Shape-transforming devices and composites for biological site stabilization and therapeutic delivery

Abstract

The embodiments herein provide for shape-transforming devices comprising planar materials or gel materials capable of transitioning from a shape-conforming state to a shape-retentive state. These devices are biocompatible and can be placed onto or into a subject in need thereof. These devices can also provide for combination with and / or sustained, in situ release of pharmaceutical agents.

Description

Docket No. 89380.0006\WOSHAPE-TRANSFORMING DEVICES AND COMPOSITES FOR BIOLOGICAL SITE STABILIZATION AND THERAPEUTIC DELIVERYGOVERNMENT FUNDING

[0001] This invention was made with government support under Contracts No. W81XWH21P0019 and No. W18WXH22C0045, 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, and formulations comprising shape-transforming adsorbent particle composites and methods for making and using same, and the use of these embodiments for the treatment of tissue and structural repair or protection.BACKGROUND

[0004] An open wound is an injury involving an external or internal break in body tissue, usually involving the skin. There remains a need for improved technologies to provide protection or therapy for tissues in need thereof, such as wounds and penetrating wounds as well as soft and hard tissue injuries, bone and joint defects, tendon and ligament repairs, and surgical exposure.SUMMARY

[0005] The present embodiments provide medical devices, compositions, formulations, and methods for making and using these. More specifically, the present embodiments provide for devices comprising shape-transforming materials, specifically adsorbent composite particles or solutions comprising such particles, prepared as shape-conforming sheets or gels that, upon contact with a physiological medium or other medium of similar ionic strength, such as the tissue of a wound bed, conform to the three-dimensional shape of the wound bed, tissue defects, or surgical exposure sites and thereafter transform to shape-retentive materials that fill the application site and cover the injury or exposed area, and thereafter transform to shape-retentive materials that fill the application site and cover the injury or exposed area.Docket No. 89380.0006\WG

[0006] Although many embodiments and examples described herein relate to wounds and wound management, such references are provided by way of illustration and not limitation. The compositions, devices, kits, and methods disclosed are equally applicable to broader biological sites requiring protection, stabilization, hemostasis, or localized delivery of pharmaceutical agents. Such sites include, without limitation, soft tissue defects, hard tissue defects, bone or joint defects, tendon or ligament repairs, surgical exposures, organ surfaces, and other anatomical sites where coverage, moisture balance, or sustained release of a therapeutic agent is beneficial. Accordingly, the present disclosure should not be construed as limited to wound applications.

[0007] In one aspect, the shape-transforming device is a planar material (e.g., a sheet or film) capable of transforming from a shape-conforming state to a shape-retentive state. In another aspect, the shape-transforming device is a gel material capable of transforming from a shape-conforming state to a shape-retentive state. These materials are capable of providing a healing matrix at and within the application site. In at least one embodiment, the shapetransforming sheet or gel materials described herein fill the wound bed and provide a temporary skin, incrustation (scab), or graft.

[0008] In an aspect of the embodiments, the sheet or gel materials comprise at least one pharmaceutical agent, such as a therapeutic agent, such as a hemostatic agent or antibiotic, or both. In at least one embodiment, the shape-transforming sheet or gel materials provide a drug delivery device for the sustained release of a pharmaceutical agent, such as a therapeutic agent. In at least one embodiment, the shape-transforming sheet or gel materials provide a drug delivery device for the sustained release of at least two pharmaceutical agents. In a further aspect, the shape-transforming devices of the present embodiments may be combined to provide layered wound dressings, temporary skins or scabs, or therapeutic agent-delivering systems.

[0009] One aspect of the present embodiments provides a medical device comprising a shape-transforming material prepared as a planar form (e.g., a flat sheet, film, or pad) of pliable, shape-conforming material that upon contact with a physiological medium or other medium of similar ionic strength transforms to a shape-retentive material / device. In at least one embodiment, the shape-conforming planar material is lyophilized material prepared from a solution comprising 51% to 99.9% weight / weight of a solution of adsorbent composite polymeric particles of alpha hydroxy methacrylated polymers, such as 50% to 70% polymer particles, and about 0.1% to about 49% excipients such as a mixture of water or other polar liquid and glycerin, poloxamer, or both glycerin and poloxamer. In at least one embodiment, the polymer particles of the sheet material are prepared from a suspension of poly-2-hydroxy ethylmethacrylate (pHEMA) particles and poly-2-hydroxypropylmethacrylate (pHPMA) particles, forDocket No. 89380.0006\WO example at a ratio of pHEMA:pHPMA of about 80:20 to about 90: 10, inclusive and including ratios therebetween, such as about 85: 15. In at least one example, the dry planar material comprises, by weight, about 63% pHEMA:pHPMA of 85: 15 ratio, about 32% pol oxamer, and about 5% glycerin. In at least one embodiment, the planar device is provided as a dry material.

[0010] Another aspect of the present embodiments provides a medical device comprising a shape-transforming material prepared as a 3 -dimensional form (e.g., a cylinder, cone, sphere, bowl or shape composed of complex elements of 3 -dimensional shapes) of pliable shapeconforming material, that upon contact with a physiological medium or other medium of similar ionic strength transforms to a shape retentive material / device. In at least one embodiment, the shape conforming 3 -dimensional forms are lyophilized material prepared from a solution comprising 51% to 99.9 % w / w of a solution of adsorbent composite polymeric particles of alpha hydroxy methacrylated polymers such as 50% to 70% polymer particles, and about 0.1% to about 49% excipients such as sodium dodecyl sulfate or sodium deoxycholate. In at least one embodiment, the polymer particles of the 3 -dimensional shapes are prepared form a suspension of poly-2-hydroxyethyl-methacrylate (pHEMA) particles and poly-2-hydroxypropyl- methacrylate (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 about 85: 15.

[0011] Another aspect of the present embodiments provides a medical device consisting of a transforming material prepared as a planar form that is then compressed or molded under pressure into a shape with different dimensions from the initial material. In at least one embodiment, a planar sheet, film, or pad composed of polymeric particles is compressed under weight to form a planar sheet with a decreased thickness. In at least one example, the dry planar material is compressed between two metal plates decreasing thickness by greater than 50%. After compression, the material after compression still behaved as a shape conforming sheet, and in at least some embodiments the compressed material exhibited increased resistance to tearing and failure during deformation.

