Compositions and devices for extended efficacy and customization of pharmaceutical agents through composite powder combinations

Abstract

The embodiments herein provide shape-transforming pharmaceutical compositions and modular kits for the treatment of soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical or organ exposures. The compositions comprise sterile, dry adsorbent composite polymer particles that are hydrated in situ with a sterile liquid containing one or more pharmaceutical agents. Hydration causes the particles to aggregate and transform into a conforming, shape-retentive device that provides extended coverage and sustained or controlled drug release. Kits enable powders and liquids to be applied sequentially or simultaneously, allowing tailored therapy at the point of care. Therapeutic agents may include antimicrobial, anti-inflammatory, hemostatic, regenerative, or analgesic compounds. These devices retain structure for extended durations, support customizable release kinetics, and may serve as a temporary implant to protect tissue while delivering localized therapy. The invention provides a versatile platform for prolonged, modular drug delivery across clinical and surgical settings.

Description

Docket No. 89380.0007\WOCOMPOSITIONS AND DEVICES FOR EXTENDED EFFICACY AND CUSTOMIZATION OF PHARMACEUTICAL AGENTS THROUGH COMPOSITE POWDER COMBINATIONS, LIQUID FORMULATIONS, KITS, AND USES THEREOFGOVERNMENT FUNDING

[0001] This invention was made with government support under Contracts No. W81XWH21P0019, No. W18WXH22C0045, No. HT942525CE032, and No. HT942525C0002, awarded by the United States Department of Defense. The government has certain rights in the invention.RELATED APPLICATIONS

[0002] This application claims the priority benefit of United States Provisional Application No. 63 / 701,373, filed 30 September 2024, which is incorporated fully herein by reference for all purposes.FIELD

[0003] The present embodiments relate to medical devices, compositions, formulations, and methods for customizing and extending the localized efficacy of pharmaceutical agents, particularly in the context of tissue and structural repair, comprising shape-transforming adsorbent particle composites, and methods for making and using same.BACKGROUND

[0004] Soft and hard tissue injuries, bone and joint defects, tendon and ligament repairs, and surgical exposures often require both physical coverage of the affected site and localized delivery of therapeutic agents. Current modalities — including ointments, gels, irrigants, and coated or impregnated implants — commonly release active compounds rapidly and are limited by short duration of activity, rapid washout, and lack of conformability to complex tissue geometries, requiring frequent re-application, secondary coverage and limiting effectiveness. Even depot implants, which function as local drug reservoirs, may extend release only briefly, are invasive to place or remove, and are typically restricted in the range of drugs they can deliver. Accordingly, there remains a need for adaptable therapeutic platforms that provide conforming and extended coverage while enabling controlled, sustained release of a broad spectrum of agents — such as hemostats, antimicrobials, anti-inflammatories, anesthetics, or growth factors — which can be assembled into modular kits for point-of-care use in civilian, surgical, and military settings.Docket No. 89380.0007\WOSUMMARY

[0005] The present embodiments answer the unmet needs of current modalities by providing shape-transforming particle composites and related systems that can be deployed either in dry form, in combination with other powders, or in combination with biocompatible liquid carriers, enabling both physical protection and customizable, sustained delivery of therapeutic agents.

[0006] The present embodiments provide compositions, devices, and methods for sustained release and extended efficacy of pharmaceutical agents, in forms that are easily prepared for the prolonged treatment of soft and hard tissue injuries, bone and joint defects, tendon and ligament repairs, and surgical exposures. More specifically, the present embodiments provide for shape-transforming adsorbent composite polymer particles that, upon contact with a physiological medium or other medium of similar ionic strength, transform into conforming, shape-retentive devices capable of providing both prolonged coverage and sustained delivery of pharmaceutical agents, thereby extending their efficacy over time, such as for days or weeks. The present embodiments further provide shape-transforming adsorbent particle composites that may be used alone, in combination with other dry powders, or mixed with or sequentially combined with, biocompatible liquid carriers to form customizable drug delivery platforms. Upon combination and application, whether powder-powder, powder-liquid, or combinations thereof, the components interact to form a conforming, adherent matrix capable of retaining and gradually releasing therapeutic agents. These platforms are adaptable for diverse clinical applications, including soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical exposures. The embodiments further relate to methods of making, packaging, and using such composites and formulations to provide extended efficacy of therapeutic agents such as hemostatic factors, antimicrobials, anti-inflammatory drugs, anesthetics, and regenerative biologies.

[0007] An aspect of the present embodiments provides a customizable platform for the prolonged treatment of soft and hard tissue injuries, bone and joint defects, tendon and ligament repairs, defects, and surgical exposures, comprising (a) a sterile, dry preparation of biocompatible adsorbent composite particles; and (b) a sterile isotonic solution comprising at least one pharmaceutical agent. The two components may be applied concurrently or sequentially, in any order, and re-applied individually or together as needed. Upon contact, the solution hydrates the powder to form a shape-conforming matrix that occludes and retains at least a portion of the pharmaceutical agent, and then transforms to a shape-retentive device that adheres at the site of application and remains in place for extended durations. Importantly, theDocket No. 89380.0007\WO matrix provides a device that serves as both a physical covering - holding the agent in contact with the tissue preventing wash-off or displacement - and a delivery system - releasing at least a portion of the agent over time, thereby extending the efficacy of the agent for days or weeks without reapplication. In at least one embodiment of this aspect, the sterile isotonic solution is a regulatory-approved formulation with at least one pharmaceutical agent (e.g. ophthalmic, otic, or intravenous, lyophilized or resuspension, or other regulatory agency-approved solution or preparation available to medical providers). This platform allows the medical provider to select an agent or combination of agents at the point of care from known, approved, available solution formulations at the time of service, and apply the solution(s) with the preparation of sterile, dry biocompatible, adsorbent composite particles directly to the surface to meet the specific needs of the injury. In at least one embodiment, the preparation of sterile, dry biocompatible, adsorbent composite particles is a transforming powder based composition comprising methacrylate polymer particles. In one embodiment, the adsorbent composite particles composition a mixture of lyophilized poly-2-hydroxy ethyl -methacrylate (pHEMA) and poly-2-hydroxypropyl- methacrylate (pHPMA) particles combined in a ratio of 85: 15. In a pre-clinical porcine infection model, for example, a single application of a matrix formed by the concurrent application of adsorbent composite particles and ciprofloxacin in the form of ciprofloxacin, 0.3% ophthalmic solution, prevented methicillin-resistant Staphylococcus aureus infection for at least 14 days without any reapplication.

[0008] Another aspect of the present embodiments provides for sustained release devices for the sustained release of at least on pharmaceutical agent to a biological site in need of treatment. In this aspect, the embodiments provide a composition comprising adsorbent composite particles comprising at least one pharmaceutical agent, capable of transforming from a shape-conforming state to a shape-retentive state, thereby providing a device that delivers a pharmaceutical agent from the device in contact with the tissue, defect or surgical exposure or repair site for a sustained period of time (e.g., hours, days or weeks). In at least one embodiment, the shape-transforming materials described herein provide a temporary skin substitute, scab-like covering, or graft-like layer that provides sustained release of a pharmaceutical agent. In at least one embodiment, the shape-transforming materials provide a drug delivery device for the sustained release of a therapeutic agent. Accordingly, in at least one embodiment, the adsorbent composite particles / device comprises at least one pharmaceutical agent, such as a therapeutic agent, for example a hemostatic agent or antibiotic, or both. In at least one embodiment, the shape-transforming adsorbent composite particles provide a drug delivery device for the sustained release of two or more therapeutic agents and may be formed alone, in powderpowder combinations, powder-liquid combinations, or combinations thereof.Docket No. 89380.0007\WO

[0009] Another aspect of the present embodiments provides for a device that extends the efficacy of a pharmaceutical agent at the site in need thereof. In this aspect, the embodiments provide a composition comprising adsorbent composite particles comprising at least one pharmaceutical agent, capable of transforming from a shape-conforming state to a shape- retentive state, thereby providing a device that delivers a pharmaceutical agent from the device in contact with the tissue, defect or surgical exposure. Importantly, the device extends the duration of therapeutic efficacy of the agent, independent of the in vitro release kinetics. For example, in vitro analysis of release kinetics of ciprofloxacin from a matrix comprising adsorbent composite particles and 0.3% ciprofloxacin ophthalmic solution indicated that over 90% of the drug was released within 24 hours. However, in vivo porcine infection models demonstrated that this same matrix was able to prevent methicillin-resistant Staphylococcus aureus (MRS A) and Pseudomonas aeruginosa infections for at least 7 to 14 days with a single administration, without reapplication. This finding demonstrates that the conforming, adherent nature of the matrix prolongs efficacy at the site of treatment beyond the expected release profile.

[0010] Another aspect of the present embodiments provides for sustained release devices for the sustained release at least on pharmaceutical agent to a biological site in need of treatment. In this aspect, the embodiments provide a composition comprising adsorbent composite particles comprising at least one pharmaceutical agent, capable of transforming from a shape-conforming state to a shape-retentive state, thereby providing a device that delivers a pharmaceutical agent from the device in contact with the tissue, defect or surgical exposure or repair site for a sustained period of time (e.g., hours, days or weeks). In at least one embodiment, the shape-transforming materials described herein provide a temporary skin substitute, scab-like covering, or graft-like layer that provides sustained release of a pharmaceutical agent. In at least one embodiment, the shape-transforming materials provide a drug delivery device for the sustained release of a therapeutic agent. Accordingly, in at least one embodiment, the adsorbent composite particles / device comprises at least one pharmaceutical agent, such as a therapeutic agent, for example a hemostatic agent or antibiotic, or both. In at least one embodiment, the shape-transforming adsorbent composite particles provide a drug delivery device for the sustained release of two or more therapeutic agents and may be formed alone, in powderpowder combinations, powder-liquid combinations, or combinations thereof.

[0011] According to the aspects of the present embodiments, in at least one embodiment the adsorbent composite polymer particles described herein are provided as a dry, flaked powdered preparation that, upon contact with a physiological medium or other medium of similar ionic strength, transforms to a conforming, shape-retentive material (device). In at leastDocket No. 89380.0007\WO one embodiment, the adsorbent composite polymer particles are prepared from a suspension of poly-2-hydroxyethyl-methacrylate (pHEMA) particles and poly-2-hydroxypropylmethacrylate (pHPMA) particles, for example at a ratio of pHEMA:pHPMA of about 80:20 to about 90: 10, inclusive and including ratios therebetween, such as a pHEMA:pHPMA ratio of about 85: 15, although other ratios may also be used depending on the desired performance. In some embodiments, the composite particles may be blended with additional powders - such as hemostatic agents (e.g., tranexamic acid, chitosan), antimicrobials (e.g., vancomycin, gentamicin), or growth factors (e.g., VEGF, PDGF, EGF) - to create powder-powder combinations. In other embodiments, the composite particles may be hydrated or co-applied with biocompatible liquid carriers, or combinations thereof, to form conforming matrices tailored to the biological site in need of treatment.

