the scope of the claims.

[0241] EXAMPLES

[0242] The following examples are set forth below to illustrate the methods and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods, compositions, and results. These examples are not intended to exclude equivalents and variations of the present invention, which are apparent to one skilled in the art.

[0243] Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.

[0244] The following standard test methods were utilized to characterize materials and compositions described herein.

[0245] Example 1. Tunable Non-Solidifying Medical Foam (MF) for the Topical Delivery of Pharmaceutical and Biological Agents

[0246] This Example describe the development of a wound and infection care composition (Medical Foam “MF” composition). The MF composition is an aqueous foam composition that includes one or more active agents to be administered to treat a wound. For example, the composition can include a therapeutic concentration of a hemostatic agent, an analgesic drug, an antimicrobial agent (e.g., an antibiotic), an innate immune system activator, an orthobiologic agent, a senolytic agent, or any combination thereof.

[0247] The MF composition can provide one or more therapeutic benefits when applied to a wound, including infection prophylaxis / asepsis, blood loss management, pain control, enhancement of wound healing (e.g., of a traumatic wound), an improvement in wound health, Attorney Docket No. 10975-078W01 or a combination thereof. Such compositions can also be used for topical treatment of chronically infected tissues, such as diabetic foot ulcers and other infected soft tissues. The MF composition can utilize a tunable biocompatible biopolymer foam which allows for the incorporation of pharmaceutical and / or biological agents in the field or clinic immediately prior to application. The agent-loaded, non-solidifying, viscous foam can be generated from a biocompatible foamforming agent which can be, for example, a biopolymer, such as carboxymethyl cellulose (CMC).

[0248] In certain examples, individual active agents are stored as dry powders, then rapidly combined with a viscous biopolymer foam matrix (i.e., a continuous liquid phase) with a dispersed vapor phase (i.e., bubbles of an expansion gas), and then dispensed using a foam generating and pharmaceutical / biological agent mixing device (foam delivery system). This foam delivery system can be engineered to efficiently introduce high concentrations of the selected active agents directly into the 3D wound volume.

[0249] The potential advantages of foam delivery over liquid, gel, and dry powder delivery include greater wound contact time, more effective filling of wound voids, more sustained local drug concentrations, and the inherent wound healing properties of the biopolymer foam itself. Together, these properties create a composition that addresses a significant for the improved treatment of wounds.

[0250] Summary

[0251] There is a need for effective compositions for topical drug delivery capable of addressing various medical conditions. These conditions include acute injuries (infection control and hemostasis), surgical wounds (infection control, analgesia) as well as chronic soft tissue infections (infection control, analgesia, and wound healing in diabetic ulcers, infected bum wounds, and infected devitalized tissues).

[0252] Current drug delivery technologies (for example, dry and wet bandages, hydrocolloids and gels, liquids, and dry powders) often fail to provide efficient and localized drug delivery, especially in complex wounds requiring precise volumetric therapeutic targeting for full wound coverage. The development of a viscosity-tunable, biologically compatible foam that can be readily combined with active agents can substantially improve topical drug delivery, especially in the setting of early drug delivery in the field (e.g., by EMTs) or on the battlefield (e.g., by warfighters). The foam delivery system described herein allows for the controlled release of pharmaceutical and biological agents directly at the surface of wounds with complex surface Attorney Docket No. 10975-078W01 geometry (e.g., blast injuries, gunshot wounds, limb crushing injuries, complicated diabetic foot ulcers), relying on the inherent volume-occupying properties of the MF composition to fdl the volume of the wound. The MF composition provides uniform wound surface coverage and maintains effective drug concentrations for periods of hours to days. The ability to customize the foam -drug composition's properties — such as viscosity, bio-adhesion, kinetic release of the agents, and degradation rate — enables tailored treatment strategies across a broad spectrum of clinical applications.

[0253] Data indicates a critical window of 6-8 hours post-injury for effective mitigation to prevent secondary complications in acute wounds. Current wound management strategies, such as a hemostatic dressing containing kaolin, typically focus on single aspects of wound care, such as hemostatic management. However, most current strategies fail to address other critical wound management priorities, particularly in complex, austere, or emergency environments. Contemporary methods are particularly limited in their ability to deliver therapeutics effectively to areas with disrupted blood supplies, such as is expected in most trauma injuries. The limitations of current treatments underscore the necessity for innovative technologies capable of comprehensively managing the primary (blood loss) and secondary (infection, pain, and poor healing) complications associated with wounds rapidly in the field without extensive medical support, such as intravenous access. Wound care in austere settings (e.g., battlefield, first responders) requires an encompassing, versatile, ready-to-use solution.

[0254] The MF compositions, as described herein, are designed to address a spectrum of wound types, including acute wounds and chronic soft tissue infections, as discussed below.

[0255] Acute Wound Management (< 8 hrs. post-injury)

[0256] Bleeding control. Traditional hemostatic agents and mechanical barriers, such as gauze and bandages, effectively initiate clot formation to stem bleeding. However, they may be inadequate for severe or complex wounds characterized by diffuse bleeding deep in the wound interstices or multiple small vessel bleeds. The MF composition’s viscous, flowable nature allows it to fill and conform to simple and complex wound geometries. This enables the topical delivery of hemostatic agents, such as tranexamic acid (TXA), directly into the three- dimensional volume of the wound, reducing reliance on a viable blood supply that is required for systemic or injectable agent transport.

[0257] Infection prophylaxis. For injuries that occur in the field, the time to antibiotic administration to prevent infection is critical and is generally defined as a period less than 6 to 8 Attorney Docket No. 10975-078W01 hours after the initial tissue injury. In some situations, it may not be possible to administer antibiotics orally or by IV injection in time to meet this window. In addition, in severe trauma cases, such as gunshot wounds or significant accidents, disrupted blood supply frequently impedes the effective delivery of antibiotics to the wound site. The MF composition can topically deliver effective antibiotics for prophylaxis of infection, including macrolide antibiotics (e.g., vancomycin), beta-lactam targeted drugs (e.g., Augmentin, Unasyn), or aminoglycoside antibiotics (e.g., tobramycin) throughout the wound site.

[0258] Pain Management. Traditional pain management for acute wounds typically relies on the local injection of analgesic agents (e.g., lidocaine, bupivacaine) or oral or systemic administration of opioids (e.g., oxycontin). For more rapid and readily applied analgesia, a topical drug delivery option would also be desirable. Thus, the MF composition’s delivery of topical analgesic agents (e.g., bupivacaine) represents a viable alternative. The foam delivery technology can help ensure prompt relief and may reduce the reliance on opioid drugs for pain relief.

[0259] Subacute (< 48 hrs. post-injury) to Chronic (> 48 hrs. post-injury) Wound Management

[0260] Stimulation of wound healing. An important aspect of managing subacute to chronic wounds is wound healing stimulation. Numerous technologies have been designed to deliver topical growth factors that stimulate wound healing (e.g., EGF, PDGF, IGF). While these growth factors exhibit early effects, they require repeated administration to sustain the growth factor effects. The MF composition can be used to deliver these growth factors more effectively as recombinant proteins, allowing greater contact time with the wound surface and less frequent application. Notably, a biopolymer material which has inherent wound-healing properties (such as CMC) can be utilized to form the foam within the MF composition.