[0012] Another aspect of the present embodiments provides a medical device comprising a shape-transforming material prepared as a free-flowing shape-conforming gel material that upon contact with a physiological medium or other medium of similar ionic strength transforms to a shape-retentive material. In at least one embodiment, the gel material comprises 1% to 40% weight / weight of a plurality of lyophilized polymeric particles of alpha hydroxy methacrylated polymers, such as about 10% to about 15% polymer particles, and about 50% to about 99% water, and optionally about 1% to about 50% excipient. In one embodiment, the excipient is a polyacrylic acid polymer such as Carbopol® polymer excipient. In one embodiment, the excipient is silica. In some embodiments, the gel material comprises 5% to 80% weight / weightDocket No. 89380.0006\WO of a plurality of lyophilized polymeric particles, such as about 10% to about 15% polymer particles, and about 20% to about 95% alcohol or other polar liquid, such as about 97% alcohol or other polar liquid. Optionally, a gel formulation may include a strengthening agent such as fuming silica or Carbopol to provide a firmer shape-retentive state after transformation. In at least one embodiment, the polymer particles of the gel comprise adsorbent lyophilized composite particles of poly-2-hydroxyethyl-methacrylate (pHEMA) particles and poly-2- hydroxypropyl-methacrylate (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 about 85: 15.

[0013] Another aspect of the present embodiment provides a drug delivery device in which the materials (sheet / film or gel) described herein comprise, and then in use release, at least one pharmaceutical agent. This aspect provides a device for the sustained release of at least one therapeutic agent. In at least one embodiment, the gel or planar material comprises at least one therapeutic agent, such as a growth factor, debriding agent, anti-inflammatory agent, painmanagement agent, enzyme, antimicrobial agent, biofilm-inhibiting / dispersal agent, hemostatic agent or a combination of any of these. In one embodiment, the planar or gel material comprises both an antimicrobial agent and a hemostatic agent. In one embodiment, the gel or planar material comprises at least one of doxycycline hyclate, vancomycin, gentamicin, tobramycin, collagen, chitosan, polyhexamethylene biguanide, tranexamic acid, or silver sulfadiazine. In at least one embodiment, the pharmaceutical agent is included at a concentration range of about 0.01% by weight to about 10.0% by weight.

[0014] Another aspect of the present embodiments provides a layered device system comprising two different shape-transforming materials for sequential placement in or on a tissue in need thereof. At least one embodiment provides different shape-transforming materials used in combination, optionally wherein at least one of the materials includes a therapeutic agent. In one embodiment, a shape-transforming gel material as described herein is contacted with tissue, and thereafter a shape-transforming sheet as disclosed herein is disposed over all or part of the tissue treated with the gel material, forming a device of shape-retentive layers. In another example embodiment, a hydrogel particle powder may be contacted with tissue (such as a wound or bum), and thereafter a sheet as disclosed herein is placed over all or part of the tissue treated with the particle powder, forming a device of shape-retentive layers. One or more layers of the device may comprise at least one therapeutic agent or a combination of therapeutic agents that is / are released / diffuses to the contacted tissue. As just one example, the layer in direct contact with tissue may comprise a hemostatic agent and the layer exterior to that may comprise an antibiotic that diffuses to the tissue.Docket No. 89380.0006\WO

[0015] In another aspect of the present embodiments, the sheet or gel shape-transforming forms comprising adsorbent composite particles described herein may provide hemostatic properties, antimicrobial properties, debriding properties, anti-biofilm properties, or provide an environment that decreases the inflammatory response by signaling a proliferative rather than an inflammatory response.

[0016] In at least one embodiment, the pharmaceutical agent is at least one of ciprofloxacin, tobramycin, minocycline, doxycycline, ceftriaxone, trovafloxacin, tranexamic acid, corticosteroids, dexamethasone, betamethasone, methylprednisone, unfractionated heparin, low molecular weight heparin, a Vitamin K antagonist such as warfarin, a direct thrombin inhibitor, andexanet alfa, or ciparantag.

[0017] The gel and sheet shape-transforming forms of the present embodiments are easy to use at the point of injury, 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 planar sheet or film may be applied to surfaces or voids where a significant volume is required or where wound application needs overlap with the surrounding skin surface, where thereafter it attains a shape-retentive state; or because of the pliability of the shape-conforming sheet, it can be rolled into a tight cylinder shape and inserted into a void or tunnel, whereafter it attains a shape-retentive state. As another example, a shapeconforming gel form may be spread over a wound surface or injected into a wound void or tunnel, whereafter it transforms to a shape-conforming state.

[0018] Another aspect of the present embodiments provides methods of providing therapy, such as wound treatment, to a subject in need thereof. For example, a planar sheet or film of the present embodiments, while in the shape-conforming state, is applied to a tissue, such as a burn or abrasion wound, or rolled or folded into a shape insertable into a puncture or tunneling wound, wherein the shape-conforming sheet or film conforms to the shape of the tissue and then transforms to a shape-retentive state to provide therapy to the tissue. In a further embodiment, the shape-retaining film is removed from the tissue. As another example, a gel material while in shape-conforming state can be injected through a small opening, such as that of a 2 mm syringe, onto or into a puncture, avulsion, tunneling, or similar wound, and thereafter the gel transforms to a shape-retaining state to provide therapy to the wound. In a further embodiment, the shape-retaining gel is subsequently removed from the wound.

[0019] 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 structureDocket No. 89380.0006\WO hydrates and aggregates to form a conforming, shape-retentive matrix that provides extended coverage and localized delivery of one or more pharmaceutical agents.

[0020] 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.

[0021] These embodiments allow for dual modes of delivery: (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 and / or controlled release of pharmaceutical agents, and customizable combinations of therapeutic modalities.

[0022] Another aspect of the present embodiments provides methods of making the shape-conforming planar forms or gels as described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. l is a graph showing the sustained release of vancomycin from embodiments of shape-retentive gel and planar (sheet) materials compared with powder formulations, as a percent of vancomycin in formulation released over time. Shape-conforming materials were immersed into the simulated wound fluid composed of phosphate buffered saline at pH= 7.4 and 110 mmol / L Na+ions and allowed to transform to shape-retentive state and release drug. Aliquots of the saline were taken and analyzed for free drug molecules. Y-axis % vancomycin released; X-axis time; • powder; ■ sheet comprising Pluronic; + sheet comprising poloxamer; x gel comprising Carbopol; * gel comprising silica; gray symbols: drug at low (0.05%) concentration; black symbols: drug at high (0.1%) concentration.