[0012] Another aspect of the present embodiment provides a drug delivery device in which the materials described herein comprise, and in use release, at least one pharmaceutical agent. This aspect provides a device for the sustained release of at least one or more therapeutic agents at the biological site in need of treatment. In at least one embodiment, the adsorbent composite polymer particles preparation comprises at least one therapeutic agent, selected (without limitation) from one or more of the following groups: growth factors or other regenerative agent, secretome, exosome, extracellular vesicle, debriding agent, antiinflammatory agent, analgesic, enzyme (for example, oxidase, peroxidase, horseradish peroxidase), antimicrobial agent, antiviral agent, antifungal agent, antibacterial agent, biofilm- inhibiting / dispersal agent, hemostatic agent or a combination of any of these. In one embodiment, the device comprises an analgesic or local anesthetic, such as lidocaine, pramoxine HC1, capsaicin, clonidine, or menthol. In one embodiment, the device comprises a nonsteroidal anti-inflammatory agent (NS AID), such as aspirin, diclofenac, or ibuprofen. In one embodiment, the device comprises a corticosteroid anti-inflammatory, such as dexamethasone, triamcinolone, betamethasone, or methylprednisolone. In one embodiment, the device comprises a traditional antimicrobial or antibiotic, such as ciprofloxacin, minocycline, doxycycline, vancomycin, gentamicin, ceftriaxone, trovafloxacin, polyhexamethylene biguanide, or silver sulfadiazine. In one embodiment, the device comprises an antifungal agent, such as amphotericin B, nystatin, fluconazole, or voriconazole. In one embodiment, the device comprises an antiviral agent, such as acyclovir, ganciclovir, cidofovir, or interferon-based therapies. In one embodiment, the device comprises a next-generation pathogen-agnostic antimicrobial, such as antimicrobial peptides, bacteriophages, nitric oxide donors, phage lysins, or broad-spectrum synthetic antimicrobial polymers. In one embodiment, the device comprises a pharmaceutical agent for causing clotting or slowing traumatic bleeding, such as tranexamic acid, chitosan, thrombin, or fibrin. In oneDocket No. 89380.0007\WD embodiment, the device comprises a regenerative or biologic therapeutic, such as a growth factor (e.g., VEGF, PDGF, or EGF), collagen, enzymes (for example, oxidase, peroxidase, horseradish peroxidase), debriding agents , biofilm-inhibiting / dispersal agents, secretome preparations, or exosomes / extracellular vesicles containing therapeutic cargos such as RNAs, proteins, or lipids. In one embodiment, the device comprises stem cells or stem cell-derived products, including mesenchymal stem cells, hematopoietic stem cells, induced pluripotent stem cells (iPSCs), or their conditioned media. In one embodiment, the device comprises a combination therapy, such as an antibiotic and a corticosteroid (e.g., ciprofloxacin and dexamethasone), to provide simultaneous antimicrobial and anti-inflammatory activity.

[0013] In at least one embodiment, the pharmaceutical agent is included in the shapetransforming preparation or device at a concentration range of about 0.01% by weight to about 10.0% by weight of the shape-transforming material.

[0014] In one embodiment, the concentration is selected to provide sustained release of the pharmaceutical agent for at least 3 to 30 days, or more, depending on the formulation and agent selected. For example, in porcine infection models, a preparation comprising adsorbent composite particles with 0.6% ciprofloxacin by weight provided effective local antimicrobial activity and protection against infection for up to 14 days without reapplication at least one embodiment, the pharmaceutical agent is included in the shape-transforming preparation or device at a concentration range of about 0.01% by weight to about 10.0% by weight of the shape-transforming material.

[0015] In another aspect of the present embodiments, shape-transforming device comprising adsorbent composite particles described herein may provide hemostatic properties, antimicrobial properties (including antibacterial, antifungal, antiviral, and pathogen-agnostic activity), debriding properties, anti-inflammatory, anti-biofilm properties, or regenerative properties. In some embodiments, the device provides an environment that decreases the inflammatory response by signaling a proliferative rather than an inflammatory response. In other embodiments, the device provides localized analgesia or pain relief.

[0016] At least one embodiment provides a sustained release composition comprising adsorbent composite particles comprising pHEMA:pHPMA at a ratio of about 85: 15 and about 0.6% ciprofloxacin by weight, wherein said adsorbent composite particles function to provide sustained release of ciprofloxacin. In vitro testing demonstrated that on average about 20% of the total ciprofloxacin was released within 96 hours when assessed using a Franz Diffusion Cell apparatus, with a receptor solution at physiological pH (7.4) and 37°C. Despite this release profile, in vivo porcine infection models showed that the same composition preventedDocket No. 89380.0007\WO methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infection for at least 7 to 14 days following a single application without re-dosing.

[0017] The shape-transforming adsorbent composite polymer particle drug delivery systems of the present embodiments are easy to use at the point of care, are biocompatible, remain non-toxic and non-sensitizing over extended periods of time, and provide pain relief and relatively unrestricted movement to the subject. For example, a shape-conforming adsorbent polymer particles preparation may be applied to tissue surfaces, defects, or voids, where thereafter it attains a shape-retentive state.

[0018] Another aspect of the present embodiments provides methods of providing therapy to a subject in need thereof. For example, while in the shape-conforming state, the adsorbent composite polymer particle / drug delivery system is applied to a biological site such as tissue surface, defect, graft site, bone cavity, tendon repair or surgical exposure, wherein the shape-conforming powder conforms to the shape of the tissue and then (upon contact with physiological fluids), aggregates and transforms to a shape-retentive device to deliver drug and provide therapy. In some embodiments, the shape-retentive device dries and flakes off on its own over time. In a further embodiment, the shape-retaining device is removed after the intended treatment period. Accordingly, an aspect of the present embodiments provides devices and methods for customized treatment in a wide range of clinical conditions.

[0019] Another aspect of the present embodiments provides methods of making the sustained release systems as described herein. In at least one embodiment, methods include preparing adsorbent composite polymer particles from suspensions of pHEMA and pHPMA, blending with additional agents or powders as desired, lyophilizing or flaking to form a dry preparation, and packaging in sterile unit doses for point-of-care use.

[0020] In another aspect of the present embodiments, the adsorbent composite particles may be used to provide sequential or staged delivery of multiple pharmaceutical agents. In one embodiment, a first therapeutic agent is incorporated into the dry preparation of adsorbent composite particles, and a second therapeutic agent is introduced via a biocompatible liquid carrier at the time of application. In another embodiment, two or more liquid carriers containing different agents are applied at different times to an already-formed matrix, resulting in sequential loading and staged release. In at least one embodiment, the system delivers a hemostatic agent during initial application, an antimicrobial agent during early healing, and a regenerative agent (e.g., growth factor, secretome, or stem cell-derived product) during later stages of repair. This provides controlled, time-staggered therapy adapted to the evolving biological needs of the injury or surgical site.Docket No. 89380.0007\WO

[0021] In another aspect, the shape-retentive device formed in situ may be re-activated or re-hydrated after initial application. In one embodiment, a biocompatible liquid carrier containing a therapeutic agent is applied to an existing matrix days after its initial formation, wherein the matrix absorbs the liquid and incorporates the new agent without the need for removal or replacement. In some embodiments, the reactivated matrix provides extended therapy beyond the original treatment window, allowing medical providers to refresh or supplement drug delivery at the site without disturbing the underlying tissue. In at least one embodiment, this reactivation approach enables prolonged point-of-care management of infection, inflammation, or regeneration by permitting multiple rounds of drug loading into a single conforming device.

[0022] In at least one embodiment, the shape-transforming adsorbent composite particles are provided in a pre-formed lyophilized structure, such as a cake, wafer, or sheet. In this format, the lyophilized mass may be used directly as a sustained-release device without the need for sieving into discrete particles. Upon hydration at the site of application, the lyophilized structure hydrates and aggregates to form a conforming, shape-retentive matrix that provides extended efficacy and localized delivery of at least one pharmaceutical agent.

[0023] In another embodiment, the adsorbent composite particles or lyophilized structures are further provided in combination with a backing or support layer, such as a sponge, foam, mesh, fabric, hydrogel sheet, or polymer film. The backing layer may provide mechanical strength, handling ease, and directional release, such that drug release is preferentially oriented toward the underlying tissue while the backing shields the opposite surface from desiccation or contamination. The backing layer may be bioresorbable, semi-resorbable, or non-resorbable, depending on clinical requirements.

[0024] These embodiments allow for dual modes of delivery, such as: (1) kit-based reconstitution, where sterile powders are combined with liquid carriers at the bedside, and (2) pre-formed solid devices (e.g., lyophilized cakes or sponge-backed composites) that may be directly applied without reconstitution. In some aspects, the pre-formed solid devices may also be hydrated with compatible liquid formulations at the point of use, thereby enabling incorporation of additional pharmaceutical agents and tailoring of release kinetics. Both approaches provide extended wear time, sustained or controlled release of pharmaceutical agents, and customizable combinations of therapeutic modalities.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. l is a line graph comparing in vitro ciprofloxacin release kinetics with in vivo efficacy in preventing infection in pre-clinical models. Y-axis: Percent of ciprofloxacinDocket No. 89380.0007\WO released in vitro from the total ciprofloxacin in the embodiment, percent control of bacterial infection the embodiment provided in an in vivo model of infection; X-axis: time (days); circles in vitro ciprofloxacin release; squares: in vivo efficacy.

[0026] FIG. 2. is a bar graph comparing antimicrobial activity (zones of inhibition) of embodiments of antibiotic-loaded adsorbent polymer particle formulations in a Kirby-Bauer disk diffusion susceptibility test of inhibition of Pseudomonas (first three data panels) or Staphylococcus aureus (three right panels). Y-axis: zone of inhibition (mm); Bars: bottom, dark gray = 24 hours, middle gray = 48 hours, top light gray = 72 hours; X-axis: high concentration or low concentration of drug indicated at top of each data section, from left-to-right: doxycycline, gentamycin, vancomycin.

[0027] FIG. 3 is a line graph showing the results of an in vivo model of healing of individual and sequential applications of growth factor-loaded embodiments as described herein. Y-axis: wound area (% of original size); X-axis: time (days); circles: VEGF; squares: PDGF; triangles: EGF; diamonds: sequential.DETAILED DESCRIPTION

[0028] It should be understood that this invention is not limited to the particular embodiments, methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. The invention is further illustrated by examples herein, which are not intended to limit the scope of the claims.

[0029] All patents and other publications identified are incorporated herein by reference for the purpose of describing and disclosing, for example, the methodologies described in such publications that might be used in connection with the present embodiments, but are not to provide definitions of terms inconsistent with those presented herein. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on information available to the applicants and do not constitute any admission as to the correctness of the dates or contents of these documents.

[0030] As used herein and in the claims, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise. Throughout this specification, unless otherwise indicated, “comprise,” “comprises,” and “comprising” are used inclusivelyDocket No. 89380.0007\WO rather than exclusively, so that a stated integer or group of integers may include one or more other non-stated integers or groups of integers. The term “or” is inclusive unless modified, for example, by “either.” Thus, unless context indicates otherwise, the word “or” means any one member of a particular list and also includes any combination of members of that list.

[0031] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations that may be varied by increments of ±1% to ±10% as would be accepted by one skilled in the art depending on context. Accordingly, other than in the operating examples, or where otherwise indicated, all numbers expressing quantities or reaction conditions used herein should be understood as modified in all instances by the term “about.” It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example, “10-50%” includes 10.0%, 10.1%, 10.2%, 10.3%, 10.4%, etc., up to and including 50.0%.

[0032] In order that the present disclosure can be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.

[0033] As used herein, the term “shape-conforming” means that a material will take the shape of its container. In applications in tissue repair, the shape-conforming material may start as a powder or fine flakes and will conform to a tissue surface or defect shape.

[0034] As used herein, the term “shape-retentive” means that a material retains a shape as a fixed material and will generally not conform to a different shape.

[0035] As used herein, the term “shape-transforming” refers to a property of a material that allows the material to initially act as shape-conforming material but then transform to a shape-retentive material. Accordingly, the adsorbent polymer particle materials are shapeconforming. After a transformation by contact with physiological fluids, the material aggregates and becomes shape-retentive. In tissue applications, the shape-conforming powder is applied to a tissue site of irregular, undefined geometry, the material conforms to the tissue surface, filling voids, and then transforms to a shape-retentive material that retains the three-dimensional shape of the tissue geometry.