[0261] A second strategy to stimulate wound healing is to trigger brief activation of innate immune responses at the wound surface, using innate immune agonists such as Toll-like receptor agonists (e.g., TLR3 or TLR9 agonists) or cytosolic activation agonists (e.g., STING agonists). These agonists are known to stimulate the early healing response, in part by recruiting woundhealing macrophages.

[0262] Treatment of chronic infections at body surfaces. Chronic wounds at cutaneous surfaces often become infected, and the MF composition can be designed to deliver an effective combination of appropriate antibiotics with a wound healing agent such as a growth factor (e.g., Attorney Docket No. 10975-078W01

[0263] EGF) and / or an innate immune agonist (e.g., TLR3 agonist). Combining antibiotics with an innate immune agonist may be a particularly effective composition to be delivered.

[0264] To summarize, the MF compositions described herein can comprise a non-solidifying biologically active foam capable of being rapidly formulated with different pharmaceutical and biological agents, designed to improve infection control, wound healing, wound hemostasis, and wound pain.

[0265] Advantages

[0266] Currently, medications can be delivered to the wound's surface using liquids, gels, powders, and drug-impregnated bandage materials. These wound treatment strategies offer unique advantages and challenges. Notably, using foam as a drug delivery technology provides specific advantages over the aforementioned strategies. These include excellent conformity to complex wound shapes, extended drug contact times, and formulation with biomaterial such as CMC with intrinsic wound healing properties. The foam structure can facilitate controlled, sustained drug release, making it highly effective across various wound geometries. Liquid formulations may lack foam's sustained release capabilities and structural stability. Their fluid nature can lead to difficulties maintaining localized treatment at the wound site, especially in mobile or vertical wound areas. Gels for drug delivery help solve the drug contact time issue but cannot be forced into wound cavities as efficiently as foam. Drugs that have been impregnated in bandage materials (e.g., wet-dry bandages) also do not contact the entire wound surface and suffer from unpredictable drug delivery rates due to their dependence on wound exudates for wetting.

[0267] Example Medical Foam (MF) Compositions

[0268] Example MF compositions can include a continuous phase (i.e., a liquid phase, such as an aqueous phase, including a foam forming agent (e.g., a biopolymer) dissolved or dispersed in a solvent such as water) and a vapor phase (i.e., bubbles of an expansion gas dispersed / entrained within the continuous liquid phase). The MF composition can further include one or more active agents dissolved or dispersed in the continuous phase. Optionally, the MF composition can further include one or more pharmaceutically acceptable excipients.

[0269] The MF, characterized by its non-solidifying, viscous properties, can be formulated using a biocompatible, biodegradable, non-toxic foam-forming agent. In some examples, the foamforming agent can comprise a biopolymer. Some examples of biopolymers include hydrogel biopolymers such as carboxymethyl cellulose (CMC), chitosan, cellulose, or various co- Attorney Docket No. 10975-078W01 polymers, which can be formed into stable wet foams. These inherent surface tension properties of the biopolymers are capable of maintaining the stability of the vapor phase of gases (e.g., N2, CO2, room air) embedded within the continuous liquid matrix. This capability produces a foam that can retain its structure and pharmaceutical properties, namely drug incorporation and release. Additionally, these biopolymers can be readily sterilized and are known to exhibit excellent shelf stability in their precursor liquid forms, making them ideal for medical and field applications where durability and safety are paramount.

[0270] Medical Foam (MF) Production

[0271] The MF is a semi-solid, volume-filling substance with a creamy, mousse-like texture, that exhibits a uniform, frothy appearance with fine bubbles. When dispensed, it maintains its form briefly, allowing it to conform to various surface shapes and wound geometries before beginning to break down. This characteristic enables it to cover and fill wound areas effectively, adapting to the contours and depths of the injury site.

[0272] The MF composition is aerated to create a volume-filling foam. The incorporation of air bubbles into the biopolymer solution to form the foam can be achieved through various methods. Manual aeration is possible through agitation techniques, such as vigorous shaking, which introduces air into the biopolymer, forming a foam. Alternatively, the foam may be generated by introducing compressed gases such as carbon dioxide, nitrous oxide, propane, butane, or medical-grade air into the biopolymer under controlled conditions using specialized equipment allowing for greater control over the MF's density and bubble size. Sterilized atmospheric air may also be an economical and readily available aeration medium.

[0273] If desired, surfactants like Pluronic Fl 27 can be introduced to stabilize the foam structure, enhancing its integrity and longevity. The incorporation of a surfactant can promote the formation of finer bubbles, contributing to a more consistent and stable foam. Each of these aeration techniques provides a scalable approach to producing a homogeneously MF tailored to specific wound care needs.

[0274] Foam-Forming Agents (e.g., Biopolymers)

[0275] The MF composition includes one or more foam-forming agents. In some examples, the MF utilizes a biopolymer base to form the stable, non-solidifying wet foam that serves as the delivery vehicle for therapeutic agents. Such biopolymers exhibit biocompatibility and biodegradability and can be aerated into a stable foam structure. Additionally, it should be Attorney Docket No. 10975-078W01 amenable to incorporating various therapeutic agents without compromising their stability or activity.

[0276] Several classes of biopolymers are suitable for use as the MF base. The non-exhaustive list of examples below may be used either individually or in combination.

[0277] Polysaccharides: These natural polymers are composed of repeating sugar units and often exhibit excellent biocompatibility and biodegradability. Some examples include:

[0278] Carboxymethyl Cellulose (CMC): A water-soluble cellulose derivative with excellent thickening, stabilizing, and film-forming properties. CMC has an established safety profile, versatility, and the ability to form stable foams.

[0279] Alginate: A natural polysaccharide derived from seaweed that forms hydrogels in the presence of divalent cations. Alginate has been used in various biomedical applications, including wound dressings and drug delivery.

[0280] Hyaluronic Acid (HA): A naturally occurring glycosaminoglycan found in connective tissues. HA is highly biocompatible and possesses viscoelastic properties, making it suitable for wound healing applications.

[0281] Proteins: These natural polymers are composed of amino acids and can be derived from various sources, including animals and plants. Some examples include:

[0282] Collagen: The most abundant protein in the human body, collagen is a major component of the extracellular matrix and plays a crucial role in wound healing. Collagen-based foams have been used in various biomedical applications.

[0283] Gelatin: A protein derived from collagen that forms thermoreversible gels. Gelatin has been used in various pharmaceutical and biomedical applications, including drug delivery and tissue engineering.

[0284] Synthetic Polymers: These polymers are artificially synthesized and can be tailored to specific properties, such as biodegradability and biocompatibility. Some examples include:

[0285] Polylactic Acid (PLA): A biodegradable polyester derived from renewable resources. PLA has been widely used in medical implants and drug -delivery devices.

[0286] Polyglycolic Acid (PGA): Another biodegradable polyester with similar properties to PLA. PGA has also been used in various biomedical applications.