[0024] FIG. 2 is a graph showing the sustained release of doxycycline from embodiments of shape-retentive gel, planar (sheet), and powder formulations, as a percent of doxycycline in formulation released over time, tested as outlined for FIG. 1. Y-axis % vancomycin released; X-axis time; • powder; ■ sheet comprising Pluronic; + sheet comprisingDocket No. 89380.0006\WO poloxamer; x gel comprising Carbopol; * gel comprising silica; gray symbols: drug at low (0.05%) concentration; black symbols: drug at high (0.1%) concentration.

[0025] FIG. 3 is a graph showing the sustained release of gentamycin from embodiments of shape-retentive gel and planar (sheet) materials compared with powder formulations, as a percent of gentamycin in formulation released over time, tested as outlined for FIG. 1. Y-axis % vancomycin released; X-axis time; • powder; ■ sheet comprising Pluronic; + sheet comprising poloxamer; x gel comprising Carbopol; * gel comprising silica; gray symbols: drug at low (0.05%) concentration; black symbols: drug at high (0.1%) concentration.

[0026] FIG. 4 is a bar graph comparing antimicrobial activity (zones of inhibition) of embodiments of antibiotic-loaded shape-retentive planar (sheet) materials compared with powder formulations measured at 24, 48, and 72 hours.

[0027] FIG. 5 is a schematic showing an embodiment comprising three layers of shape- retentive material placed on a wound. J, = direction of diffusion of agent(s) from material to wound.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.

[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 inclusively rather than exclusively, so that a stated integer or group of integers may include one or moreDocket No. 89380.0006\WO 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. 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. The shape-conforming material may start as a flat plane, for example a sheet of material, and when pressed into a concave shape such as a bowl, a shape-conforming material will assume the shape of the bowl. In applications in wound healing, the material will conform to a wound surface or shape. In at least one embodiment, the shape-conforming material provided herein as a planar sheet, film, or pad is sufficiently pliable to be rolled or folded into a structure that can be inserted into an opening, whereafter it transforms to a shaperetaining state within that opening.

[0034] As used herein, the term “shape-retentive” means that a material retains a shape as a fixed material and will not conform to a container. For example, if a shape-retentive material is shaped as a cylinder or sphere, the material and will retain the shape of the cylinder or sphere regardless of its surrounding environment. A shape-retentive material may deform under pressure but if the pressure is released, a shape retentive material will return to the original shape. An example would be a shape-retentive foam ball that has the shape of a sphere that can be deformed by pressure to temporarily assume a shape of a disc, but when the pressure is removed the shape conforming ball will return to the original sphere 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. An example would be a planar sheet that is shape conforming: The plane-shaped material can be pressed into a surface that is concave or any other shape that acts as a mold. After a transformation, the material is shape-retentive and retains the shape of the mold. In wound care, the example would be a wound dressing with the shape of a sheet, whenDocket No. 89380.0006\WO the shape-conforming sheet is pressed into a wound of an irregular, undefined shape, the material conforms to the shape of the 3 dimensional wound bed, filling the wound bed, and then transforms to a shape-retentive material that retains the shape of the wound bed.

[0036] As used herein, the term “gel” refers to a three-dimensional structure comprising adsorbent composite particles prepared as a shape-conforming gel that, after contact with a physiological surface, transitions to a shape-retentive state.

[0037] As used herein, a “suspension” refers to a uniformly distributed, stable dispersion of solid particles in a liquid in which the solid is not soluble. By “stable” is meant that solids remain uniformly dispersed for at least 24 hours, unless subjected to disrupting external forces such as, centrifugation or filtration.

[0038] The term “polar liquid,” as used herein has the meaning generally understood by those skilled in the chemical art. In brief, a polar liquid is one in which the electrons are unevenly distributed among the atoms of its molecules and therefore create an electrical dipole. To be polar a molecule must contain at least one atom that is more electronegative than other atoms in the molecule. Examples of polar liquids include, without limitation, water, where the oxygen atom bears a partial negative charge and the hydrogen atoms a partial positive charge, and alcohols, wherein the O-H moiety is similarly polarized. Typically, in the medical arts, water and ethanol are polar liquids that may be used as solvents herein.

[0039] 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 animals 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.

[0040] 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.

[0041] As used herein, the term “plurality” refers to more than one, i.e., two or more.

[0042] As used herein the term “dry weight” means the weight of particles without the weight of any polar liquid(s).

[0043] 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, hemostatic agents, chemotherapeutics (in particular platinum compounds andDocket No. 89380.0006\WO taxane and its derivatives), analgesics, antidepressants, antibiotics, antimicrobials, antifungals, antivirals, 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, polypeptdes, DNA, RNA, ribozymes enzymes, growth factors (e.g., PDGF, EGF, VEGF), 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.

[0044] “Therapy” refers to treatment intended to relieve or heal a disorder in a subject.

[0045] 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.

[0046] 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.

[0047] As used herein, a “charged” gel 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 (-NH3 ) ion.

[0048] 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 sugarsDocket No. 89380.0006\WO(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).

[0049] 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.

[0050] 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. Regarding the embodiments provided herein, substances may be absorbed by and retained in, i.e., occluded by, gels and sheet of the present embodiments during their preparation.

[0051] 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 gel or planar materials of the present embodiments.

[0052] 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.

[0053] A “pharmaceutical composition” is intended to include the combination of an active pharmaceutical agent with an excipient, such as a gel or planar material as described herein, in which the pharmaceutical composition suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.

[0054] 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.

[0055] The shape-transforming sheet and gel 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 stabilized as sheet or gel formulations. These sheet and gels have numerous applications, one of which is wound healing.Docket No. 89380.0006\WOIn the context of wound healing the gel or sheet is shape-conforming until contacted with wound fluid at physiological pH and ionic strength, and thereafter transforms to become shape- retentive. The resulting shape-retentive material is non-resorbable and contains adsorbed water. Optionally, the sheet or gel materials may contain at least one active therapeutic agent that is released (e.g., diffuses from the sheet or gel material) from the material over time. In the context of a wound dressing, the therapeutic agent is passively delivered from the sheet or gel into the wound surface and, for example, affects changes to the wound healing rate or minimizes the level of bacterial contamination.