[0036] As used herein, the term “gel” refers to a three-dimensional structure comprising adsorbent composite particles prepared as a shape-conforming material that, after contact with a physiological surface, transitions to a shape-retentive state. In some embodiments, the shapetransforming adsorbent composite particles may adopt a gel-like consistency during preparation or aggregation, or may retain gel-like characteristics in the shape-retentive state.

[0037] A “subject” is intended to be an animal such as a mammal, avian or otherwise. Mammals include, but are not limited to, mice, rats, monkeys, dogs, cats, humans, farm animalsDocket No. 89380.0007\WO such as cattle or sheep, sport animals such as horses, zoo animals, and domestic pets. A subject may be a human patient or a non-human patient.

[0038] As used herein, a “monomer” has the meaning understood by those skilled in the chemical art. That is, a monomer is a small chemical compound that is capable of forming a macromolecule of repeating units of itself, i.e., a polymer. Two or more monomers (that may be the same or different monomer types, i.e., different molecules) may react to form a polymer in which each of the monomers is repeated numerous times, the polymer being referred to as a copolymer to reflect the fact that it is made up of more than one type of monomer.

[0039] As used herein, the term “plurality” refers to more than one, i.e., two or more.

[0040] As used herein the term “dry weight” means the weight of particles without the weight of any polar liquid(s).

[0041] The terms “pharmaceutical agent” or “pharmaceutically active agent” refer to both small molecule and to macromolecular compounds used as drugs, devices, or diagnostic agents (e.g., dyes), and is not limited to therapeutic agents. Small molecule compounds include, without limitation, dyes, hemostatic agents, antibiotics, chemotherapeutics (in particular platinum compounds and taxol and its derivatives), analgesics, antidepressants, antibiotics, antimicrobials, anti-allergenics, anti -rejection agents such as immunosuppressive or toleranceinducing agents, debriding agents, antiarrhythmics, anti-inflammatory compounds, CNS stimulants, sedatives, anti-cholinergics, anti-arteriosclerotics, and the like. Macromolecular compounds include, without limitation, monoclonal antibodies (mAbs), Fabs, proteins, peptides, cells, antigens, nucleic acids, genes, proteins, growth factors, antigens, polypeptides, DNA, RNA, ribozymes, enzymes, growth factors, and the like. A pharmaceutically active agent may be intended for topical or systemic use. Examples of pharmaceutically active agents include, without limitation, biomedical agents and biologically active substances such as hemostatic agents, antibiotics, polypeptides or proteins, growth factors, monoclonal antibodies or portions thereof, and antigens or immunogens. Dosing of pharmaceutically active or therapeutic agents can be modified and determined based on existing therapeutic dosage levels with a high and low range around the recommended dosage levels. Dosages can be maintained within the non-toxic range established by the FDA utilizing US-Pharmacopeia standards, or other equivalent regulatory guidelines.

[0042] “Therapy” refers to treatment intended to relieve or heal a disorder in a subject.

[0043] As used herein, the term “cross-linking agent” refers to a di-, tri-, or tetrafunctional chemical entity that is capable of forming covalent bonds with functional groups on polymeric strands resulting in a three-dimensional structure.Docket No. 89380.0007\WO

[0044] As used herein, the term “hydrogen bond” refers to the electronic attraction between a hydrogen atom covalently bonded to a highly electronegative atom and another electronegative atom having at least one lone pair of electrons. The strength of a hydrogen bond, about 23 kJ (kilojoules) mol’1, is between that of a covalent bond, about 500 kJ mol’1, and a van der Waals attraction, about 1.3 kJ mol’1. Hydrogen bonds have a marked effect on the physical characteristics of a composition capable of forming them.

[0045] As used herein, a “charged” particle refers to a particle that has a localized positive or negative charge due to ionic content of the monomers making up the polymer strands of the particle and the environment in which these particles find themselves. For example, without limitation, particles comprising acrylic acid as a co-monomer will, under basic conditions, exist in a state in which some or all of the acid groups are ionized, i.e., -COOH becomes -COOT Another example is the amino (-NH2) group, which, in an acidic environment, will form an ammonium (-NHC) ion.

[0046] In general, an “excipient” or “pharmaceutically acceptable excipient” refers to an inert substance added to a therapeutic composition to facilitate its administration. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars (e.g., glucose and dextrose), types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. A “pharmaceutically acceptable excipient” does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound (pharmaceutical or therapeutic agent). The term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical carriers, such as a phosphate buffered saline, water, emulsions, and various types of wetting agents. Excipients can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see REMINGTON’S PHARMA. SCI. 15th Ed. (Mack Publ. Co., Easton, Penn. 1975). In at least one embodiment, the compositions, modules, kits and the like, comprising adsorbent composite particles as provided herein, further comprise at least one pharmaceutical excipient, for example sterile saline solution.

[0047] As used herein, the term “hydrophilic / hydrophobic interactions” refers to the inter-or intra-molecular association of chemical entities through physical forces, whereby hydrophilic compounds or hydrophilic regions of compounds tend to associate with other hydrophilic compounds or hydrophilic regions of compounds, and hydrophobic compounds or hydrophobic regions of compounds tend to associate with other hydrophobic compounds or hydrophobic regions of compounds.

[0048] As used herein, the term “occlude” has the meaning generally understood by those skilled in the chemical art, that is, to absorb and retain a substance for a period of time.Docket No. 89380.0007\WORegarding the embodiments provided herein, substances may be absorbed by and retained in, i.e., occluded by, the present embodiments during their preparation.

[0049] As used herein, the term “entrapped” refers to the retention for a period of time of a substance in the voids between the particles within the adsorbent polymer particles or adsorbent polymer particle aggregates of the present embodiments.

[0050] As used herein, the term “elastic modulus” refers to the stiffness of a given material, and is the ratio of linear stress in a body to the corresponding linear strain within the limits of elasticity.

[0051] A “pharmaceutical composition” is intended to include the combination of an active pharmaceutical agent with an excipient, such as a composition comprising adsorbent composite particles as described herein, in which the pharmaceutical composition suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.

[0052] An “effective amount” is an amount sufficient to effect beneficial or desired results. Methods for determining the effective amount, as determined by the desired or beneficial result, are well-known in the art.

[0053] The shape-transforming formulations of the present embodiments comprise, or consist essentially, or consist of adsorbent composite particles (e.g., prepared from a suspension) of alpha hydroxy methacrylate polymers particles and further comprise at least one pharmaceutical agent. These embodiments have numerous applications, including sustained, localized drug release and coverage for soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical exposures. The drug-loaded adsorbent composite particles are shape-conforming until contacted with the physiological fluids at, biocompatible liquid carriers applied to, the application site, and thereafter aggregate and transform to become a shape-retentive drug-delivery device. In the context of tissue coverage or repair, the therapeutic agent is passively delivered from the shape-retentive device at the site of application and, for example, modulates the local biological response or minimizes microbial contamination. In at least one embodiment, the formulations are provided in modular kits containing sterile unit-dose powders and compatible liquid vials, allowing rapid, point-of-care preparation without the need for specialized equipment.

[0054] In contrast to conventional drug carriers, the shape transforming materials presented herein, are uniquely capable of changing from a shape-conforming state to a shape- retentive state in situ, while simultaneously providing extended coverage and prolonged drug efficacy. When applied to a site of soft or hard tissue injury, bone or joint defect, tendon or ligament repair, or surgical exposure, the material conforms to the contours of the site and thenDocket No. 89380.0007\WO transforms into a stable, adherent matrix that maintains its dimensions. Advantageously, the material provides both (1) a protective barrier covering the biological site, and (2) a sustained- release platform for therapeutic agents. The modular nature of the kits enables the powders and liquids to be combined either sequentially or simultaneously, permitting bedside customization of therapy to address bleeding, infection, inflammation, or regeneration according to clinical need. If desired, the device may later be removed intact and atraumatically (as the material does not physically attach to the underlying tissue) by medical personnel, or it may gradually displace as the tissue stabilizes or repairs, providing flexibility in clinical management without the need for reapplication. These properties distinguish the present embodiments from conventional localized drug carriers such as ointments, gels, irrigants, injectables, or prefabricated depots, which are limited by rapid clearance, invasive placement, or lack of modularity. In contrast, the present formulations provide a modular, point-of-care system that transforms from a flexible, shape-conforming powder into a stable, shape-retentive aggregate capable of sustained therapeutic function.

[0055] Further regarding the transformation to a shape-retentive state, powder flakes undergo nearly immediate transformation (e.g., under 5 minutes) from shape-conforming material to shape-retentive material. Regarding the transformation process, the “solvent front” of fluid from the application site is rapidly adsorbed and flows through the powder material so that as the hydration occurs, the material instantly and irreversibly transforms from a powder and aggregates all in the same process. In the embodiments provided herein, the powder flakes have been further augmented by adding one or more pharmaceutically active agents such as, but not restricted to, antimicrobial agents, hemostatic agents, anti-biofilm agents, regenerative or biological agents (e.g., growth factors, extracellular vesicles, or secretome), anti-inflammatory agents, pain-management agents, enzymes, or other therapeutic substances that enhance tissue repair or stabilization. Such material also provides a device for the sustained release or controlled release of at least one therapeutic or pharmaceutically active agent, and, when provided in modular powder-liquid kits, enables sequential or simultaneous loading of agents at the point of care to extend therapeutic efficacy for days or weeks without repeated interventions.

[0056] Desirable properties for the shape-retentive materials that forms irreversibly after aggregation include rate of aggregation, tensile strength, bulk modulus, elastic modulus, percent moisture / water, physical dimensions, and volume change with aggregation, sustained or controlled release rates that can be tuned for a given therapeutic index or clinical indication, adaptability for sequential or simultaneous loading of agents, and ease of preparation in modular powder-liquid kits. Optionally, the materials may also be designed for ease of removal from the site of placement or for gradual displacement as the tissue stabilizes or repairs.Docket No. 89380.0007\WO

[0057] In at least one embodiment, the materials described herein are manufactured from lyophilized polymer particles of alpha hydroxy methacrylated polymers, such as particles having hydroxy-terminated methacrylate monomers, such as 2-hydroxyethylmethacrylate (HEMA) and / or 2-hydroxypropylmethacrylate (HPMA), from which poly-2-hydroxyethyl-methacrylate (pHEMA) and poly-2-hydroxypropylmethacrylate (pHPMA) adsorbent composite particles are prepared. Such powders may be composed of ratios of poly-a-hydroxy olefinic methacrylate polymers formed as suspensions, that can be one component or mixed components, purified, and freeze dried. These materials are selected to ensure that the transformation occurs from a shapeconforming state to a shape-retentive state when the material contacts physiological fluids or aqueous solutions of physiological pH and ionic strength. In at least one embodiment, the ultimate shape-retentive sustained release devices are biocompatible and not quickly biodegradable - thus retaining their shape after aggregation. Unlike prior art directed primarily to wound dressings, the present embodiments may be provided as modular kits containing sterile, unit-dosed powders and compatible liquid carriers. The powders and liquids may be combined either sequentially or simultaneously at the point of care, enabling clinicians to prepare extended-wear devices that provide both physical coverage (capable of remaining in place for days to weeks) and customizable drug delivery. This dual functionality allows localized, sustained release of pharmaceutical agents while maintaining prolonged tissue coverage across soft and hard tissue injuries, bone and joint defects, tendon and ligament repairs, and surgical exposures. Additional adsorbent polymer particles may be prepared using 2- alkenoic acid, a hydroxy (2C-4C) alkyl 2-alkenoate, dihydroxy (2C-4C) alkyl 2-alkenoate, hydroxy (2C-4C) alkoxy (2C-4C) alkyl 2-alkenoate, (1C-4C) alkoxy (2C-4C) alkoxy (2C-4C) alkyl 2-alkenoate, or vicinyl epoxy (1C-4C) alkyl 2-alkenoate monomers. Generally, suitable polymer particles are prepared by polymerizing an effective amount of a monomer or two or more monomers of 2-alkenoic acid, hydroxy (2C-4C) alkyl 2-alkenoate, dihydroxy (2C-4C) alkyl 2-alkenoate, hydroxy (2C-4C) alkoxy (2C-4C) alkyl 2-alkenoate, (1C-4C) alkoxy (2C-4C) alkoxy (2C-4C) alkyl 2-alkenoate or vicinyl epoxy (1C-4C) alkyl 2-alkenoate with a polar liquid, or a mixture of two or more miscible liquids at least one of which is polar, and, optionally, from about 0.01 to about 0.1 percent (w / w) of surfactant to produce a suspension of a plurality of polymeric particles, then (if warranted for a specific formulation) lyophilizing the mixture.