[0287] Poly caprolactone (PCL): A biodegradable polyester with slower degradation kinetics than PLA and PGA. PCL has been used in long-term drug delivery and tissue engineering applications. Attorney Docket No. 10975-078W01

[0288] In some embodiments, the MF can be produced from different biopolymer concentrations, ranging from 0.5% - 7%; in some embodiments the concentrations range from 1- 3%. The specific concentrations are optimized based on each selected biopolymer’s comprehensive evaluation of its properties, including biocompatibility, biodegradability, foam stability, and compatibility with incorporated therapeutic agents.

[0289] Physical and Mechanical Attributes of MF

[0290] The MF composition can exhibit specific physical and mechanical properties that can be finely tuned to optimize its efficacy and usability.

[0291] Viscosity. The MF's viscosity can impact its ease of application and ability to stay in place (retention at the wound site). It can be engineered to be sufficiently viscous to fill and conform to wound geometries without running off or dissipating prematurely. The viscosity can be adjusted by modifying the concentration of the base biopolymer liquid and the aeration process used to introduce air bubbles into the biopolymer. The MF can exhibit a variable viscosity profile, which is controllable by manipulating bubble size distribution and degradation kinetics. If desired, viscosity modifiers (e.g., viscosity-modifying polymers, crosslinking agents, etc.) can also be incorporated in the MF to modify rheological behavior.

[0292] Two example formulation types have been characterized; however, it is envisioned that other formulations are applicable to various wound needs.

[0293] Example High Viscosity / Stable Foams can exhibit an Initial Bubble Size of 200-600 pm, a Pre-Breakdown Bubble Size of from 1000-2000 pm, a Post-Breakdown Bubble Size of from 200-600 pm, a Time to Breakdown Onset of from 20-40 minutes, and a Complete Breakdown Time of ~3 hours.

[0294] Example Low Viscosity / Unstable Foams can exhibit an Initial Bubble Size of from 400- 800 pm, a Pre-Breakdown Bubble Size of from 1000-3000 pm, a Post-Breakdown Bubble Size of from 200-600 pm, a Time to Breakdown Onset of from 1-20 minutes (dependent on pressure, solution viscosity, etc.), and a Complete Breakdown Time of from 5 minutes - 2 hours.

[0295] The dynamic nature of the MF allows for initial volumetric filling of complex wound cavities, followed by a controlled collapse of the foam structure, facilitating sustained release of therapeutic agents and intimate contact with the wound bed. This adaptability ensures optimal drug delivery and enhances the therapeutic efficacy of the MF. Attorney Docket No. 10975-078W01

[0296] Adjusting formulation parameters, such as biopolymer concentrations, gas infusion rate, and the presence of stabilizing agents, can tailor the MF's viscosity and breakdown kinetics to specific clinical applications.

[0297] Bubble Size, Distribution, and Density. The MF's structural integrity and mechanical properties are primarily influenced by the size, distribution, and density of the air bubbles incorporated during its formation. Smaller, more uniformly distributed bubbles tend to produce a foam with finer texture and greater stability, which can provide stable hemostasis, maintaining effective therapeutic agent delivery.

[0298] Bubble Breakdown Time. The breakdown time of the MF is directly related to its bubble structure. Finer bubbles with a more uniform distribution tend to have a slower breakdown time, which modifies the duration of therapeutic action at the wound site. This slow breakdown ensures that the foam remains in the wound long enough to deliver therapeutic agents effectively while protecting the wound with a physical barrier, reducing further contamination.

[0299] Mechanical Stability. The mechanical stability of the MF can relate to its function as a delivery system in dynamic and moist wound environments. The interactions between the foamforming agent (e.g., the biopolymer), incorporated agents, and the air bubbles influence stability. Enhanced stability is achieved through the optimal balance of bubble size and the viscous properties of the base biopolymer solution, allowing the MF to withstand slight mechanical stresses without collapsing.

[0300] These properties make the MF adaptable to varying wound types and conditions, ensuring it can deliver therapeutic agents efficiently while supporting the natural healing process. The careful calibration of viscosity, bubble characteristics, and mechanical stability ensures that the foam can be applied easily, remain in place, and provide sustained therapeutic benefits to the wound area.

[0301] Example Active Agents

[0302] In some embodiments, MF products are generated by mixing the MF powders (biopolymers) with the excipient powders individually, or potentially, compartmentally, allowing for the mixing of multiple ingredients with the MF powder(s) prior to the generation of the specific foam products. Some examples of potential agents that can be incorporated into the foam composition described below.

[0303] Antimicrobial Agents. The MF can incorporate a broad spectrum of antimicrobial agents for topical delivery, targeting both gram-positive and gram-negative bacteria. The Attorney Docket No. 10975-078W01 following categories of antibiotics are considered for inclusion based on their proven efficacy, safety profile, and compatibility with biopolymers. The non-exhaustive list of examples below may be used either individually or in combination:

[0304] Aminoglycosides (tobramycin, neomycin): These bactericidal antibiotics inhibit protein synthesis. They are effective against a wide range of gram-negative bacteria and some grampositive bacteria.

[0305] Peptide antibiotics (vancomycin, bacitracin): Vancomycin is a glycopeptide antibiotic that inhibits cell wall synthesis by binding to the D-alanyl-D-alanine terminus of peptidoglycan precursors. It is primarily effective against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Bacitracin is a cyclic polypeptide antibiotic that interferes with bacterial cell wall synthesis by inhibiting the dephosphorylation of bactoprenol. It is effective against a variety of gram-positive bacteria.

[0306] Beta-lactam drugs (ceftazidime, ceftriaxone, cefazolin): These bactericidal antibiotics inhibit cell wall synthesis by binding to penicillin-binding proteins (PBPs). They are effective against a broad spectrum of bacteria, including gram -positive, gram -negative, and anaerobic species.

[0307] Polymyxins (polymyxin B, colistin): These cationic polypeptide antibiotics disrupt the bacterial cell membrane by interacting with phospholipids. They are primarily effective against gram -negative bacteria, including multidrug -resistant strains.

[0308] The MF can deliver a range of antibiotic concentrations between 0. 1 mg / mL to 10 mg / mL, ensuring therapeutic levels at the wound site while minimizing systemic exposure. In some embodiments, the concentration of antimicrobial agent can range from 0.1 mg / mL to 2 mg / mL. The specific concentration can be optimized based on the selected antibiotic and the desired therapeutic effect.

[0309] Analgesic Agents. The MF can incorporate a broad range of analgesic agents for targeted pain relief at the wound site. This minimizes the need for systemic analgesics, reducing the risk of adverse side effects, especially in austere environments where close monitoring may be limited. The following analgesic agent classes and specific drugs are considered for inclusion based on their efficacy, safety profile, and compatibility with biopolymers. The non-exhaustive list of examples below may be used either individually or in combination: Attorney Docket No. 10975-078W01

[0310] Local Anesthetics (Amides): These agents reversibly block voltage-gated sodium channels, inhibiting nerve impulse propagation and providing localized numbness and pain relief. Some examples include:

[0311] Lidocaine: A fast-acting amide local anesthetic with rapid onset and moderate duration of analgesia.

[0312] Bupivacaine: A long -acting amide local anesthetic offering a slower onset but a significantly longer duration of analgesia.

[0313] Mepivacaine: An amide local anesthetic with a similar profile to lidocaine but with a lower vasodilation risk.