[0056] Typical moist wound healing devices are currently composed of highly adsorbent dehydrated materials such as hydrocolloids, hydrocellulose, hydrogels, or alginates that are supplied in the form of gels, or woven or pre-formed pads or sheets. When these types of materials are placed on the wound, the wound fluids, including blood and exudate, hydrate these dehydrated materials. Consequently, as they adsorb a high volume of water (often in excess of 100% of their original mass) upon hydration, the materials become soft and gelatinous and help retain moisture at the wound surface. Features of these types of common, current materials include high fluid absorption and retention, but these materials may not be resistant to shear, and may lack suitable adherence or non-adherence properties. Their low moisture-vapor transpiration rates also limit the release of excess moisture, creating a potential risk of wound maceration. Moreover, although they may conform to a shape, they do not retain their shape, making it cumbersome to remove them from wound surfaces.

[0057] In contrast, the shape transforming materials presented herein, which change from a shape-conforming state to a shape-retentive state, are substantially different in composition from conventional sheet, gel, or woven pad materials. In particular, when a shapetransforming gel or sheet of the present embodiments is placed in contact with a wound surface or is placed in a wound cavity, it assumes the shape of the wound bed, cavity, or tunnel. As the material of the present embodiments hydrates with physiological fluids, it aggregates irreversibly, forming a shape-retentive material that maintains the original wound dimensions and volume that, if left in place, will eventually shrink and flake over time (e.g., as a wound heals). Advantageously, as a wound heals, the material may be gradually forced out of the wound bed; or the material may be pulled intact out of a tunnel or cavity when the wound is sufficiently healed, stable, or in the case where further intervention is needed at the site of injury. As such, the present embodiments provide a temporary barrier / covering, incrustation, skin, or graft. In some aspects, the present embodiments provide a device that mimics a hardened exudate but provides additional therapeutic benefit.Docket No. 89380.0006\WO

[0058] As noted, other conventional materials exhibit high water uptake and pure shape conforming properties with very low strength-to-water-ab sorption properties. In addition, these materials, especially hydrocolloids, do not permit sufficient moisture vapor transpiration. By contrast, the materials described herein that transform from shape conforming to shape retentive have lower water absorption properties, typically becoming 50-70% water by mass (a level closer to skin moisture content) at full absorption, but are much stronger after the full absorption and shape retention transformation. In addition, when the shape retentive materials provided herein are in a wound where one surface is against the moist, exudative wound bed and the other surface in contact with air, the shape transforming materials (gels or sheets described herein) have high moisture vapor transpiration rates that pull excess moisture through pores within the materials and drive it off as a vapor. This high transpiration rate results in several physical properties including maintaining moisture without saturating the wound bed with wound fluid, decreasing temperature as the water vapor is driven off and producing a slight negative pressure between the aggregate material and the wound surface which helps in the adhesion and has also been shown to facilitate wound healing. As noted above, these properties allow the present gels and planar forms to provide a temporary cover / barrier, skin or graft device.

[0059] These properties of the embodiments provided herein are relevant differentiators between a conventional moisture-retaining material (whether in a hydrogel, foam, or gauze dressing) and a shape-transforming material that can transform from a flexible shapeconforming sheet or gel to a shape-retentive aggregate.

[0060] Furthermore, the gel and sheet materials described herein exhibit characteristics distinct from those of current transforming powder preparations. For example, current powder preparations do not include water, glycerin, or poloxamers as do the present sheets or gels; and are provided as powder flakes instead of the present wet, aqueous gels or dry flexible planar materials. In use, the current powder can be used to “dust” a surface, and care may be taken to apply the powder evenly over a sometimes irregular surface to ensure coverage; whereas the gels provided herein can be, for example, injected directly into a void or tunnel and then allowed to transform and form an aggregate within that void or tunnel; and the sheets provided herein can be pressed to a surface, or rolled-up, folded or otherwise formed as a plug that can be inserted into a void or tunnel and then allowed to transform within that void or tunnel. Regarding the rate of hydration, the current powder has a nearly instantaneous hydration rate with immediate uptake of fluid; whereas the present gel exhibits very slow hydration as the material is initially fully hydrated and high ionic strength wound fluid must exchange with lower ionic strength gel which indues aggregation slower; and the sheet exhibits initial near instantaneous with rapid uptake of fluid followed by slow diffusion of excipients while aggregation occurs.Docket No. 89380.0006\WO

[0061] 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, whereas the gels provided herein undergo a 30 minute to 56 hour transformation from shape-conforming to shape-retentive material, and the sheets provided herein undergo 5 minute to 2 hour transformation from shape conforming material to shape retentive material. Regarding the transformation process, in current powders, the “solvent front” of fluid from the wound surface 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 contrast, the present gel is initially fully hydrated with at least about 51% water (e.g., about 50% to about 99% water) and the gel does not rapidly adsorb fluid because it is fully hydrated: the gel material begins to exchange the high ionic strength fluid of the wound with the low ionic strength of the gel, and because this diffusion is electronic (due to potential differences between the materials), the rate of ion transport is faster than that of simple diffusion, but because the material is not adsorbing water, the rate of aggregation is orders of magnitude slower than the powder (or the sheet), and thus the gel aggregates at the interface of the gel surface and the higher ionic strength fluid and as a result the gel aggregates from the exterior to the center rather than in a “wave” as exhibited when adsorbing liquid rapidly flows through the material in a sheet or powder. The present sheet adsorbs water and some of the particles begin to aggregate, but energy of the adsorption is also used to dissolve the excipient (glycerin or poloxamer) resulting in a slower aggregation that is slightly more porous than the powder.