[0058] As noted, active pharmaceutical agents or therapeutic molecules included in the preparations described herein are selected from classes of molecules for their desired effects, for example to control bleeding, prevent infection, reduce inflammation, provide analgesia, or promote regeneration in soft and hard tissue injuries, bone and jointDocket No. 89380.0007\WG defects, tendon and ligament repairs, or surgical exposures. Formulations of the present embodiments can contain antimicrobials, anti-inflammatories, or other agents prepared by blending actives with the polymer particles during manufacture or by loading them at the point of care using the modular powder-liquid kit format. In use, the active is then released at a sustained or rate, depending on the physical properties of the compound and composition of the matrix. Accordingly, antibiotics can be added to the particle formulations to provide an antibiotic-releasing shape-transforming device. Non-limiting examples include vancomycin, gentamicin sulfate, doxycycline hyclate, and analogs and derivatives thereof. In another embodiment, the preparations may include an antiseptic or biofilm-inhibiting / dispersal agent, such as polyhexamethylene biguanide (PHMB) or derivatives thereof. For example, a suspension of pHEMA:pHPMA polymer particles may be prepared and then combined either with excipients during manufacture or with an active solution at the bedside, producing a sustained-release therapeutic device tailored to the clinical need

[0059] In at least one embodiment, the shape-transforming material of adsorbent composite polymer particles comprises a hemostatic agent. Non-limiting examples of hemostatic agents that may be incorporated into the present embodiments include tranexamic acid (TXA), chitosan or collagen or other powdered or liquid clotting agents. In at least one embodiment, the shape-transforming material of adsorbent composite polymer particles comprises a hemostatic agent. Examples of hemostatic agents that may be incorporated into the present embodiments include tranexamic acid (TXA), chitosan or collagen or other powdered clotting agents. More specifically, for example, chitosan, analogs and derivatives thereof can also be added. Chitosan is a (poly (b-(l,4)-2-amino-2-deoxy-D-glucopyranose), a natural cationic glycosaminoglycan, has been used for wound healing applications because of its excellent biocompatibility and mucoadhesive characteristics. Reports show that chitosan, when fabricated into beads, gels, sponges, or microcarriers, exhibits pH-sensitive swelling and drug release by diffusion through its porous structure. See, e.g., (Shu & Zhu, 233 IntT J. Pharma. 217 (2002). Additionally, chitosan is a glycosaminoglycan (GAG) having natural ability to interact with host cells, and also similar to the integral component of extracellular matrix (ECM). See Agnihotri et al., 100 J. Control Release 5-28 (2004); Berger et al., 57 Eur. J. Pharma. Biopharm. 19 (2004). Surprisingly, it was found that the shape-retentive devices comprising adsorbent composite polymer particles combined with a hemostatic agent such as TXA or chitosan exhibited synergistic coagulation activity during in vitro testing, beyond that observed with either material alone or would be expected from mere additive effect thereof.Docket No. 89380.0007\WO

[0060] Collagen, and analogs and derivatives thereof, can also be included in the shape-transforming materials provided herein as a hemostatic agent. Collagen is the major extracellular matrix (ECM) component present in interstitial tissues, providing approximately 30% of all ECM proteins. It is the prototypic substrate for immune defense and wound repair. See, e.g., Brett, 20 Wounds 347 (2008); Chattopadhyay & Raines, 101 Biopolymers 821 (2014). Incorporation of collagen into the adsorbent composite particles enhances both hemostatic performance and biological integration, supporting localized repair in soft and hard tissue injuries, bone and joint defects, tendon and ligament repairs, and surgical exposures.

[0061] In at least one embodiment, the shape-transforming device comprises at least two therapeutic modalities, such as an antibiotic for treating or preventing infection and a hemostatic agent for affecting clotting (hemostasis). By combining different agents in a single powderliquid preparation or by sequential loading using the modular kit format, providers can deliver multi-modal therapy at a single site. For example, a powder may be pre-formulated with a hemostatic agent and then hydrated at the bedside with an antibiotic solution, yielding a conforming matrix that provides both rapid clotting and sustained antimicrobial release. In another embodiment, a combination of ciprofloxacin and dexamethasone (cipro / dex) can be delivered to provide simultaneous antimicrobial and anti-inflammatory effects. Additional combinations may include, for example: (a) an analgesic such as lidocaine with an antimicrobial to provide infection control with local pain relief; (b) a regenerative agent with an anti -biofilm agent to promote healing in contaminated tissue defects; or (c) a hemostatic agent with an antiinflammatory corticosteroid to manage bleeding while reducing secondary inflammation. This dual-modality approach extends efficacy and allows tailored therapy based on the clinical scenario.

[0062] Additionally, preliminary results of clotting in preclinical laboratory tests described herein indicate that the shape-transforming materials when mixed with a clotting agent provide superior capability of stopping gravity-fed blood flow through a perforated surface, Importantly, the synergistic effect was observed when the adsorbent composite particles were combined with tranexamic acid, chitosan, or collagen, resulting in improved coagulation compared to any of the agents used alone. Without being bound by theory, this effect appears to occur because of the combined aggregation of the particles and the more uniform exposure of blood to the clotting agent within the matrix. The synergistic efficacy of the combined shapetransforming material / clotting agent was unexpected and surprising.

[0063] Regarding preparation of shape-transforming adsorbent composite polymer particle preparations, general polymer synthesis may be performed by dissolving monomer inDocket No. 89380.0007\WO purified water or other pharmaceutically acceptable polar solvent (e.g., ethanol) to provide a solution. Typically, the monomer concentration may be between about 1.5% and about 4%, such as 2.6% in the solution prior to polymerization. . Polymer particles may be engineered in different ratios of pHEMA and pHPMA, or other alpha-hydroxy methacrylate monomers, to achieve desired physical and drug-release characteristics. These particles may be blended with additional functional agents during manufacture or packaged in sterile, lyophilized form for later combination with liquid carriers at the point of care. This modular preparation allows medical providers to tailor therapy by selecting powder-liquid combinations that match the clinical scenario. The following (Table 1) hydroxyl-terminated methacrylate monomers and ratios by percentage of the above monomer concentrations in solution can be combined to make polymer particles through free radical initiation. It should be understood that these examples are not limiting, and the ratios or monomer types may be modified to alter drug release kinetics, mechanical strength, hydration behavior, or other properties of the resulting matrix.Docket No. 89380.0007\WO

[0064] Further, within the noted polymers and copolymers it is further possible to combine particles of the polymers provided above at ratios (ranging from 100% polymer “A” to 100% polymer “B”), such that the polymer(s) would be combined so that the total percentage of polymer remains at about 50% to about 80%, but the formulation is a mixture of distinct polymer particles. This approach enables uniform distribution of two different polymer particle types within a suspension, and the same distribution is preserved upon lyophilization to yield the adsorbent composite preparation. Such mixtures allow tuning of physical and functional characteristics, including matrix strength, hydration behavior, aggregation rate, and drug release kinetics. The following (Table 2) illustrates example mixtures of polymers can be formulated and freeze dried, with the resulting materials characterized for strength, hydration and aggregation.Docket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WODocket No. 89380.0007\WO

[0065] The shape-transforming preparations / devices described herein include at least one pharmaceutical agent for sustained release thereof. The rate of sustained release can be modified by changing the composition of the formulation (e.g., adjust polymer, particle, excipient, active) of the device to allow for different release profiles within a desired therapeutic range. This tunability enables treatment strategies that align with the specific demands of soft tissue coverage, bone or joint deficit, tendon or ligament repair, or surgical exposure.

[0066] As provided herein, a composition comprising adsorbent composite particles may prepared from the synthetic family of polymers of n-hydroxy-n-alkyl-m-methylprop-2-enoate polymers where n and m can range from 1-3. Alkyl can be, for example, methyl, ethyl, butyl, orDocket No. 89380.0007\WO propyl. In at least one embodiment, the composition comprising adsorbent composite particles is composed of one or more polymers from the synthetic family of polymers of n-hydroxy-n-alkyl- m-methylprop-2-enoate polymers where n and m can range from 1 to 3, and alkyl is methyl, ethyl, or propyl. Different polymer backbones and ratios may be selected to alter hydration, aggregation, and release kinetics, providing modular design flexibility.

[0067] In at least one embodiment, the composition comprising adsorbent composite particles and at least one pharmaceutical agent further comprises at least one pharmaceutically acceptable excipient. Excipients may be selected to enhance stability, improve reconstitution, or modulate tissue adherence.

[0068] In at least one embodiment, the dehydrated shape-conforming composition hydrates with a liquid that contains one or more active therapeutic agents suspended or dissolved in the liquid so that the adsorbent polymer particles preparation adsorbs the liquid containing the suspended or dissolved therapeutic agent as the material transforms and traps the therapeutic agent in the shape-retentive matrix. This process provides an efficient mechanism for bedside customization of therapy using FDA-approved liquid formulations.

[0069] In at least one embodiment, the hydration of the shape conforming composition can occur with a polar liquid with a solute or solutes that are active therapeutic agents. As the hydration of the shape conforming polymer composition occurs, the polar liquid moves into the polymer composition rapidly through a solvent front in which a high percentage of the polar liquid is pulled into the polymer matrix. The polymer composition aids in the solvent front by actively adsorbing the polar liquid into and between the polymer particles. The dissolved active pharmaceutical agent(s) are carried with the solvent front into the polymer matrix which during hydration and aggregation occludes and traps some of the active pharmaceutical agent molecules between or within the polymer particles. At equilibrium, the shape conforming composition has transformed to a shape retentive composition, and a percentage of the active pharmaceutical agent is trapped in and between the particles of the shape retentive material. This mechanism provides localized retention and prolonged exposure of the active at the treatment site.

[0070] In at least one embodiment, the entrapped / occluded active pharmaceutical agent within the shape retentive composition is released from the shape retentive composition through passive diffusion from the polymer matrix within and between the polymer particles into the surrounding tissue environment which can include soft or hard tissue injuries, bone and joint defects, tendon or ligament repairs, and surgical exposures.

[0071] In at least one embodiment, the concentration of the entrapped / occluded pharmaceutical agent within the shape retentive polymer composition can be varied by changing the concentration of the active pharmaceutical agent within the liquid carrier before hydration.Docket No. 89380.0007\WOThis property supports sequential and simultaneous therapy by permitting controlled layering of different drug-polymer combinations.

[0072] In at least one embodiment, the transformed (shape-retentive) device provides that after hydration and trapping of one or more therapeutic agents, the therapeutic agent(s) is released from the composition into tissue over time in a predetermined sustained release profile. In another embodiment, the release occurs according to a controlled-release profile. Providers may therefore select formulations designed for short-term, intermediate, or extended release, including extended wear periods of at least 30 days.