[0314] Ropivacaine: A long -acting amide local anesthetic with less motor blockade than bupivacaine, potentially advantageous for certain wound types.

[0315] Nonsteroidal Anti-inflammatory Drugs (NSAIDs): These agents inhibit cyclooxygenase (COX) enzymes, reducing prostaglandin production and providing analgesic, anti-inflammatory, and antipyretic effects. Some examples include:

[0316] Diclofenac: A potent NSAID with analgesic and anti-inflammatory properties, available in topical formulations.

[0317] Ketoprofen: Another NSAID with similar properties to diclofenac, also available in topical forms.

[0318] Opioids: These agents bind to opioid receptors in the central and peripheral nervous system, modulating pain perception. While primarily used systemically, some opioids are available in topical formulations for localized pain relief. Some examples include:

[0319] Morphine: A potent opioid analgesic with potential for topical delivery in low concentrations.

[0320] Fentanyl: A synthetic opioid analgesic significantly more potent than morphine, requiring even lower concentrations for topical use.

[0321] The MF can deliver a range of analgesic concentrations between 0.5% to 20%, ensuring effective pain relief while minimizing the risk of local toxicity; in some embodiments the MF can deliver concentrations at approximately 5% by volume. The specific concentration can be optimized based on the selected agent, the extent of pain, and the desired duration of analgesia.

[0322] Hemostatic Agents. The MF can incorporate hemostatic agents to promote rapid and effective bleeding control at the wound site. These agents can act through various mechanisms to enhance clot formation and stability, reducing blood loss and improving outcomes in traumatic Attorney Docket No. 10975-078W01 injuries. The following hemostatic agents are considered for inclusion based on their efficacy, safety profile, and compatibility with biopolymers. The non-exhaustive list of examples below may be used either individually or in combination:

[0323] Antifibrinolytics: These agents inhibit fibrinolysis, the process of clot breakdown, thereby promoting clot stability and preventing further bleeding.

[0324] Tranexamic Acid (TXA): A synthetic lysine analog that competitively inhibits plasminogen activation, preventing the conversion of plasminogen to plasmin, the enzyme responsible for fibrinolysis. TXA can be delivered in a 5% solution in the foam, with an optimal range of 1% to 10%.

[0325] Coagulation Factors: These proteins are essential components of the coagulation cascade, the complex series of reactions that lead to clot formation. Supplementation with specific coagulation factors can enhance hemostasis in cases where deficiencies or inhibitors are present.

[0326] Recombinant Factor Vila (rFVIIa): A recombinant form of factor VII, a vitamin Independent clotting factor. rFVIIa activates factor X, bypassing the intrinsic pathway of coagulation and promoting thrombin generation.

[0327] Prothrombin Complex Concentrates (PCCs): Concentrated preparations of vitamin Independent clotting factors (II, VII, IX, and X). PCCs can rapidly replenish deficient clotting factors, enhancing hemostasis.

[0328] Fibrinogen Concentrates: Concentrated preparations of fibrinogen (factor I), a key protein involved in clot formation. Fibrinogen concentrates can be used to treat hypofibrinogenemia or other conditions associated with low fibrinogen levels.

[0329] Desmopressin: A synthetic analog of vasopressin that promotes the release of von Willebrand factor and factor VIII from endothelial cells, enhancing platelet adhesion and coagulation.

[0330] The MF can incorporate various concentrations of hemostatic agents to achieve optimal bleeding control. It can also deliver a range of hemostatic agent concentrations between 0.5% to 20%. In some embodiments, the MF can deliver concentrations at approximately 5% by volume. The specific concentration can be optimized based on the selected agent, the severity of bleeding, and the desired duration of action.

[0331] Biological Wound Healing Agents. The MF can incorporate biological wound healing agents to accelerate tissue repair and regeneration. These agents stimulate cellular processes involved in wound healing, such as angiogenesis, cell proliferation, and extracellular matrix Attorney Docket No. 10975-078W01 deposition. The following growth factors (GF) are considered for inclusion based on their established roles in wound healing and compatibility with biopolymers. The non-exhaustive list of examples below may be used either individually or in combination:

[0332] Fibroblast Growth Factors (FGFs): This family of growth factors stimulates angiogenesis, fibroblast proliferation, and collagen synthesis, all of which contribute to wound healing.

[0333] Epidermal Growth Factor (EGF): This growth factor promotes keratinocyte proliferation and migration, which contribute to re-epithelializing the wound surface.

[0334] Platelet-Derived Growth Factor (PDGF): This growth factor stimulates angiogenesis, fibroblast proliferation, and extracellular matrix deposition, contributing to granulation tissue formation and wound closure.

[0335] In some embodiments, the MF can include growth factors at concentrations from 1 pg / mL to 1000 pg / mL (e.g., approximately 100 pg / mL) The specific concentration will be optimized based on the selected agent and the desired therapeutic effect.

[0336] Local Immune Stimulation Agents (Healing, Infection Control) Agents. The MF can incorporate local immune stimulation agents to enhance the body's natural defense mechanisms against infection and accelerate wound healing. These agents target various components of the innate immune system, triggering responses that promote tissue repair and regeneration. The following classes of immune stimulators are considered for inclusion based on their efficacy, safety profile, and compatibility with biopolymers. The non-exhaustive list of examples below may be used either individually or in combination:

[0337] Toll-like Receptor (TLR) Agonists: These agents activate TLRs, a family of pattern recognition receptors that play a key role in the innate immune response. Activation of TLRs leads to the production of cytokines and chemokines, recruiting immune cells to the wound site and promoting inflammation, phagocytosis, and tissue repair. Some examples include:

[0338] Polyinosinic-polycytidylic acid (poly(EC)): A synthetic analog of double- stranded RNA that activates TLR3, stimulating the production of type I interferons and other pro-inflammatory cytokines.

[0339] CpG Oligonucleotides: Synthetic DNA sequences containing unmethylated CpG dinucleotides that activate TLR9, triggering a similar immune response to poly(EC). Attorney Docket No. 10975-078W01

[0340] Cytosolic Receptor Agonists: These agents activate intracellular receptors that detect microbial or damage-associated molecular patterns (DAMPs), initiating immune responses. Some examples include:

[0341] 2'3 '-cyclic di-GMP (c-di-GMP): A second messenger molecule that activates the STING pathway, leading to the production of type I interferons and other pro-inflammatory cytokines.

[0342] ADU-S100 (MIW815): A small molecule STING agonist with similar effects to c-di- GMP.

[0343] DMXAA (Vadimezan): A potent STING agonist with additional anti- angiogenic properties.

[0344] In some embodiments, the MF can include immune stimulation agents at concentrations of from 1 pg / mL to 1000 pg / mL (e.g., from approximately 10 pg / mL). The specific concentration can be optimized based on the selected agent and the desired therapeutic effect.

[0345] Extracellular Vesicles, Exosomes Agents. The MF can incorporate extracellular vesicles, particularly exosomes, to enhance wound healing and tissue regeneration further. Exosomes are nanoscale vesicles secreted by cells that carry bioactive molecules such as proteins, lipids, and nucleic acids. They play a crucial role in intercellular communication and can modulate various physiological processes, including inflammation, angiogenesis, and cell proliferation.