[0062] Regarding delivery to the wound, a current commercial powder (e.g., Altrazeal® transforming polymer-based powder) is typically sprinkled from a package onto a wound surface. In contrast, the gel comprising fully hydrated adsorbent composite particles as provided herein can be spread over a wound surface or syringed into a void or tunnel wound, and the sheet preparation as provided herein can be laid directly on a wound surface. Accordingly, although the current powders provide advantageous application on open, irregular surface wounds without significant cavities or tunnels, the present gels are advantageous for wounds with cavities or tunnels, and the present sheets are suitable for flat surfaces or voids, where a significant volume is required, where application that overlaps the surrounding skin surface is necessary, or for applying to vertical wounds where a relatively horizontal surface is not presented. It should be noted that both the gel and sheet embodiments would be more stable in settings with high winds relative to a powder that may be blown away.

[0063] In one embodiment, the planar device (horizontal sheet, pad, film, flat foam) has the appearance of a thin, soft foam material with thickness that can be varied in manufactureDocket No. 89380.0006\WO depending on the desired final application. The sheet can be pre-formed into a practical size or shape, or cut into any shape either during manufacturing or shortly before or upon application to a wound. The shape-conforming sheet material is pliable and can be rolled, stretched, or otherwise manipulated as needed. In at least one embodiment, the shape-transforming planar material has a thickness of about 0.25 cm to about 1.0 cm, inclusive, such as 0.25 cm, 0.5 cm, 1.0 cm, or thicknesses therebetween. When the sheet contacts solutions such as blood, serum, wound fluid, or saline, which have physiological ranges of pH and ionic strength, the polymer particles dispersed into the shape-conforming sheet then aggregate to form a shape-retentive material. The shape-retentive material is hydrated, non-resorbable, and will not revert to a shapeconforming material. The material properties of both the shape-conforming sheet and the resulting shape-retentive aggregate depend on the formulation of the polymer particles, the composition of the sheet (including strengthening agents and stabilizing molecules), but in general follow the transformation discussed herein. The material can further be augmented by adding one or more pharmaceutically active agents such as, but not restricted to, antimicrobial, hemostatic agent, debriding agent, anti-biofilm agent, wound-healing biological agent, a growth factor, anti-inflammatory agent, pain-management agent, enzyme, or other substance that, for example, enhances wound healing. Such material also provides a device for the sustained release or controlled release of at least one therapeutic or pharmaceutically active agent.

[0064] In one embodiment, the shape transforming device comprises a sheet composed of layers of sheet material. In this embodiment, the layers are formed by alternately freezing liquids containing the polymer particles, strengthening agents and viscosity enhancers and then adding layers of different compositions of liquids containing the polymer particles, strengthening agents and viscosity enhancers. These layers of liquids can be augmented by adding one or more pharmaceutically active agents as, but not restricted to, antimicrobial, hemostatic agent, debriding agent, anti-biofilm agent, wound-healing biological agent, a growth factor, anti-inflammatory agent, pain-management agent, enzyme, or other substance that, for example, enhances wound healing. Such material also provides a device for the sustained release or controlled release of at least one therapeutic or pharmaceutically active agent. The resulting frozen layers of polymer particles with viscosity enhancers and strengthening agents with pharmaceutical agents can be layered in such a way as to provide a set of profiles of drug delivery through the device after the frozen layers are dried under vacuum freeze drying.

[0065] In one embodiment, the shape transforming device comprises a sheet composed of one or more layers of sheet material with or without an active pharmaceutical agent. In this embodiment, the specific mold used to form the shape conforming sheet is designed in such a way as to provide ridges or contours to the shape conforming sheet after freeze drying.Docket No. 89380.0006\WD

[0066] In one embodiment, the shape-transforming device comprises a gel formulation that has the appearance of a gel with a viscosity above water that conforms to a shape or an orifice. The gel can be dispensed through a tube with an orifice, such as a syringe and can be injected into a narrow opening such as a tunneling wound or fistula or can be applied over a wound surface. When the gel contacts solutions such as blood, serum, or wound fluid and eschar, which have physiological ranges of pH and ionic strength, the polymer particles dispersed into the shape-conforming gel irreversibly aggregate to form a shape-retentive material. The material properties of the shape-retentive aggregate are dependent on the formulation of the polymer particles, the composition of the gel including viscosity enhancing components, strengthening components and other stabilizing molecules that are added to adjust either the properties of the shape-conforming gel or the final material properties of the shape- retentive aggregate. In addition, the shape-retentive gel can be used as a sustained release or controlled release system for therapeutic or pharmaceutically active agents.

[0067] Desirable properties for the shape-conforming gel state include viscosity for handling and injection capability, spreading for the capability of filling voids or tunnels and otherwise handling the material; changing the chemical properties to aid in the incorporation of active ingredients for controlled delivery.

[0068] Desirable properties for the shape-conforming sheet state include strength and pliability, ease of cutting and shaping, and the capability to roll or compress the material prior to placing it at its therapeutic location, such as onto or into a wound.

[0069] Desirable properties for the shape-retentive materials (sheet or gel) 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, controlled release rates that can be tuned for a given therapeutic index, and, optionally, ease in removing the material from the site of placement. Advantageously, the aggregated (shape- retentive) gel is firm enough so that a large volume of aggregated gel may be removed (i.e., pulled by tweezers or forceps) from a small orifice of a wound opening without breaking.

[0070] In at least one embodiment, the gels and sheets described herein are manufactured from lyophilized polymer particles of alpha hydroxy methacrylated polymers, such as particles having hydroxy-terminated methacrylate monomers, such as 2-hydroxy ethylmethacrylate (HEMA) and / or 2-hydroxypropylmethacrylate (HPMA), from which poly-2-hydroxyethyl-methacrylate (pHEMA) and poly-2-hydroxypropylmethacrylate (pHPMA) adsorbent composite particles are prepared and marketed as Altrazeal™ (Altrazeal Life Sciences Inc., Addison, Texas, USA). See, e.g., U.S. Patents No. 7,910,135, No. 7,811,605, No. 7,351,430. Such powders may be composed of ratios of poly-a-hydroxy olefinicDocket No. 89380.0006\WO 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 shape-conforming state to a shape-retentive state when the material contacts wound fluid or aqueous solutions of physiological pH and ionic strength. In at least one embodiment, the ultimate shape-retentive gels or sheets are biocompatible and not quickly biodegradable - thus retaining their shape after aggregation. 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 orvicinyl 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.