[0073] In at least one embodiment, the transformed (shape-retentive) device provides sustained release properties of one or more therapeutic agents to optimize therapeutic effect. In another embodiment, the transformed (shape-retentive) device provides controlled release properties of one or more therapeutic agents to optimize therapeutic effect. The release properties are determined by the polymer composition, excipients, and hydration conditions, agent dosing and solubility and can be engineered to match clinical requirements across multiple tissue types.

[0074] The compositions described herein may be prepared easily by combining with the requisite agents by dry-blending with their powdered forms or by hydrating with their liquid forms that are easily available in the market in the form of ophthalmic or ear droppers (lower doses) and IV injections (higher doses). In another embodiment, therapeutic agents may be incorporated directly into the polymer suspension prior to lyophilization, yielding preformulated drug-loaded powders. In one aspect, a modular kit is provided comprising sterile unit doses of polymer powders and matched liquid vials, enabling rapid point-of-care preparation without specialized equipment. Such kits may use selective, safe, and cost-effective FDA- approved and commercially available agents, expanding the applicability of the materials in diverse environments. When aggregates form, covalent crosslinking of the methacrylate backbone traps active agents within the polymer network and ensures sustained release. Sequential, simultaneous, or layered application of powders and liquids enables modulation of release kinetics and therapeutic sequencing, providing customized multi-modal treatment at the bedside.

[0075] In at least one embodiment, the shape-transforming adsorbent polymer particles composition comprises an anti-inflammatory agent. In one embodiment, the anti-inflammatory agent is dexamethasone. In at least one embodiment, the shape-transforming adsorbent polymer particles composition comprises a hemostatic agent. In one embodiment, the hemostatic agent is tranexamic acid (TXA). In at least one embodiment, the shape-transforming adsorbent polymer particles composition comprises an antimicrobial agent. In one embodiment, the antimicrobialDocket No. 89380.0007\WO agent is ciprofloxacin. In at least one embodiment, the shape-transforming adsorbent polymer particles composition comprises both an antimicrobial agent and an anti-inflammatory agent. In one embodiment, the composition comprises ciprofloxacin and dexamethasone. In some embodiments, one or more of these active agents are incorporated into the polymer suspension prior to lyophilization, generating pre-formulated drug-loaded powders, while in other embodiments the agents are combined with powders or liquids at the bedside. This multifunctional approach allows a single device to provide antimicrobial, anti-inflammatory, and hemostatic effects concurrently or sequentially.

[0076] The compositions provided herein enable provision of a comprehensive kit with anti-inflammatory, hemostatic, and antimicrobial agents, or to regenerative agents to provide protection and restoration for tissue and structural repair or protection. The compositions provided herein enable provision of a comprehensive modular kit with anti-inflammatory, hemostatic, antimicrobial, and / or regenerative agents for protection and restoration in soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical exposures. The modular kit format allows powders and liquids to be combined sequentially or simultaneously at the bedside, tailoring therapy to the clinical scenario. Alternatively, therapeutic agents may be pre-loaded into the polymer particles during manufacture, creating unit doses of drug-loaded powders that can be directly hydrated at the point of care. Upon hydration, the polymer irreversibly aggregates to form a conforming, shape-retentive device that provides extended coverage and sustained local drug delivery. If required, the non-adhesive material can be removed by moistening with saline and lifting away, ensuring both safety and flexibility of use.

[0077] In at least one embodiment, the shape-transforming adsorbent polymer particle composition comprises a regenerative agent. Non-limiting examples include growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), or bone morphogenetic proteins (e.g., BMP -2), as well as stem cells or cell-secreted factors such as stem cell-derived secretomes or exosomes. These agents may be incorporated into the polymer particles during manufacture or added at the point of care via modular kit hydration. The regenerative composition enhances repair of soft and hard tissue injuries, bone and joint defects, and tendon or ligament repair by stimulating local cellular proliferation, angiogenesis, and matrix remodeling.

[0078] In at least one embodiment, the shape-transforming composition comprises an analgesic or anesthetic agent to provide localized pain management. Examples include lidocaine, bupivacaine, ropivacaine, or other pharmaceutically acceptable local anesthetics. When incorporated into the polymer matrix, these agents provide sustained, localized analgesia at theDocket No. 89380.0007\WO site of application, thereby reducing the need for systemic opioids and improving patient comfort following surgical exposure, orthopedic repair, or tendon / ligament procedures.

[0079] In at least one embodiment, therapeutic sequencing is achieved through sequential or layered application of powders and liquids, wherein one active agent is introduced in a first layer and a second agent in a subsequent layer, or wherein powders are hydrated with different solutions in series. This modular approach allows clinicians to customize therapy in real time, for example applying a hemostatic agent first to stabilize bleeding, followed by an antimicrobial agent to control infection, and then a regenerative factor to promote healing.

[0080] In at least one embodiment, the aggregated shape-retentive matrix is engineered to be biodegradable, such that it gradually resorbs in vivo as the underlying tissue stabilizes or repairs. In another embodiment, the matrix is non-resorbable and can be removed intact when desired by medical personnel. The choice of resorbable versus non-resorbable compositions provides flexibility across different surgical and therapeutic use cases.

[0081] In at least one embodiment, the aggregated shape-retentive matrix is designed to maintain structural integrity for an extended period (e.g., up to several weeks) without rapid degradation, thereby providing prolonged drug delivery and coverage of the treated site. In certain embodiments, the matrix may be removed intact by medical personnel when desired, ensuring controlled management of the therapeutic device.

[0082] In at least one embodiment, the aggregated matrix functions as a temporary conforming sealant for surgical exposures and tissue defects, including but not limited to bone surfaces, joint cavities, tendon or ligament repair sites, or organ, cranial or dural or organ exposures. Whereas prior art barrier materials, including wound dressings, have been limited primarily to coverage of cutaneous wounds and lack modular drug-delivery integration, the present device simultaneously provides localized, sustained release of pharmaceutical agents while protecting the underlying tissue from contamination and mechanical disruption.

[0083] In at least one embodiment, the shape-transforming compositions described herein function as temporary implants within a tissue cavity, bone defect, tendon or ligament repair site, or organ cavity. Upon hydration, the particles aggregate into a conforming, shape- retentive device that provides mechanical protection, fills void space, and delivers one or more pharmaceutical agents in a sustained fashion. The implant remains in place for an intended therapeutic period, after which it may be removed intact or gradually displaced as the tissue stabilizes or regenerates.

[0084] In another embodiment, the temporary implant is applied to cranial, dural, or organ exposures, where it serves both as a barrier against contamination and as a local drug delivery platform. In these contexts, the conforming, adherent device protects delicate exposedDocket No. 89380.0007\WG tissue or neural structures while releasing agents such as antimicrobials, anti-inflammatories, or regenerative biologies over days to weeks.

[0085] Unlike conventional wound dressings or barrier materials that are limited to cutaneous or superficial applications, the temporary implants of the present embodiments are designed for internal use in bone, tendon, ligament, or organ cavities, and are uniquely capable of simultaneously providing (a) localized, sustained release of pharmaceutical agents and (b) physical protection of underlying tissues from contamination or mechanical disruption.EXAMPLESExample 1. Polymer particles for use in sustained-release devices

[0086] An example of adsorbent composite particles suitable for use in compositions as described herein are particles commercially available as Altrazeal® Transforming Powder Dressing (available from Altrazeal Life Sciences Inc., Addison, Texas, USA). These particles are sterile, odorless, crystalline, white powder composed of a mixture of lyophilized poly-2- hydroxyethyl-methacrylate (pHEMA) and poly-2-hydroxypropylmethacrylate (pHPMA) particles combined in a ratio of 85: 15. A description of the processes for preparing such lyophilized particles is provided in U.S. Patent No. 7,811,605. Briefly, pHEMA and pHPMA suspensions were prepared separately by the following free radical polymerization process: pHEMA suspension was prepared by mixing pure HEMA monomer with purified water containing a surfactant, then heating the mixture to a specified temperature. The addition of reaction initiator initiates the pHEMA polymerization, which was quenched using a specific process. pHPMA synthesis progressed similarly by replacing the HEMA monomer with HPMA monomer. After both polymer suspensions were prepared, the percentage of solid contents of both suspensions were measured and the total suspended solids calculated for each providing a known range of solids in pHEMA and pHPMA suspensions. More specifically, the solids were mixed to form a suspension with a pHEMA:pHPMA at a ratio of 85: 15 (w / w). The 85: 15 suspension was purified by tangential flow filtration (TFF) to remove unreacted monomer and exchange the surfactant with biocompatible known surfactant solution. After filtration and concentration, the suspension (TPD suspension) was poured into trays and placed into a freeze drier system for lyophilization. Lyophilization resulted in a cake of the suspension particles that, after crushing and sifting, yielded a fine powder of known size ranges.

[0087] Copolymer particles comprising pHEMA and pHPMA may be synthesized using HEMA monomer and HPMA monomer. Table 3 shows the relative masses and mmol of monomers added to 150 mL bottles.Docket No. 89380.0007\WD

[0088] The above polymer particles are collectively called “polymer particles,” and may be in suspension form or be lyophilized or suspension form. These represent the form of polymer particles that remain stable and may be used in the production or preparation of pharmaceutical compositions comprising at least one pharmaceutical agent. In some embodiments, such polymer particles may be distinguished from a suspension of polymer particles or freeze dried flakes of polymer particles, as both are used respectively in different formulations as indicated by context.Example 2. Sustained pharmaceutical release profiles.

[0089] Two sustained release ciprofloxacin devices were prepared using the adsorbent composite particles (transforming powder). For one device, “Cipro-dry,” adsorbent composite particles (Altrazeal® transforming powder, Altrazeal Life Sciences) were combined with a dry form of the antibiotic ciprofloxacin. For the second device, “Cipro-liq,” the particles were mixed with an ophthalmic solution containing 0.3% (wt) ciprofloxacin in isotonic saline (Ciprofloxacin Ophthalmic Solution USP 0.3% as base, sterile, 5 mL, from Leading Pharma). Both devices were designed to contain the same amount of ciprofloxacin per gram of adsorbent composite particle.

[0090] Table 4 shows the results of hydration tests for the Cipro-dry and Cipro-liq devices. Table 4 also shows the results of hydration tests for other combinations of other dry- and liquid-based pharmaceuticals that have been combined with the adsorbent composite particles. All liquid aggregation devices were prepared with FDA-approved ophthalmic or injectable pharmaceutical solutions: Dexamethasone Sodium Phosphate Ophthalmic Solution, USP, 0.1%, 5 mL (Bausch & Lomb), Ciprofloxacin 0.3% and Dexamethasone 0.1% Otic Suspension, USP, sterile, 7.5 mL (Amneal®), and Tranexamic Acid, Injection, USP, 1000 mg / 10 mL (100 mg / mL) (Avet Pharma®).

[0091] All tested devices were prepared similarly to the ciprofloxacin devices and had a final hydration percent at 5 minutes of between 60% and 86% moisture by mass.Docket No. 89380.0007\WG

[0092] Tobramycin and other formulations utilizing combinations referenced above are expected to exhibit sustained release. Examples of other combinations that have been developed include, without limitation, 0.05% vancomycin-dry, 0.1% vancomycin-dry, 0.05% doxycycline- dry, 0.6% vancomycin-dry, 2.5% vancomycin-liq, 1.0 % doxycycline-dry, 0.05% gentamycin- dry, and 0.1% gentamycin-dry, 0.0025% VEGF-dry, 0.00025% VEGF-dry, 0.000025% VEGF- dry, 0.000025% EGF-dry, and 0.000025% PDGF-dry. These are expected to exhibit sustained release in this model.