[0346] In some embodiments, the MF can utilize exosomes derived from mesenchymal stromal cells (MSCs). MSCs are multipotent stem cells found in various tissues, including bone marrow and adipose tissue, and are known for their regenerative and immunomodulatory properties. MSC-derived exosomes have been shown to promote wound healing, reduce inflammation, and enhance tissue regeneration in various preclinical models.

[0347] In some embodiments, the MF includes exosomes at concentrations of from IxlO6particles / mL to IxlO10particles / mL of foam (e.g., approximately IxlO9particles / mL of foam). The specific concentration will be optimized based on the source of MSCs, the exosome isolation method, and the desired therapeutic effect.

[0348] Senolytic Agents. The MF can incorporate senolytic agents to target and eliminate senescent cells (SCs) within the wound environment. SCs are characterized by a state of permanent cell cycle arrest and the secretion of pro-inflammatory factors that can impair tissue regeneration and contribute to chronic wounds. Senolytic agents selectively induce apoptosis in SCs, potentially mitigating their detrimental effects and promoting a pro- regenerative Attorney Docket No. 10975-078W01 environment. The following senolytic agents are considered for inclusion based on their emerging evidence in preclinical and clinical studies. The non-exhaustive list of examples below may be used either individually or in combination:

[0349] Tyrosine Kinase Inhibitors: These agents inhibit tyrosine kinases, enzymes involved in various cellular signaling pathways. Some tyrosine kinase inhibitors have shown senolytic activity by targeting specific anti-apoptotic pathways in SCs.

[0350] Dasatinib: A tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). It has demonstrated senolytic activity in preclinical studies and is currently being investigated in clinical trials for age- related conditions.

[0351] Flavonoids: This class of plant-derived compounds includes several agents with reported senolytic activity.

[0352] Quercetin: A flavonoid found in various fruits and vegetables. It has shown senolytic activity in preclinical studies and is often used in combination with dasatinib.

[0353] Fisetin: A flavonoid found in strawberries and other fruits. It has demonstrated senolytic activity in preclinical models and is being investigated for its potential in treating age-related diseases.

[0354] In some embodiments, the MF can include dasatinib at a range of 10-100 pM. In other embodiments, the MF can include quercetin or fisetin at a range of 10-50 pM.

[0355] Example Formulations

[0356] The MFs described herein can provide a platform that can be adapted to the generation of diverse foams with single or multiple pharmaceutical or biological agents. Thus, specific formulations (e.g., drug concentration, drug solutions, excipients, solvents, diluents, buffering agents) can be varied depending on a proposed. It should be understood that the versatility of the MF allows for several different compounds to be readily formulated as a robust, field-deployed medical treatment for traumatic or chronic wounds.

[0357] In one example, the MF composition comprises Carboxymethyl Cellulose (CMC) having both a continuous and vapor phase, and which include one or more of tobramycin, vancomycin, ceftazidime, polymyxin B, lidocaine, Tranexamic Acid (TXA), Fibroblast Growth Factors (FGFs), Platelet-Derived Growth Factor (PDGF), 2'3'-cyclic di-GMP (c-di-GMP), exosomes derived from mesenchymal stromal cells (MSCs) and Fisetin.

[0358] Figure 1 schematically illustrates the use of an example MF to enhance acute wound Attorney Docket No. 10975-078W01 management in situ. In this example, the MF composition includes a viscous biopolymer-based medical MF that can rapidly simultaneously deliver the antibiotic vancomycin, the hemostatic agent tranexamic acid (TXA), and a STING agonist (2'3'-cGAMP), and a wound healing macrophage (M<b) activator, directly to the surface of a wound having complex geometries.

[0359] Figure 2 illustrates an example system and method for foaming the foams described herein. In this example, the MF composition includes vancomycin, tranexamic acid (TXA), and STING agonists (2'3'-cGAMP). These components can be stored in separate segments of a tube as dry powders. Another segment of the tube can include a viscous biopolymer solution (e.g., aqueous carboxymethyl cellulose) and an expansion gas. The segments of the tube can be separated by barriers that break as the tube is compressed, allowing for mixing of the MF components. As the tube is further compressed, the components pass out of the tube through a microfluidic nozzle, introducing a vapor phase (i.e., bubbles of an expansion gas) to the MF composition and mixing the agents, forming a stable therapeutic foam. The MF composition is applied topically ensuring volume-fdling delivery to the wound site.

[0360] Figure 3 shows the assessment of an example carboxymethyl cellulose (CMC) foam placed in a mouse closed wound model. As shown in Panel A (left), the CMC foam was surgically introduced into a closed wound in a mouse model rotator cuff partial transection model. Histological evaluation (H&E staining) of the wound site post-CMC application at 3- weeks (Panel B) revealed negligible immunological response and no adverse tissue reactions. An H&E-stained tissue section from an unaltered, healthy area of the same model (Panel C) served as a baseline for evaluation.

[0361] We also evaluated the ability of the example foams to effectively deliver active agents. As shown in Figure 4, in a proof-of-principle study, a CMC MF loaded with vancomycin was applied to agar plates pre -inoculated with the bacterium Staphylococcus aureus. Observations at 24-hour post-application revealed significant bacterial eradication, indicating the successful delivery and antibacterial action of Vancomycin in a CMC foam.

[0362] We also evaluated an example foam’s hemostatic properties. As shown in Figure 5, in a proof-of-principle study, a CMC MF loaded with TXA was applied on a smooth plate inclined at 30 degrees. The foam maintained structural and rheologic integrity and effectiveness in the presence of blood, as evidence by it not flowing down the inclined plate due to blood clotting.

[0363] As shown in Figure 7, MF compositions exhibited enhanced wound conformity. In particular, application of example MF compositions to simulated wounds demonstrated Attorney Docket No. 10975-078W01 improved contact between the composition and the wound surface throughout the wound bed as compared to, for example, a putty or a dry powder.

[0364] We also evaluated the morphology, backdown profile, and rheological profile of example foams generated using 3% by weight foam-forming agent (e.g., Polysorbate 20 (Figures 8A-8B), Poloxamer 407 (Figures 9A-9B), polyvinyl alcohol (Figures 10A-10B), polyethylene glycol (Figures 11A-11B), sodium alginate (Figures 12A-12B), methyl cellulose (Figures 13A-13B), gelatin methacryloyl (Figures 14A-14B), and chitosan (Figures 15A-15B)). In all cases, the foams were generated using a whipped cream dispenser equipped with a nitrous oxide canister. An aqueous solution of Polysorbate 20 was placed in the dispenser. The dispenser was inverted and shaken fifty times, at which point the foam was dispensed. Photographs were taken of the foams initially, at volumetric loss onset, and at breakdown (times noted). The bubble size of the foams at each time was assessed using image analysis. The volumetric expansion ratio and rheological characteristics of the foam (viscoelastic crossover strain, viscoelastic crossover modulus, and flow type) were also assessed. Varying foam-forming agents could be used to provide foams with varying morphology, backdown profile, and rheological profile.

[0365] The compositions and methods of the appended claims are not limited in scope by the specific compositions methods described herein, which are intended as illustrations of a few aspects of the claims and any methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative materials and method steps disclosed herein are specifically described, other combinations of the materials and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of’ and “consisting of’ can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. Attorney Docket No. 10975-078W01

[0366] As used in this disclosure and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise.