[0071] Thus, in one aspect provided herein are formulations for shape-transforming materials comprise, or consisting essentially of, or consist of from about 5% to about 99% adsorbent polymer particles; optionally from 0% to about 40% at least one stabilizer, optionally from 0% to about 40% of a viscosity enhancer, optionally from 0% to about 40% of a strengthening compound, each of which may affect the physical and chemical characteristics of the material, before or after transformation to a shape-retentive state; and optionally from 0% to about 10%, or more, therapeutic or pharmaceutically active agents.

[0072] Regarding shape-transforming planar materials (sheets or films), these forms must have sufficient strength, flexibility, and stability for commercial production (including, e.g., handling, packaging, shipping, storing) and practical use. The present embodiments reflect extensive effort, expense, and time in testing various formulations - especially selection of appropriate excipients - to provide the required features. Particular excipients suitable for inclusion in the shape-transforming sheet formulations are glycerin and poloxamers. In particular, poloxamers (such as Pluronic or other poloxamers) may act as stabilizers to prevent separation of the adsorbent composite particle materials so that the sheet maintains a uniform consistency and viscosity throughout, and maintains shape-conforming properties until contact with physiological fluid upon with aggregation and shape-transformation occurs.Docket No. 89380.0006\WO

[0073] Strengthening compounds or agents are selected for their effects on the resulting shape-retentive properties of the material after state transformation. In certain situations, such as tunneling wounds, puncture wounds, or bullet holes, it is desirable to form a “plug” of material composed of the shape-retentive material (that has transformed in situ from its shapeconforming state) that is strong enough to allow the material to be pulled out of the wound intact. This requirement means that the shape-retentive material must have a significant tensile strength and possibly a strong bulk modulus. These properties can be enhanced for the aggregate through the incorporation of strengthening agents such as polymers or silicate materials. Without being bound by theory, these strengthening agents, at the molecular level, can be considered like the addition of fibrous material or rebar to cement: as cement cures, the strengthening agents are trapped within the aggregate and give the resulting material increased strength that would not be possible with the base aggregate alone. Polymers such as methyl or ethyl cellulose, silicates such as fuming silica or hydroxylated silica, and carbon nanotubes may be added to the formulation of the shape-conforming gel and are trapped within the shape-conforming gel that then, in use, transforms to a shape-retentive gel. These strengthening materials change the tensile strength of the final shape retentive aggregate and allow the properties to be adjusted per application, e.g., performance in wound treatment.

[0074] As noted, active pharmaceutical agents or therapeutic molecules are selected from classes of molecules for their desired effects, for example on the wound healing pathway. For example, gel or sheet materials of the present embodiments can contain antimicrobials prepared by blending active agents with described polymer particles in solution during manufacture. In used, the active is then released at a sustained or rate, depending somewhat upon the physical properties of the bioactive compound used. Accordingly, antibiotics can be added to the gel and sheet formulations to provide an antibiotic-releasing shape-transforming device. There are a variety of broad-spectrum antibiotics that can be effective topical agents. Non-limiting examples include vancomycin, gentamicin sulfate, doxycycline hyclate, and analogs and derivatives thereof. As another example, the gels and sheets of the present embodiments may include an antiseptic or biofilm inhibiting / dispersal agent, such as polyhexamethylene biguanide (PHMB), analogs, or derivatives thereof. For example, a suspension of pHEMA:pHPMA polymer particles may be prepared and mixed with optional excipients (depending on the desired form) and the appropriate amount of antiseptic, to provide a gel or sheet material as described herein.

[0075] In at least one embodiment, the gel or sheet comprises a hemostatic agent. Examples of hemostatic agents that may be incorporated into the present embodiments includeDocket No. 89380.0006\WOTranexamic acid, 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 Int’l 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).

[0076] Collagen, and analogs and derivatives thereof, can also be included in the hydrogel gel or sheet 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).

[0077] 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 providing one drug to treat one indication and a second drug to treat a second indication it is possible to use the shapetransforming materials described herein to deliver both active agents for treatment of a clinical indication using a single device. The present embodiments provide for the incorporation of more than one active ingredient during device material formulation at preselected concentrations and then the delivery of those active agents to a site in need thereof (e.g., a wound) or to stack two different formulations (e.g., powder with hemostat covered with an antimicrobial sheet). See, e.g., FIG. 5. Indeed, the technology described herein has the potential for many drug combinations to treat different therapeutics indications that require more than one active agent for clinical improvement.

[0078] In at least one embodiment, the shape transforming device is composed of two or more layers of polymer materials that can be either or gel or sheet formulations. The example device can consist of layers that contain different active therapeutic agents. For example, a three layered device could be formed as shown in FIG. 5 where the device when applied to a wound contains an example therapeutic agent that is known to cause clotting. The composition of the device would allow the clotting agent to diffuse into the wound tissue. Subsequent diffusion could allow a second therapeutic such as anDocket No. 89380.0006\WO antibiotic to diffuse into the wound tissue by passing from the middle layer into the wound tissue. A third active agent could be in the top layer (shown as layer A in the diagram) which would diffuse following the clotting agent and antimicrobial and could be an active such as a matrix inducing therapeutic such as denatured collagen that stimulates wound healing. The structure of this layered device can be tuned with differences in the gel or sheet transforming materials and the thickness and choice of therapeutic agent to allow for tailored delivery rates for effective delivery of actives to the wound bed.

[0079] In at least one embodiment, the shape transforming device is composed of a formulation of gel or sheet that is adhered to a backing layer. The backing layer is selected from a field of materials that include woven and non-woven planar materials composed of natural or polymer materials suitable for contact with wound and surrounding epithelial tissue. The gel or sheet material is attached to the backing layer such that the entire device has a set of dimensions that can cover a wound and the backing layer overlaps the wound bed onto intact skin. The backing layer can include an adhesive that will adhere to intact skin. The backing layer is perforated or naturally porous to allow moisture vapor transpiration through the transformed gel or sheet and into the atmosphere.

[0080] In at least one embodiment the shape transforming gel is packaged in a device that allows for injection into a wound cavity. The device can be a syringe with a plunger that can be activated by a spring or by manual depression. The gel can be injected into a wound cavity where the transforming gel will solidify to form a shape retentive aggregate.