[0093] In vitro drug release experiments were conducted using a Franz diffusion apparatus (see, e.g., USP General chapter <1724>) to establish a 'finite dose' calculation. Briefly, a device was placed on top of the Franz diffusion apparatus and hydrated with either a phosphate buffered saline (PBS) or the pharmaceutical agent solution, for the first and second devices, respectively. Addition of the fluid (PBS or pharmaceutical solution) initiated aggregation and shape-transformation of the test material. The lower (receiving) portion of the Franz cell membrane remained in constant contact with a physiological synthetic serum electrolyte solution (0.601 g NaCl, 0.235 g NaHCCh, 0.0283 g Na2HPO4, and 0.0284 g Na2SO4per 100 mL water, supplemented with 1% fetal bovine serum) (SSES). Samples were removed from the receiving portion of the Franz cells at specified time intervals and tested for pharmaceutical agent content (e.g., by comparing the spectra to a standard curve generated for the appropriate drug or using other detection methods as may be appropriate for the agent). This assay was used to characterize the in vitro release profiles of further devices described herein. Devices containing growth factors were incubated in 50 mL PBS at 37°C. Samples were removed at defined timepoints and quantified using commercially-available ELISA kit.

[0094] Results of several in vitro sustained release analyses are shown in Tables 5-7.Docket No. 89380.0007\WO

[0095] Sustained release devices were also generated with the capacity to simultaneously deliver two different pharmaceutical agents. As an example, one dry device and one liquid aggregate devices was prepared using the antibiotic ciprofloxacin and the anti-inflammatory agent dexamethasone (0.6 Cipro and 0.2% Dexamethasone-dry; 0.3% Cipro and 0.1% Dexamethasone-liq). Both devices had similar hydration and aggregation characteristics to the devices made with only cipro or only dexamethasone (Table 4). Table 5 contains the drug release kinetics from the dry device (cipro / dex-dry). Table 5 contains the drug release kinetics from the liquid aggregate device (cipro / dex-liq). When hydrated with PBS, 10-20% of the active agents were released from the device within the first hour of application, followed by decreasing rate of elution of the next few days of sampling. Importantly, the amount of active agent and the kinetics of release were similar to those of the cipro-dry device and the dexamethasone-dry device. These data strongly suggest that the active agents do not negatively impact the ability of the other agent to access the wound surface.Docket No. 89380.0007\WO

[0096] The cipro / dex-liq also had similar elution kinetics as the cipro-liq and dexamethasone-liq devices. However, there was a significant reduction in the amount of the dexamethasone eluted from the cipro / dex-liq device. It is hypothesized that this difference is due to the cipro / dex ophthalmic solution more so than the interaction of the drugs with the adsorbent composite particles. When the cipro ophthalmic solution was combined with the dexamethasone ophthalmic solution, the combined solution became a suspension. Therefore, when applied to the adsorbent composite particles, the dexamethasone within the combination device is more likely to become ‘trapped’ during the liquid aggregation phase.

[0097] Some embodiments exhibited sustained release of API for more than 48 hours, or more than 72 hours. The tested APIs have different solubility constants and different interactions between the particles in the aggregate matrix, and this may result in a relative difference in the rate of API release. The first order component of release, with a steeper slope, reflects the “burst” release component. Roughly, for a given matrix, the initial rate of “burst release” was fastest for gentamicin sulfate and slower for vancomycin and doxycycline. The release of each active varies from a sustained release over 96 hours to a full burst release of 100% within the first 6 hours due to the given surface area of contact between the material and the simulated biological fluid. This provides the opportunity to engineer desired release profiles from powder formulations by considering API, hydration / aggregation profiles, surface areas of material / subject (e.g., acute or chronic state of injury), and subject / health provider need.

[0098] As noted in Table 7, above, sustained release profiles were generated for devices comprising PDGF and VEGF. A further experiment studied the impact of ACP particle size on VEGF release. The results are shown in the following table:Docket No. 89380.0007\WO

[0099] These experiments show that desired release profiles from powder formulations can be engineered by considering particle size, API, hydration / aggregation profiles, surface areas of material / subject (e.g., acute or chronic state of injury), and subject / health provider need.Example 3. Antimicrobial properties

[0100] Antimicrobial efficacy of sample preparations was tested and validated by prepopulating Staphylococcus aureus and Pseudomonas aeruginosa bacteria in petri dishes using a Kirby Bauer model. The bacteria were incubated to form a “carpet” of the respective species in a 24-hour period. Powder formulations were pre-aggregated in a 1-cm mold to provide a shape- retentive device. After the full colony was formed, a 1-cm piece of antibiotic-loaded shape- retentive material was added to the surface of the “carpet.” The petri dish containing the colony and test sample was then observed after 24 hours and the zone of inhibition measured with calipers. The disk of material was then transferred to a fresh “carpet” of the same species of bacteria and incubated. The repeat process of incubation, measurement, and transfer was then repeated for 72 hr. Data indicated that the relative zones of inhibition for the two bacterial strains used in testing can be maintained in an in vitro test for a period of at least 72 hours even at the lowest dosage levels (0.05-0.1%). FIG. 2 provides the zone of inhibition data of the various sustained release antibiotic combinations over 72 hr while stacking the combined zones of inhibition for each 24-hour period. Devices with higher doses had larger kill zones and nearly all the materials provided microbicidal efficacy over 72 hr. These data confirm that it is possible to formulate a shape-transforming material that can provide inhibition of these bacteria strains for at least 72 hr, provide a dose response, and release antimicrobial agents over a longer period. Importantly, and unexpectedly, although the sustained analysis indicated that gentamycin was released as a burst with little sustained release, the gentamycin-loaded disk materials nevertheless provided extended antibacterial efficacy for at least 72 in this model.Example 4. Shape-transforming devices comprising antibiotic and hemostatic agents

[0101] Shape-transforming powder formulations comprising both an antibiotic and a hemostatic agent can be prepared used to provide shape-retentive devices comprising both anDocket No. 89380.0007\WO antibiotic and a hemostatic agent. The antibiotics doxycycline hyclate, gentamicin sulfate, and vancomycin are selected because each has known dosage curves and activities. The hemostats bovine collagen, chitosan, and tranexamic acid (TXA) are selected because these have been commercialized as clotting agents.

[0102] Each sample is observed for stability of the material, and for the ability to form a shape-retentive material when exposed to phosphate buffered saline to simulate a wound.Example 5. Application to wound therapy

[0103] In general, wound healing is a dynamic interactive cascade of events involving chemical mediators, extracellular matrix and various cell types. Acute wounds follow a healing pattern which involves synchronized overlapping phases of coagulation, inflammation, and repair which consists of proliferation / granulation and matrix formation. An imbalance in the healing events causes an impairment in the healing process resulting in conversion of acute to chronic state. Chronic wounds result from complex and multiple intriguing factors and no single primary factor contributes to impaired wound healing. There is a large body of literature characterizing mechanistic insights leading to acute and chronic wound healing states. Despite this, the cellular and molecular mechanisms involved during wound healing are still not fully understood. Nonetheless, the key factors leading to impaired healing is due to the imbalance in inflammatory cytokines (e.g. IL-6, IL-ip, and TNF-a) and matrix remodeling enzymes (matrix metalloproteinases (MMP)), which are restored to physiological levels in the acute healing process. Another compounding clinical problem during healing is pain. Though pain is a common manifestation in both acute and chronic wounds, acute wound pain is perceived for a shorter duration, whereas in chronic wounds it remains persistent. Wound healing is a complex process requiring a multidimensional treatment approach and is complicated substantially by the risk of infection, blood loss and aggravated systemic immune responses experienced during traumatic injuries.

[0104] Wound healing can be enhanced by the early application of a multi-functional device that is easy to apply, portable, and contains requisite elements to treat complex injuries with multi-faceted needs. This may require a device(s) that can provide hemostatic properties and / or antimicrobial properties and further provides an environment that decreases the inflammatory response by signaling a proliferative rather than inflammatory response. Such devices should be easy to use at the point of injury, biocompatible, and remain non-toxic and non-sensitizing over extended periods of time, while bringing comfort to the patient by providing both pain relief and unrestricted movement. Additionally, the device should beDocket No. 89380.0007VWO capable of delivering pharmaceutical agents, sometimes for extended periods of time, so that their efficacy is maintained in cases of prolonged need.

[0105] Animal studies are conducted in compliance with the Animal Welfare Act, the implementing Animal Welfare regulations, or the principles of the Guide for the Care and Use of Laboratory Animals, National Research Council, in accredited research facilities such as accredited by, for example “AAALAC International.”

[0106] For antibiotic and infection studies, adsorbent composite particle formulations, each containing a dose (such as one of two doses (high and low)) of an antibiotic (such as gentamycin, doxycycline, vancomycin, or silver sulfadiazine), are tested for anti-microbial efficiency using an established porcine partial thickness infected wound model. Controls include a negative control (no treatment) and a commercial control (e.g., silver containing standard of care material, e.g., Silverlon® from Cura Surgical, Geneva, Ill. USA). For example, reproducible 1 cm2excision wounds (10 mm punch) are infected with either Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus (MRS A). On day 1, forty-four wounds are created, and experimental conditions are tested. Under anesthesia, up to 10 mL blood may be drawn via percutaneous stick of the vena cava in the neck region periodically (for example, per day on days 0, 1, 3, 7) for CBC and biochemistry. At a suitable time point (such as on day 3), individual biopsies for each experimental group are obtained and reapplication of all experimental materials are performed. Individual biopsies are obtained again thereafter (such as on day 7). Animals are humanly euthanized. Primary endpoints may include, for example, reduction of bacterial load on day 3, as defined by a 103reduction from initial inoculum, (reduction to 1 x 103CFU / gram of tissue or below in bacterial load); or a static level (minimum desirable) via biopsy count of < U I 05CFU / gram of tissue. Secondary endpoints may include safety and subjective observation of any adverse events in the wounds. Such studies may be repeated and extended to 14 days for the most efficacious preparations.

[0107] As an example hemostatic screening, partial thickness wounds (1 cm2) are treated in experimental groups. Each group will have wounds for pharmaceutic agents (e.g., collagen, TXA low, TXA high, or chitosan), a negative control (no treatment), and a commercial control (e.g., QuickClot®). An example 7-day study follows the infection study protocol with respect to biopsies at day 3 and day 7 (sacrifice). The primary endpoints may include clotting time and clot strength; the secondary endpoint may include safety, subjective observation of any adverse events in the wounds, and wound closure. Kinetics of blood clotting on the surface of the wound may be a difficult to measure, but the residual plasmin activity within the wound may be assessed using a modified fibrin plate method. The efficiency of agents (e.g., chitosan, collagen, TXA) in the wound dressing to affect plasminogen conversion to plasmin may be semiDocket No. 89380.0007\WO quantitatively assessed using the modified fibrin plate method. This study may also be repeated and extended to 14 days for the most efficacious powder formulations. The study may also incorporate antimicrobial liquid carriers or dry mixed formulation which will also be tested in infection studies.Example 6. Sustained release of antibiotics in porcine studies

[0108] An animal study was undertaken to demonstrate the efficacy of sustained antibiotic release shape-transforming materials described herein. All animal studies described were performed under IACUC and ACRUO approval for the ethical treatment of animals. Animal studies were conducted in compliance with the Animal Welfare Act, the implementing Animal Welfare regulations, or the principles of the Guide for the Care and Use of Laboratory Animals, National Research Council, in accredited research facilities such as accredited by, for example, AAALAC International.

[0109] Briefly, Yorkshire Cross pigs received 10-mm biopsy punch wounds that were then infected with 1 x 106colony forming units (CFU) of either Pseudomonas aeruginosa (PA) or methicillin-resistant Staphylococcus aureus (MRSA). Wounds were then treated with control or antibiotic-loaded devices. Each animal also received 10-mm biopsy punch wounds that remained uninfected, which served as a negative (no infection) control. Each animal also received a wound that was infected but remain untreated, which served as a positive control for infection.