Claims

Attorney Docket No. 10975-078W01CLAIMSWhat is claimed is:

1. A flowable aqueous foam composition comprising a continuous aqueous phase comprising water, a biocompatible foam-forming agent, and an active agent; and bubbles comprising an expansion gas dispersed within the continuous phase; wherein the foam composition exhibits a complete breakdown time of from 1 minute to 12 hours at 25 °C and 1 atm.

2. The foam composition of claim 1, wherein the aqueous foam composition exhibits a viscosity of from 1,000 cP to 200,000 cP at 25°C and 1 atm, such as a viscosity of from 10,000 cP to 200,000 cP, from 25,000 cP to 200,000 cP, or from 50,000 cP to 200,000 cP at 25°C and 1 atm.

3. The foam composition of any one of claims 1-2, wherein the aqueous foam exhibits an average initial bubble size of from 100 microns to 1000 microns, as determined by image analysis.

4. The foam composition of any one of claims 1-3, wherein the aqueous foam exhibits an average bubble size at volumetric loss onset of from 800 microns to 3500 microns, as determined by image analysis.

5. The foam composition of any one of claims 1-4, wherein the aqueous foam exhibits a time to breakdown onset of from 30 seconds to 8 hours at 25°C and 1 atm, such as from 1 minute to 5 hours, from 1 minute to 2 hours, from 1 minute to 1 hour, from 1 minute to 45 minutes, from 1 minute to 20 minutes, or from 20 minutes to 40 minutes at 25°C and 1 atm.

6. The foam composition of any one of claims 1-5, wherein the aqueous foam exhibits a complete breakdown time of from 5 minutes to 5 hours at 25°C and 1 atm, such as from 5 minutes to 2 hours, or from 2 hours to 4 hours at 25°C and 1 atm.

7. The foam composition of any one of claims 1-6, wherein the aqueous foam composition is sterile.Attorney Docket No. 10975-078W018. The foam composition of any one of claims 1-7, wherein the aqueous foam composition exhibits a density of from 2 Ibs / gal to 8 Ibs / gal.

9. The foam composition of any one of claims 1-8, wherein the aqueous foam composition exhibits a foam quality of at least 40%, such as a foam quality of from 60% to 95%.

10. The foam composition of any one of claims 1-9, wherein the aqueous foam composition exhibits non-Newtonian shear-thinning behavior.

11. The foam composition of any one of claims 1-10, wherein the aqueous foam composition exhibits a viscoelastic crossover modulus of from 1 Pa to 30,000 Pa at 25°C and 1 atm.

12. The foam composition of any one of claims 1-11, wherein the foam-forming agent comprises a polymeric foam forming agent, such as a biopolymeric foam-forming agent.

13. The foam composition of any one of claims 1-12, wherein the foam-forming agent comprises a polysaccharide (e.g., alginate, chitosan, agarose, carrageenan, a cellulosic polymer such as carboxymethyl cellulose (CMC), hyaluronic acid, an alkyl polyglycoside, or a combination thereof), a protein (e.g., collagen, gelatin, whey protein, ovalbumin, conalbumin, globulins, ovomucin, or a combination thereof), a synthetic polymer (e.g., polyvinyl alcohol, polyvinyl acetate, a polyalkylene oxide (e.g., a crosslinked polyethylene glycol), a polyester (e.g., polylactic acid, polyglycolic acid, poly caprolactone)), or a combination thereof.

14. The foam composition of any one of claims 1-13, wherein the foam-forming agent comprises a surfactant, such as a non-ionic surfactant, an anionic surfactant, a zwitterionic surfactant, or a combination thereof.

15. The foam composition of claim 14, wherein the surfactant comprises a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or a combination thereof; an alkylAttorney Docket No. 10975-078W01 polyglycoside; sodium lauryl sulfate (SLS); sodium cocoyl isethionate (SCI); potassium lauryl sulfate; a glycoside saponin, such as a glycoside saponin extracted from Quillaja saponaria. a glycoside saponin extracted from soapwort (Saponaria officinalis), a glycoside saponin extracted from senega root (Polygala senega), a glycoside saponin extracted from sarsaparilla (Smilax ornata),' cocamidopropyl betaine; or a combination thereof.

16. The foam composition of any one of claims 1-15, wherein the foam-forming agent comprises a poloxamer, such as Poloxamer 407 (PEOioiPPOsePEOioi), Poloxamer 188 (PEO75PPO29PEO75), Poloxamer 338 (PEO141PPO44PEO141), Poloxamer 124 (PEO12PPO20PEO12), Poloxamer 237 (PEO64PPO37PEO64), and mixtures thereof; carboxymethyl cellulose (CMC); methyl cellulose, chitosan; alginate; a polyvinyl alcohol; a gelatin, such as gelatin methacryloyl; a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); or any combination thereof.

17. The foam composition of any one of claims 1-16, wherein the foam-forming agent is present in an amount of from 0. 1% by weight to 10% by weight, based on the total weight of the aqueous foam composition, such as from 0.5% by weight to 7% by weight, from 0.5% by weight to 5% by weight, from 0.5% by weight to 4% by weight, or from 1% by weight to 3% by weight.

18. The foam composition of any one of claims 1-17, wherein the active agent comprises a therapeutic agent, a prophylactic agent, a diagnostic agent, or a combination thereof.

19. The foam composition of any one of claims 1-18, wherein the active agent comprises an antimicrobial agent, an analgesic agent, a hemostatic agent, a growth factor, an immunomodulatory agent, an orthobiologic agent, an extracellular vesicle, an exosome agent, a senolytic agent, or a combination thereof.

20. The foam composition of any one of claims 1-19, wherein the active agent comprises (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immunomodulatory’ agent, wound healing agent, an analgesic agent; or a combination thereof.Attorney Docket No. 10975-078W0121. The foam composition of any one of claims 19-20, wherein the antimicrobial agent is chosen from an aminoglycoside (e.g., tobramycin, neomycin), a peptide antibiotic (vancomycin, bacitracin), a beta-lactam antibiotic (e.g., ceftazidime, ceftriaxone, cefazolin), a Polymyxins (polymyxin B, colistin), or combinations thereof.

22. The foam composition of any one of claims 19-21, wherein the hemostatic agent is chosen from an antifibrinolytic (e.g., tranexamic Acid (TXA)), a coagulation factor or analog thereof (e.g., recombinant factor Vila (rFVIIa), prothrombin complex concentrates (PCCs), fibrinogen concentrates, desmopressin), or combinations thereof.

23. The foam composition of any one of claims 19-22, wherein the immunomodulatory agent is chosen from a Toll-like Receptor (TLR) agonist (e.g., Polyinosinic-poly cytidylic acid (poly(I:C)), a CpG oligonucleotide), a cytosolic receptor agonist (e.g., 2'3'-cyclic di-GMP (c-di- GMP), ADU-S100 (MIW815), DMXAA (Vadimezan)), or combinations thereof.

24. The foam composition of any one of claims 19-23, wherein the wound healing agent is chosen from a wound healing macrophage (M<b) activator, a fibroblast growth factor (FGF), an epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), or a combination thereof.