[0081] Formulations of various embodiments of shape-transforming gel materials may be comprised, consisting essentially of, or consisting of polymer particles, water or alcohol, viscosity enhancer-stabilizers, or strengthening agents in the following ranges as described in Table 1 :Docket No. 89380.0006\WO

[0082] Selection of the formulation of the gel material depends on the nature of the desired material’s properties: If a higher strength and higher viscosity gel is desired, the formulation may comprise a higher concentration of the strengthening agent balanced against the concentration of liquid and polymer particles. In one embodiment, the range of polymer particles is between 10% and 15% of solids in the formulation with a strengthening agent added to the gel in a range that allows the final aggregate, after application to the wound, to achieve the desired properties of tensile strength. In particular, a gel device may be formulated such that after aggregation at the wound site, the gel device can be removed with forceps as a cohesive unit.

[0083] Table 1 designates water or alcohol as example polar solvents for preparation of the gel material. In the present embodiments, the polar solvent suspends the polymer particles so that they form a gel, and also completely surrounds and infiltrate the polymer particles serving to both act as the liquid phase inside the polymer particles (which are crosslinked networks of polymer and this liquid phase will sit inside of the 3-dimensional network) and between the polymer particles (forming the suspension). Water is an example pharmaceutically acceptable polar solvent that works advantageously with hydroxyl-terminated methacrylate polymers of the present invention, which a methacrylate carbon-carbon backbone connected to an acetal group which terminates in an alcohol. Water repels the hydrophobic carbon-carbon backbone, preventing this polymer from becoming super adsorbent and acting like a gelatin or jelly; andDocket No. 89380.0006\WO the polymer’s hydroxyl group behaves as 2 / 3 of a water molecule, such that this terminus of each link in the polymer chain grabs ahold of several water molecules in hydrogen bonding.

[0084] Other polar solvents may be used as the solvent for the gel materials herein, but are limited practically by toxicity or regulatory concerns. Possible suitable solvents (that may be used in mixtures with water or each-other) include acetic acid or alcohols such as ethanol or propanol (such as iso-propanol); for example at 0.5% to 5% by mass. Atypical solvents that may be used in the gel materials herein may include polymer agents such as polyethylene glycol; for example, at 0.5% to 5% by mass.

[0085] Also provided herein is are shape-transforming planar formulations / devices (e.g., sheet, film, pad), comprising, consisting essentially of, or consisting of from about 10% to about 50% of particles in a disparate structure uniform within the sheet material, from about 1% to about 10% by weight of one or more stabilizers or viscosity enhancers that ensure the dried sheet remains flexible, and optionally from about 1% to about 10 % of one or more strengthening compounds that affect the physical and chemical characteristics of the sheet. The solvent used in formulating the sheet materials is generally a polar solvent that is removed by sublimination as described below. In addition to water and alcohols (e.g., ethanol), ammonia or acetic acid may be included. The Examples provided herein employ lyophilization to form the planar material. Exemplary formulations are provided in Table 2:Docket No. 89380.0006\WO

[0086] General polymer synthesis may be performed by dissolving monomer in 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. The following (Table 3) 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:Docket No. 89380.0006\WO

[0087] In the above polymer formulations (Table 3), a further extension of the formulation can be made by adding between about 0.5 and about 5% methacrylic acid monomer, inclusive, to each formulation prior to polymerization to impart a negative charge on the polymer particle in solutions with physiological pH. Each polymer particle can be purified by tangential flow filtration and characterized by, e.g., particle size or zeta potential.

[0088] In the preparation of planar devices provided herein, the polymer suspensions just described may be combined with poloxamer and glycerine to make the following solutions in water (Table 4):Docket No. 89380.0006\WO

[0089] When the polymer particle, poloxamer and glycerin suspensions are in solution, they can be frozen and freeze dried in any thicknesses such as from about 0.25 cm to about 1.0 cm, inclusive, such as about 0.25 cm, about 0.5 cm, or about 1 cm. The resulting sheets can be characterized by hydration and aggregation (i.e., upon contact with physiological fluids) and compared for relative strength before and after hydration. It is expected that the trend among water absorption will move in this direction for the polymer compositions where: Glycerol methacrylate > Hydroxyethyl methacrylate > Hydroxypropyl methacrylate > Hydroxybutyl methacrylate. Additionally, it is expected that the incorporation of methacrylic acid will increase the water absorption of the resulting materials when the materials are placed in physiological pH and ionic strength fluids.

[0090] 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 polymer particles. This results in a uniform distribution of two different kinds of polymer particles in a suspension, which results in the same distribution within a lyophilized shape-transforming sheet. The following (Table 5) mixtures of polymers combined with poloxamer and glycerin can be formulated and freeze dried with the resulting sheet characterized for strength, hydration and aggregation:Docket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WODocket No. 89380.0006\WO

[0091] The shape-transforming gel or planar (sheet) devices described herein may 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. Pharmaceutical agents can be incorporated directly into the gel and sheet embodiments during manufacture. Alternatively, pharmaceutical agents can be added to the sheet or gel at the time of application to the wound, such as by adding the agent in an isotopic, sterile solution such as an ophthalmic solution or intravenous (IV) solution. The latter sterile solutions may be advantageous and easy as there are a number of FDA-approved antibiotic preparations available that can be advantageously applied at the time of application of the gel or sheet, whereupon transformation of the shape-conforming gel or sheet to a shape-retentive state provides an antibiotic-loaded sustained release device for sustained release of the antibiotic and the site of the wound. Other pharmaceutical agents may be applied by similar means.

[0092] In at least one embodiment, the transformed hydrogel composition provides that after hydration and trapping of one or more pharmaceutical agents, the agent(s) is released from the shape-retentive device into tissue over time in a predetermined sustained release or controlled release profile. In at least one embodiment, the sheet or gel device provides sustained or controlled release properties of one or more pharmaceutical agents to optimize therapeuticDocket No. 89380.0006\WD effect in tissue and those controlled release properties are based on polymer composition of the gel or sheet material.