[0110] Test devices were prepared as described in Examples above. Briefly, each antibiotic-loaded device was prepared and applied by one of two ways: (1) the antibiotic and shape-transforming adsorbent composite particles (ACP) were dry blended to a homogenous, shape-conforming mixture. This shape-conforming preparation was placed on the infected wound, after which exudate from the wound initiated aggregation and formation of a shape- retentive, antibiotic-releasing device. (2) dry ACP was contacted with the wound and immediately hydrated with a solution of antibiotic in ophthalmic solution, after which the solution and exudate from the wound initiated aggregation and formation of a shape-retentive, antibiotic-releasing device.

[0111] The following table details the devices that were applied and tested in this study:Docket No. 89380.0007\WO

[0112] Samples were acquired from each wound at 3, 7, or 14 days after treatment.Bacterial levels were then quantified using a standard CFU method. Briefly, wound fluid wasDocket No. 89380.0007\WO serially diluted, spread onto an appropriate substrate, and incubated overnight. Bacterial colonies were counted 24 later to calculate the CFU in each wound.

[0113] The infected MRS A control porcine wounds (four subjects) showed an average of about 1.56 x 106CFU at day 3, 3.99 x 105CFU at day 7, and 1.91 x 106CFU at day 14. For the ciprofloxacin-loaded devices and the vancomycin-loaded devices, MRSA levels were reduced to zero (0) at day 3 and remained negligible at days 7 and day 14. Wounds treated with ACP controls (no API) did not display significant inherent antimicrobial activity against MRSA. These data demonstrate that the antimicrobial function is the direct result of the incorporated ciprofloxacin or vancomycin, and that the device provided effective treatment against MRSA infection in this pre-clinical model.

[0114] Results for the percent reduction of MRSA infection levels are provided in Table 11. For each animal, wound CFU counts were normalized to MRSA CFU counts in the positive (infected) control. Data displays the average and standard deviation for 2-4 animals.

[0115] These data demonstrate that the antimicrobial function is the direct result of the incorporated ciprofloxacin or vancomycin, and that the device provided effective treatment against MRSA infection in this pre-clinical model.

[0116] Similarly, ciprofloxacin and tobramycin sustained release shape-retentive devices provided effective treatment against PA in this model. The infected PA control porcine injuries (four subjects) showed an average of 2.87x 107CFU at day 3 and 7.82 x 106CFU at day 7. Following treatment with Cipro-dry or Cipro-liq, PA levels were reduced to zero (0) at day 3 and remained negligible at day 7. Previously acquired data demonstrated that injuries treated with ACP controls (no API) did not display significant inherent antimicrobial activity against PA (data now shown). Table 6 shows the percent reduction in injury CFU counts were normalized to PACFU counts in the positive (infected) control.Docket No. 89380.0007\WO

[0117] Results for the percent reduction of PA infection levels are provided inTable 12. At each time point, wound CFU counts were normalized to PA CFU counts in the positive (infected) control. Data displays the average and standard deviation for eighteen wounds per time point. ACP-only formulations were tested on six wounds, each animal.

[0118] These data demonstrate that the antimicrobial function is the direct result of the incorporated ciprofloxacin or tobramycin, and that the device provided effective treatment against PA infection in this pre-clinical model.Example 7. Improved healing outcomes with sequential treatment regime

[0119] Three sustained release devices were prepared using adsorbent composite particles (transforming powder), with each device containing a different growth factor that promotes injury healing. Specifically, the particles were combined with lyophilized or powder forms of VEGF, PDGF, or EGF.

[0120] A partial thickness-thickness porcine injury model was utilized to assess the biological activity of the controlled-release devices containing 0.01% VEGF, PDGF, and EGF. Briefly, pigs received 5 cm x 5 cm partial thickness surgical wounds, which were treated with 0.5 g of 0.01% VEGF-dry, 0.01% PDGF-dry, or 0.01% EGF-dry. Some wounds were treated with 0.01% VEGF-dry, which was then layered with 0.01% PDGF-dry, and then 0.01% EGF-dry.

[0121] Each material independently promoted healing, with wound closure times ranging from 18 to 25 days. However, would closure was reduced to approximately 15 days when VEGF was applied first to promote vascularization, followed by PDGF to promote tissue reorganization, and then finally EGF to promote keratinocyte close. The results are shown in FIG. 3. Together, this study highlights the potential of using composite particle devices to sequentially deliver multiple active biological molecules, and thereby significantly promote the repair of soft and hard tissue.Docket No. 89380.0007\WGExample 8. Sustained Release System for Horseradish Peroxidase (HRP) Enzyme

[0122] Horseradish peroxidase (HRP), a 44 kDa enzyme with a native activity of 175 U / mg, was incorporated into a novel sustained release system comprising nanoparticle aggregates. This system was designed to protect the enzyme from proteolytic degradation while allowing sustained release over time. The enzyme was loaded into the aggregate matrix at a concentration of 100 pg per gram of nanoparticle aggregates. HRP was physically entrapped within the nanoparticle aggregates material. The loading efficiency was standardized at 100 pg HRP per gram of aggregate powder. The native enzyme activity was confirmed prior to incorporation using standard substrate assays. Sustained release of HRP from the aggregates material was monitored by measuring enzymatic activity in solution, assuming the native activity of 175 U / mg. The percentage of HRP released over time (relative to total loading) was as follows:

[0123] These results demonstrate a sustained release profile over a 48-hour period.

[0124] To evaluate the protective capability of the aggregate system, a proteolytic challenge was performed using trypsin at 1 mg / mL. HRP released into the trypsin-containing solution showed a significant reduction in activity (less than 50% of expected) after 1 hour, consistent with cleavage at the active site under Michaelis-Menten kinetics for the free enzyme against the proteolytic trypsin.

[0125] However, when the TPD material was removed from the trypsin solution and placed into fresh buffer containing substrate, the HRP released subsequently exhibited full enzymatic activity (100% of expected) at each time point. This indicates that HRP remained intact and enzymatically active while entrapped within the aggregate, and only became susceptible to proteolytic degradation upon release.

[0126] This sustained release system provides a novel method for controlled release and protection of HRP enzyme. The system effectively shields the enzyme from enzymatic degradation during entrapment, while allowing sustained release with preserved activity. ThisDocket No. 89380.0007\WO approach may be broadly applicable to other sensitive biomolecules requiring protection during delivery.

[0127] It is to be understood that the disclosure has been described in conjunction with the above embodiments, that the preceding description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages, and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Docket No. 89380.0007\WOCLAIMSWe claim:

1. A composition comprising sterile, dry, shape-transforming adsorbent composite polymer particles, wherein said particles are configured to transform upon hydration from a shape-conforming state to a shape-retentive state, and wherein said composition is formulated to occlude and release at least one pharmaceutical agent in a sustained manner and provide extended efficacy at a biological site selected from soft or hard tissue injuries, bone or joint defects, tendon or ligament repairs, surgical or organ exposures, or combinations thereof.

2. The composition of claim 1, wherein the adsorbent composite polymer particles comprise lyophilized poly-2-hydroxyethyl-methacrylate (pHEMA), poly-2-hydroxypropyl- methacrylate (pHPMA), or mixtures thereof.

3. The composition of claim 1, wherein the adsorbent composite polymer particles comprise a-hydroxy olefinic methacrylate polymers, poly-2-hydroxyethylmethacrylate, poly-2- hydroxypropylmethacrylate, hydroxybutyl methacrylate, glycerol methacrylate, or copolymers thereof.

4. The composition of any one of claims 1 to 3, wherein the pharmaceutical agent is incorporated prior to lyophilization of the polymer particles.

5. The composition of any one of claims 1 to 3, wherein the pharmaceutical agent is incorporated after lyophilization via dry blending.

6. The composition of any one of claims 1 to 3, wherein the pharmaceutical agent is introduced at the point of care in a liquid carrier, , the liquid optionally comprising a second pharmaceutical agent that is the same or different from that present in the powder.

7. The composition of any one of claims 1 to 3, wherein the particles are blended with a hemostatic agent.

8. The composition of claim 7, wherein the hemostatic agent is selected from tranexamic acid, chitosan, collagen, thrombin, fibrin, gelatin, alginate, kaolin, zeolite, polysaccharide-based hemostats, or synthetic peptide hemostats.

9. The composition of any one of claims 1 to 3, wherein the particles are blended with an antimicrobial agent.

10. The composition of claim 9, wherein the antimicrobial agent is selected from quinolones (ciprofloxacin, levofloxacin, moxifloxacin), aminoglycosides (gentamicin, tobramycin, amikacin), glycopeptides (vancomycin, teicoplanin), tetracyclines (doxycycline, minocycline, tigecycline), macrolides (azithromycin, clarithromycin, erythromycin), oxazolidinones (linezolid), lipopeptides (daptomycin), rifamycins (rifampin), or P-lactams (cefazolin, piperacillin / tazobactam).Docket No. 89380.0007\WG11. The composition of any one of claims 1 to 3, wherein the particles are blended with an antifungal agent.

12. The composition of claim 11, wherein the antifungal agent is selected from amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, micafungin, or anidulafungin.

13. The composition of any one of claims 1 to 3, wherein the particles are blended with an antiviral agent.

14. The composition of claim 13, wherein the antiviral agent is selected from acyclovir, ganciclovir, valganciclovir, cidofovir, foscarnet, remdesivir, tenofovir, lamivudine, or ribavirin.

15. The composition of any one of claims 1 to 3, wherein the particles are blended with an anti-inflammatory agent.

16. The composition of claim 15, wherein the anti-inflammatory agent is selected from dexamethasone, prednisone, triamcinolone, hydrocortisone, or NSAIDs including ibuprofen, naproxen, diclofenac, or indomethacin.

17. The composition of any one of claims 1 to 3, wherein the particles are blended with an analgesic agent selected from lidocaine, bupivacaine, ropivacaine, morphine, tramadol, or ketorolac.

18. The composition of any one of claims 1 to 3, wherein the particles are blended with regenerative biologies.

19. The composition of claim 18, wherein the regenerative biologies are selected from growth factors (VEGF, PDGF, FGF, EGF, TGF-P, BMPs), secretomes, extracellular vesicles, exosomes, stem-cell derived products, or combinations thereof.

20. A modular kit comprising: (a) a sterile unit dose of shape-transforming adsorbent composite polymer particles; and (b) a vial containing a sterile biocompatible liquid carrier with at least one pharmaceutical agent, wherein the powder and liquid components are configured to be applied sequentially or simultaneously at the point-of-care to form a conforming, shape- retentive device that provides localized sustained release of the pharmaceutical agent and extended coverage of the application site.

21. The kit of claim 20, wherein the sterile vial comprises an isotonic solution containing at least one pharmaceutical agent.

22. The kit of claim 20, wherein the pharmaceutical agent is selected from antimicrobial, antifungal, antiviral, anti-inflammatory, analgesic, hemostatic, regenerative biologic, enzyme, antioxidant, or combinations thereof.

23. The kit of claim 20, wherein the powder and liquid components are configured for sequential administration to provide staged release of therapeutic agents.Docket No. 89380.0007\WG24. The kit of claim 20, wherein the powder and liquid components are configured for simultaneous administration to provide concurrent delivery of therapeutic agents.

25. A method of treating a biological site selected from soft or hard tissue injuries, bone or joint defects, tendon or ligament repairs, or surgical or organ exposures, comprising:(a) applying shape-transforming adsorbent composite polymer particles to the site; and(b) hydrating the particles with a biocompatible liquid carrier comprising at least one pharmaceutical agent; thereby forming in situ a shape-retentive device that adheres to the site, provides physical coverage, and provides sustained release of the pharmaceutical agent.