25. The foam composition of any one of claims 19-24, wherein the analgesic agent is chosen from a local anesthetic (an amide) such as lidocaine, bupivacaine, mepivacaine, or ropivacaine; a non-steroidal anti-inflammatory drug (an NSAID) such as diclofenac or ketoprofen; an opioids such as morphine or fentanyl; or a combination thereof.

26. The foam composition of any one of claims 1-19, wherein the active agent comprises (1) an antimicrobial agent; (2) an analgesic agent; and optionally (3) an immunomodulatory agent, wound healing agent, a hemostatic agent, or a combination thereof.

27. The foam composition of claim 26, wherein the antimicrobial agent is chosen from an aminoglycoside (e.g., tobramycin, neomycin), a peptide antibiotic (vancomycin, bacitracin), aAttorney Docket No. 10975-078W01 beta-lactam antibiotic (e.g., ceftazidime, ceftriaxone, cefazolin), a Polymyxins (polymyxin B, colistin), or combinations thereof.

28. The foam composition of any one of claims 26-27, wherein the analgesic agent is chosen from a local anesthetic (an amide) such as lidocaine, bupivacaine, mepivacaine, or ropivacaine; a non-steroidal anti-inflammatory drug (an NSAID) such as diclofenac or ketoprofen; an opioids such as morphine or fentanyl; or a combination thereof.

29. The foam composition of any one of claims 26-28, wherein the hemostatic agent is chosen from an antifibrinolytic (e.g., tranexamic Acid (TXA)), a coagulation factor or analog thereof (e.g., recombinant factor Vila (rFVIIa), prothrombin complex concentrates (PCCs), fibrinogen concentrates, desmopressin), or combinations thereof.

30. The foam composition of any one of claims 26-29, wherein the immunomodulatory agent is chosen from a Toll-like Receptor (TLR) agonist (e.g., Polyinosinic-poly cytidylic acid (poly(I:C)), a CpG oligonucleotide), a cytosolic receptor agonist (e.g., 2'3'-cyclic di-GMP (c-di- GMP), ADU-S100 (MIW815), DMXAA (Vadimezan)), or combinations thereof.

31. The foam composition of any one of claims 26-30, wherein the wound healing agent is chosen from a wound healing macrophage (M<b) activator, a fibroblast growth factor (FGF), an epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), or a combination thereof.

32. The foam composition of any one of claims 1-31, wherein the foam composition comprises: a continuous aqueous phase comprising water, from 0. 1% by weight to 10% by weight of a biopolymer foam-forming agent, based on the total weight of the foam composition, and an active agent; and bubbles comprising an expansion gas dispersed within the continuous phase; wherein the active agent comprises (a) (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immunomodulatory agent, wound healing agent, an analgesic agent; a combination thereof; (b) (1) an antimicrobial agent; (2) an analgesic agent; and optionally (3) anAttorney Docket No. 10975-078W01 immunomodulatory agent, wound healing agent, a hemostatic agent, or a combination thereof; or (c) an antimicrobial agent alone.

33. The foam composition of any one of claims 1-32, wherein the active agent is present in an amount of from 0.001% by weight to 25% by weight, based on the total weight of the aqueous foam composition.

34. The foam composition of any one of claims 1-33, wherein the aqueous foam composition further comprises one or more additional components chosen from a viscosity-modifying polymer, a foam stabilizer, a pH modifying agent (e.g., an acid, an alkali agent, or a combination thereof), a chelating agent (e.g., EDTA or a salt thereof), a preservative, a colorant, a sorbent, a co-solvent, or any combination thereof.

35. The foam composition of any one of claims 1-34, wherein the aqueous foam composition further comprises a foam stabilizer.

36. The foam composition of claim 35, wherein the foam stabilizer is selected from a crosslinker, a particulate stabilizer, or any combination thereof.

37. The foam composition of any of claims 35-36, wherein the foam stabilizer comprises a crosslinker selected from a borate crosslinking agent, a Ca crosslinking agent, a Zr crosslinking agent, a Ti crosslinking agent, an Al crosslinking agent, an organic crosslinker (e.g., malonate, polyethyleneimine), or any combination thereof.

38. The foam composition of any one of claims 1-37, wherein the aqueous foam composition further comprises a viscosity-modifying polymer.

39. The foam composition of claim 38, wherein the viscosity-modifying polymer comprises a water-soluble polymer, such as a biopolymer.

40. The foam composition of any of claims 38-39, wherein the viscosity-modifying polymer is chosen from xanthan, guar, a scleroglucan, a schizophyllan, hydroxyethyl cellulose (HEC), orAttorney Docket No. 10975-078W01 any combination thereof.

41. A method of treating a wound comprising applying the foam composition of any one of claims 1-40 to the wound.

42. The method of claim 41, wherein the method further comprises generating the aqueous foam composition from an aqueous foam precursor composition and an expansion gas.

43. The method of claim 42, wherein generating the aqueous based foam comprises: shearing the aqueous foam precursor composition in the presence of the expansion gas; injecting the expansion gas into the aqueous foam precursor composition; or any combination thereof.

44. The method of any one of claims 42-43, wherein the expansion gas comprises nitrogen, CO2, air, nitrous oxide, propane, butane, or any combination thereof.

45. The method of any one of claims 42-44, wherein the aqueous foam composition exhibits a volumetric expansion ratio of from 1 to 10 upon generation of the aqueous foam composition from the aqueous foam precursor composition.

46. A sterile aqueous foam precursor composition comprising water; from 0. 1% to 10% by weight of a biocompatible polymeric foam-forming agent; and an active agent.

47. The composition of claim 46, wherein the water is present in an amount of from 5% by weight to 98% by weight, based on the total weight of the aqueous foam precursor composition.

48. The composition of claim 46, wherein the aqueous foam precursor composition is a concentrate, and the water is present in an amount of from 5% by weight to 40% by weight, based on the total weight of the aqueous foam precursor compositionAttorney Docket No. 10975-078W0149. The composition of claim 46, wherein the water is present in an amount of from 60% by weight to 98% by weight, based on the total weight of the aqueous foam precursor composition50. The composition of any one of claims 46-49, wherein the foam -forming agent comprises a polysaccharide (e.g., alginate, chitosan, agarose, carrageenan, a cellulosic polymer such as carboxymethyl cellulose (CMC), hyaluronic acid, an alkyl polyglycoside, or a combination thereof), a protein (e.g., collagen, gelatin, whey protein, ovalbumin, conalbumin, globulins, ovomucin, or a combination thereof), a synthetic polymer (e.g., polyvinyl alcohol, polyvinyl acetate, a polyalkylene oxide (e.g., a crosslinked polyethylene glycol), a polyester (e.g., polylactic acid, polygly colic acid, poly caprolactone)), or a combination thereof.

51. The composition of any one of claims 46-50, wherein the foam -forming agent comprises a surfactant, such as a non-ionic surfactant, an anionic surfactant, a zwitterionic surfactant, or a combination thereof.

52. The composition of claim 51, wherein the surfactant comprises a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), or a combination thereof; an alkyl polyglycoside; or a combination thereof.

53. The composition of any one of claims 46-52, wherein the foam-forming agent comprises a poloxamer, such as Poloxamer 407 (PEOioiPPOsePEOioi), Poloxamer 188 (PEO75PPO29PEO75), Poloxamer 338 (PEO141PPO44PEO141), Poloxamer 124 (PEO12PPO20PEO12), Poloxamer 237 (PEO64PPO37PEO64), and mixtures thereof; carboxymethyl cellulose (CMC); methyl cellulose, chitosan; alginate; a polyvinyl alcohol; a gelatin, such as gelatin methacryloyl; a polysorbate, such as polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), or polysorbate 80 (polyoxyethylene (20) sorbitan monooleate); or any combination thereof.

54. The composition of any one of claims 46-53, wherein the foam-forming agent is presentAttorney Docket No. 10975-078W01 in an amount of from 0.5% by weight to 7% by weight, such as from 0.5% by weight to 5% by weight, from 0.5% by weight to 4% by weight, or from 1% by weight to 3% by weight.

55. The composition of any one of claims 46-54, wherein the active agent comprises a therapeutic agent, a prophylactic agent, a diagnostic agent, or a combination thereof.

56. The composition of any one of claims 46-55, wherein the active agent comprises an antimicrobial agent, an analgesic agent, a hemostatic agent, a growth factor, an immunomodulatory agent, an orthobiologic agent, an extracellular vesicle, an exosome agent, a senolytic agent, or a combination thereof.

57. The composition of any one of claims 46-56, wherein the active agent comprises (1) an antimicrobial agent; (2) a hemostatic agent; and optionally (3) an immune system activator, wound healing agent, an analgesic agent; or a combination thereof.

58. The composition of any one of claims 56-57, wherein the antimicrobial agent is chosen from an aminoglycoside (e.g., tobramycin, neomycin), a peptide antibiotic (vancomycin, bacitracin), a beta-lactam antibiotic (e.g., ceftazidime, ceftriaxone, cefazolin), a Polymyxins (polymyxin B, colistin), or combinations thereof.

59. The composition of any one of claims 56-58, wherein the hemostatic agent is chosen from an antifibrinolytic (e.g., tranexamic Acid (TXA)), a coagulation factor or analog thereof (e.g., recombinant factor Vila (rFVIIa), prothrombin complex concentrates (PCCs), fibrinogen concentrates, desmopressin), or combinations thereof.

60. The composition of any one of claims 56-59, wherein the immunomodulatory agent is chosen from a Toll-like Receptor (TLR) agonist (e.g., Polyinosinic-poly cytidylic acid (poly(I:C)), a CpG oligonucleotide), a cytosolic receptor agonist (e.g., 2'3'-cyclic di-GMP (c-di- GMP), ADU-S100 (MIW815), DMXAA (Vadimezan)), or combinations thereof.

61. The composition of any one of claims 56-60, wherein the wound healing agent is chosen from a wound healing macrophage (M<b) activator, a fibroblast growth factor (FGF), anAttorney Docket No. 10975-078W01 epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), or a combination thereof.

62. The composition of any one of claims 56-61, wherein the analgesic agent is chosen from a local anesthetic (an amide) such as lidocaine, bupivacaine, mepivacaine, or ropivacaine; a nonsteroidal anti-inflammatory drug (an NSAID) such as diclofenac or ketoprofen; an opioids such as morphine or fentanyl; or a combination thereof.

63. The composition of any one of claims 46-56, wherein the active agent comprises (1) an antimicrobial agent; (2) an analgesic agent; and optionally (3) an immunomodulatory agent, wound healing agent, a hemostatic agent, or a combination thereof.

64. The composition of claim 63, wherein the antimicrobial agent is chosen from an aminoglycoside (e.g., tobramycin, neomycin), a peptide antibiotic (vancomycin, bacitracin), a beta-lactam antibiotic (e.g., ceftazidime, ceftriaxone, cefazolin), a Polymyxins (polymyxin B, colistin), or combinations thereof.

65. The composition of any one of claims 63-64, wherein the analgesic agent is chosen from a local anesthetic (an amide) such as lidocaine, bupivacaine, mepivacaine, or ropivacaine; a nonsteroidal anti-inflammatory drug (an NSAID) such as diclofenac or ketoprofen; an opioids such as morphine or fentanyl; or a combination thereof.

66. The composition of any one of claims 63-64, wherein the hemostatic agent is chosen from an antifibrinolytic (e.g., tranexamic Acid (TXA)), a coagulation factor or analog thereof (e.g., recombinant factor Vila (rFVIIa), prothrombin complex concentrates (PCCs), fibrinogen concentrates, desmopressin), or combinations thereof.

67. The composition of any one of claims 63-66, wherein the immunomodulator}' agent is chosen from a Toll-like Receptor (TLR) agonist (e.g., Polyinosinic-poly cytidylic acid (poly(I:C)), a CpG oligonucleotide), a cytosolic receptor agonist (e.g., 2'3'-cyclic di-GMP (c-di- GMP), ADU-S100 (MIW815), DMXAA (Vadimezan)), or combinations thereof.Attorney Docket No. 10975-078W0168. The composition of any one of claims 63-67, wherein the wound healing agent is chosen from a wound healing macrophage (M<D) activator, a fibroblast growth factor (FGF), an epidermal growth factor (EGF), a platelet-derived growth factor (PDGF), or a combination thereof.

69. The composition of any one of claims 46-68, wherein the active agent is present in an amount of from 0.1% by weight to 25% by weight, based on the total weight of the aqueous foam composition.

70. The composition of any one of claims 46-69, wherein the aqueous foam precursor composition further comprises one or more additional components chosen from a viscositymodifying polymer, a foam stabilizer, a pH modifying agent (e.g., an acid, an alkali agent, or a combination thereof), a chelating agent (e.g., EDTA or a salt thereof), a biocide, a colorant, a sorbent, a co-solvent, or any combination thereof.

71. The composition of any one of claims 46-70, wherein the aqueous foam precursor composition further comprises a foam stabilizer.

72. The composition of claim 71, wherein the foam stabilizer is selected from a crosslinker, a particulate stabilizer, or any combination thereof.

73. The composition of any of claims 71-72, wherein the foam stabilizer comprises a crosslinker selected from a borate crosslinking agent, a Ca crosslinking agent, a Zr crosslinking agent, a Ti crosslinking agent, an Al crosslinking agent, an organic crosslinker (e.g., malonate, polyethyleneimine), or any combination thereof.

74. The composition of any one of claims 46-73, wherein the aqueous foam precursor composition further comprises a viscosity-modifying polymer.

75. The composition of claim 74, wherein the viscosity-modifying polymer comprises a water-soluble polymer, such as a biopolymer.Attorney Docket No. 10975-078W0176. The composition of any of claims 74-75, wherein the viscosity-modifying polymer is chosen from xanthan, guar, a scleroglucan, a schizophyllan, hydroxyethyl cellulose (HEC), or any combination thereof.

77. A foamable composition comprising the aqueous foam precursor composition defined by any one of claims 46-76 and a liquefied or a compressed gas propellant.

78. The foamable composition of claim 77, wherein liquefied or a compressed gas propellant comprises nitrogen, CO2, air, nitrous oxide, propane, butane, or any combination thereof.

Images