26. The method of claim 25, wherein the device remains in place for up to 30 days.

27. The method of claim 25, wherein the device provides sustained release of pharmaceutical agent for at least 3 days, at least 7 days, at least 14 days, or at least 30 days.

28. The method of claim 25, wherein the device functions as a temporary implant for tissue stabilization or repair.

29. The method of claim 25, wherein the therapeutic effect is selected from prevention or treatment of infection, inflammation, bleeding, pain, or combinations thereof.

30. A medical device prepared in situ at the time of application comprising:(a) a preparation of sterile, dry biocompatible, adsorbent composite particles; and(b) a sterile isotonic solution comprising at least one pharmaceutical agent; whereby upon application of (a) and (b): (i) the solution hydrates the adsorbent composite particles, causing the particles to aggregate, (ii) the hydrated adsorbent composite particles form a matrix that occludes at least a portion of the pharmaceutical agent, (iii) the matrix conforms to the shape of the biological site, (iv) optionally, the matrix adsorbs bodily fluid, (v) the matrix transforms to a three-dimensional, shape-retentive, moist, flexible, oxygen-permeable device, (vi) the device is substantially non-bioerodible, (vii) the device may be left in place for up to 30 days, (viii) the device provides sustained release of the pharmaceutical agent at least 2 hours, at least 4 hour, at least 18 hours, at least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, or at least 92 hours, (ix) the device provides sustained release of the pharmaceutical agent at least Iday, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days; and / or (x) the device extends efficacy of the pharmaceutical agent for at least 3 days, at least 7 days, or 14 days.

31. The medical device of claim 30, wherein the pharmaceutical agent is selected from antimicrobial agents, hemostatic agents, anti-biofilm agents, regenerative biologies, antioxidants, anti-inflammatory agents, pain-management agents, or enzymes.Docket No. 89380.0007\WG32. A method of making a composition of claim 1, comprising: (a) preparing a suspension of one or more a-hydroxy olefinic methacrylate monomers or copolymers thereof in a polar liquid; (b) polymerizing the suspension to form composite polymer particles;(c) optionally combining the polymer particles with at least one pharmaceutical agent either before lyophilization or after lyophilization via dry blending; and (d) lyophilizing the polymer particles to yield a sterile, dry composition capable of forming a shape-retentive device upon hydration.

33. The method of claim 32, wherein the pharmaceutical agent is incorporated in a liquid carrier phase during suspension preparation so that the agent is entrapped within the lyophilized particles.

34. The method of claim 32, wherein the pharmaceutical agent is introduced at the point of care in a liquid carrier immediately prior to hydration.

35. The method of claim 32, wherein sequential addition of different liquid carriers containing different pharmaceutical agents produces a device with layered or staged release profiles.

36. The composition of claim 1, wherein the pharmaceutical agent is ciprofloxacin.

37. The composition of claim 1, wherein the pharmaceutical agent is vancomycin.

38. The composition of claim 1, wherein the pharmaceutical agent is tobramycin.

39. The composition of claim 1, wherein the pharmaceutical agent is dexamethasone.

40. The composition of claim 1, wherein the pharmaceutical agent is tranexamic acid.

41. The composition of claim 1, wherein the pharmaceutical agent is a combination of ciprofloxacin and dexamethasone.

42. The composition of claim 1, wherein the particles are provided as a lyophilized solid cake or slab prior to sieving, the solid form being rehydratable to yield a conforming, shape- retentive device.

43. The composition of claim 1, further comprising a backing layer, scaffold, or porous substrate selected from collagen sponges, gelatin foams, alginate sheets, polymer meshes, or textile supports, wherein the backing provides additional mechanical stability and handling properties.

44. The kit of claim 9, wherein the powder and liquid components are applied in sequential layers or stacked configurations, producing a composite device with staged or layered release profiles of pharmaceutical agents.

45. The method of claim 17, wherein the shape-retentive device provides prolonged coverage of the biological site for up to 30 days while simultaneously delivering sustained or controlled release of the pharmaceutical agent.Docket No. 89380.0007\WO46. A method of preventing or treating microbial infection of soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical or organ exposure in a subject in need thereof comprising administering topically and concurrently to the site:(a) a preparation of sterile, dry biocompatible, adsorbent composite particles; and(b) a sterile isotonic solution comprising at least one antimicrobial agent; whereupon the application of (a) and (b), the preparation adsorbs the solution and transforms to a matrix comprising the at least one antimicrobial agent that conforms to the three- dimensional shape of the site, and thereafter further transforms to a shape-retentive device comprising the at least one antimicrobial agent, wherein a single administration of (a) and (b) provides a device that prevents or treats microbial infection for at least 3 days, at least 7 days, or at least 14 days.

47. A method of treating soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical or organ exposures in a subject in need thereof comprising administering topically and concurrently to the soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical or organ exposures:(a) a preparation of sterile, dry biocompatible, adsorbent composite particles; and(b) a sterile isotonic solution comprising at least one pharmaceutical agent; whereupon the application of (a) and (b), the preparation of (a) adsorbs the solution and transforms to a matrix comprising the at least one pharmaceutical agent that conforms to the three-dimensional shape of the application site, and thereafter further transforms to a shape- retentive device comprising the at least one pharmaceutical agent, wherein a single administration of (a) and (b) provides a device that provides treatment of the wound for at least 3 days, at least 7 days, or at least 14 days, and wherein said treatment comprises at least one of treating or preventing inflammation, treating or preventing infection, treating or preventing bleeding, treating or preventive bioburden, or treating or preventing pain.

48. A medicinal combination for use in the treatment or prevention of soft and hard tissue injuries, bone and joint defects, tendon and ligament repair, and surgical or organ exposures comprising:(a) a preparation of sterile, dry biocompatible, adsorbent composite particles; and(b) a sterile isotonic solution comprising at least one antimicrobial agent; whereupon the application of (a) and (b), the preparation adsorbs the solution and transforms to a matrix comprising the at least one antimicrobial agent that conforms to the three- dimensional shape of the would or injury, and thereafter further transforms to a shape-retentive device comprising the at least one antimicrobial agent,Docket No. 89380.0007\WG wherein a single administration of (a) and (b) provides a device that prevents or treats microbial infection for at least 3 days, at least 7 days, or at least 14 days.

49. The method of claim 46 or 47, or the medicinal combination of claim 48, wherein the preparation of sterile, dry biocompatible, adsorbent composite particles comprises a mixture of lyophilized poly-2-hydroxyethyl-methacrylate (pHEMA) and poly-2-hydroxypropyl- methacrylate (pHPMA) particles combined in a ratio of 85: 15.

50. A modular kit comprising: (a) a sterile unit dose of shape-transforming adsorbent composite polymer particles; (b) a vial containing a dry or lyophilized pharmaceutical agent; and (c) a vial containing a sterile biocompatible liquid carrier suitable for dissolution of the dry or lyophilized pharmaceutical agent to prepare a liquid component comprising the pharmaceutical agent, wherein the powder and liquid components are configured to be applied sequentially or simultaneously at the point-of-care to form a conforming, shape-retentive device that provides localized sustained release of the pharmaceutical agent and extended efficacy of the pharmaceutical agent at the site or application.

51. The kit of claim 50, wherein the pharmaceutical agent is selected from antimicrobial, antifungal, antiviral, anti-inflammatory, analgesic, hemostatic, regenerative biologic, enzyme, antioxidant, or combinations thereof.

52. The kit of claim 50, wherein the powder and liquid components are configured for sequential administration to provide staged release of therapeutic agents.

53. The kit of claim 50, wherein the powder and liquid components are configured for simultaneous administration to provide concurrent delivery of therapeutic agents.

54. The medical device of claim 30, wherein the enzyme is peroxidase, such as horseradish peroxidase.

55. A medical device prepared in situ at the time of application comprising a sterile, dry composition comprising (a) biocompatible, adsorbent composite particles, and (b) at least one pharmaceutical agent; whereby upon application of the dry composition to a tissue comprising physiological fluids, such as a wound, injury, or surgical site, optionally with application of isotonic solution, and (i) the physiological fluid and optional isotonic solution hydrates the composition, causing the adsorbent composite particles to aggregate, (ii) the hydrated adsorbent composite particles form a matrix that entraps or occludes at least a portion of the pharmaceutical agent, (iii) the matrix conforms to the shape of the biological site,(iv) optionally, the matrix adsorbs bodily fluid, (v) the matrix transforms to a three-dimensional, shape-retentive, moist, flexible, oxygen-permeable device, (vi) the device is substantially non- bioerodible, (vii) the device may be left in place for at least 30 days, (viii) the device provides sustained release of the pharmaceutical agent at least 2 hours, at least 4 hour, at least 18 hours, atDocket No. 89380.0007\WG least 24 hours, at least 36 hours, at least 48 hours, at least 72 hours, or at least 92 hours, (ix) the device provides sustained release of the pharmaceutical agent at least Iday, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at leat 11 days, at least 12 days, at least 13 days, or at least 14 days; and / or (x) the device extends efficacy of the pharmaceutical agent for at least 3 days, at least 7 days, or 14 days.

56. The medical device of claim 55, wherein the pharmaceutical agent is selected from antimicrobial agents, hemostatic agents, anti-biofilm agents, regenerative biologies, antioxidants, anti-inflammatory agents, pain-management agents, or enzymes.

57. The composition of any one of claims 1 to 3, wherein a first pharmaceutical agent is incorporated into the powder and a second pharmaceutical agent is incorporated into a liquid carrier, the powder and liquid thereby forming a combination product providing multimodal therapy.

58. The composition of claim 1, wherein at least two different powders each comprising distinct pharmaceutical agents are sequentially or simultaneously applied and hydrated to form a stacked or layered composite device with staged release.

59. The composition of claim 1, wherein the particles are provided as a lyophilized solid cake, slab, or sheet prior to sieving, the solid form being rehydratable to yield a conforming, shape-retentive device.

60. The composition of claim 59, wherein the solid cake or slab further comprises one or more pharmaceutical agents incorporated during lyophilization.

61. The composition of claim 59 or claim 60, wherein the solid cake or slab is hydrated with a pharmaceutical liquid to load additional therapeutic agents immediately prior to use.

62. The composition of claim 1 or claim 59, further comprising a backing layer, scaffold, or porous substrate, wherein the backing provides mechanical stability, handling properties, and application versatility across anatomical sites.

63. The kit of claim 20, wherein at least two powders each containing different pharmaceutical agents are provided for layered or stacked application.

64. The kit of claim 20, further comprising a solid lyophilized cake or slab as an alternative dosage form.

65. The kit of claim 20 or 64, wherein the particles or cakes are supplied with a backing layer or scaffold for anatomical fixation, surgical application, or site protection.

66. The method of claim 25, wherein a first pharmaceutical agent is delivered via the powder and a second pharmaceutical agent is delivered via the liquid carrier.Docket No. 89380.0007\WO67. The method of claim 25, wherein sequential administration of powder-liquid- powder or other layered combinations provides staged or prolonged release.

68. The method of claim 25, wherein the particles are applied as a lyophilized solid cake or slab that is hydrated in situ with a liquid containing at least one pharmaceutical agent.

69. The method of claim 25, wherein the composition is supported on a backing layer, scaffold, or porous substrate to enhance fixation, stability, or application at a surgical or organ site.

70. The composition of claim 1, wherein the pharmaceutical agent is doxycycline, gentamycin, or minocycline.

71. The method of claim 1, wherein the pharmaceutical agent is collagen ot chitosan.

72. The method of claim 1, wherein the pharmaceutical agent is VEGF, EGF, or PDGF.

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