[0093] Accordingly, an aspect of the present embodiments provides for systems, formulations, compositions, devices, and methods for the stabilization or treatment of wounds. The sheet and gel materials may be formulated and applied to stabilize an injury, reduce the risk of infection by covering the wound and, optionally, release an antimicrobial therapeutic agent, reduce surface bleeding and optionally release a hemostatic agent, or reduce inflammation, e.g., by releasing an anti-inflammatory agent such as dexamethasone. Advantageously, this aspect allows medical providers to combine the sheet or gel embodiments with a variety of existing approved products that are in liquid form or can be solubilized (e.g., in saline) and applied to the gel or sheet at the point of service. Such products include, for example Vancomycin Hydrochloride for Injection USP, 1 g per vial, for intravenous use, sterile lyophilized powder (Slate Run Pharmaceuticals), Gentamicin Sulfate Ophthalmic Solution USP, 0.3% (Sterile) (Bausch & Lomb), Ciprofloxacin Ophthalmic Solution USP 0.3% as base, sterile, 5 mL (Leading Pharma), Tranexamic Acid, Injection, USP, 1000 mg / 10 mL (100 mg / mL) (Avet Pharma®), Dexamethasone Sodium Phosphate Ophthalmic Solution, USP, 0.1%, 5 mL (Bausch & Lomb), Tobramycin Ophthalmic Solution USP, 0.3%, 5 mL (Alembic), or Ciprofloxacin 0.3% and Dexamethasone 0.1% Otic Suspension, USP, sterile, 7.5 mL (Amneal®).

[0094] An object of this aspect provides a comprehensive kit that combines selective, safe, and well -accepted, cost-effective, FDA-approved and commercially / medically available agents with the various embodiments of shape-retentive gels and sheets described herein. When aggregation and shape-transformation occurs, covalent crosslinking of the methacrylate backbone occludes the active agents within the heterogeneous polymer network and ensure a sustained drug release. Production methods may be adapted to vary sequencing and timing of release of actives. Various active agent dose ranges can be selected based on FDA approved dosages available in the market that can be further cross-referenced versus clinical dosage information available for their use in wound treatment.

[0095] 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 (“cake”). 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 coverage and localized delivery of one or more pharmaceutical agents. For example, a suspension of polymer particles is formed of a mixture of pHEMA and pHPMA particles, which can be formed at different concentrations ranging from 1% to 10 % polymer in suspension byDocket No. 89380.0006\WO mass within an aqueous liquid. The liquid can be dispensed into a single layer and can be poured into multiple cells each with a single layer. The liquid is then frozen and the material is dried under vacuum supercritically. The resulting cake of polymer is a white or off white dry layer with a uniform density and a thickness ranging from 0.5 mm to 5 mm depending on the volume and depth of the liquid before freezing. The cake can be cut into shapes or dispensed from cells intact. This material can be sterilized and applied directly to a wound with exudate or saline to hydrate, aggregate and form an intact dressing.

[0096] A further embodiment is the layering of lyophilized cakes of polymer particles. A suspension of polymer particles can be formed of a mixture of pHEMA and pHPMA particles at a given concentration. This mixture (mixture 1) can be dispensed into a container to form a pool of liquid with a given depth. The liquid mixture can be frozen. A second suspension of polymer particles with a different concentration or different ratio of pHEMA and pHPMA particles (mixture 2) can be poured onto the frozen layer of mixture 1. This second layer can be frozen. Multiple layers can be formed in this manner with alternating freezing and adding another layer of liquid. The material can then be dried under vacuum supercritically. The resulting cake of polymer is white or off white and has different layers of polymer particles equal in depth to each layer at freezing. The stacked cake can be cut into shapes or dispensed from cells intact. The resulting material can be sterilized and applied directly to a wound with exudate or saline to hydrate, aggregate and form an intact dressing.

[0097] A further embodiment provides the incorporation of an active pharmaceutical agent into one or more layers of the lyocake. A suspension of polymer particles can be formed of a mixture of pHEMA and pHPMA particles at a given concentration with an active pharmaceutical dissolved or suspended in the mixture. This mixture can be dispensed into a container to form a pool of liquid with a given depth. The liquid mixture can be frozen. A second suspension of polymer particles with a different concentration or different ratio of pHEMA and pHPMA particles and a different active pharmaceutical agent dissolved in the mixture can be poured onto the frozen layer of mixture 1. This second layer can be frozen. Multiple layers can be formed in this manner with alternating freezing and adding another layer of liquid may or may not contain one or more actives. The material can then be dried under vacuum supercritically. The resulting cake of polymer has different layers of polymer particles equal in depth to each layer at freezing and each containing one or more active pharmaceutical agents within the structure. The stacked cake can be cut into shapes or dispensed from cells intact. The resulting material can be sterilized and applied directly to a wound with exudate or saline to hydrate, aggregate and form an intact dressing. The material can then be used toDocket No. 89380.0006\WO provide controlled release of active pharmaceutical agents at different rates and concentrations within a wound.

[0098] 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 requirement.

[0099] These embodiments allow for dual modes of delivery: (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 and / or controlled release of pharmaceutical agents, and customizable combinations of therapeutic modalities.EXAMPLESExample 1. Polymer particles for use in gels, sheets, and cakes

[0100] An example of particles suitable for use in manufacture of materials comprising adsorbent composite particles as described herein are particles commercially available as Altrazeal™ Transforming Powder Dressing (available from Altrazeal Life Sciences Inc., Addison, Texas, US). 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 are prepared separately by the following free radical polymerization process: pHEMA suspension is 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 is quenched using a specific process. pHPMA synthesis progresses similarly by replacing the HEMA monomer with HPMA monomer. After both polymer suspensions are prepared, the percentage of solid contents of both suspensions are measured and the total suspended solids are calculated for each providing a known range of solids in pHEMA and pHPMA suspensions. The solids are mixed toDocket No. 89380.0006\WG form a suspension with 85: 15 (w / w) ratio. The 85: 15 suspension is 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) is poured into trays and placed into a freeze drier system for lyophilization. Lyophilization results in a cake of the suspension particles which, after sifting, yields a fine powder of known size ranges.

[0101] 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.

[0102] The above polymer particles are collectively called “polymer particles,” hydrogel 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 of gel or planar (sheet) materials. 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. Preparation of shape-conforming gel.

[0103] A 500 mL beaker was charged with 9 g of 85: 15 (weight: weight) pHEMA:pHPMA polymer particles (see Example 1) and 90 mL of deionized water. The materials were mixed with a propeller mixer sized for the beaker until the mixture was translucent and uniform. The gel did not settle out and remained a uniform mixture that is capable of being injected into tunnels or spread over surfaces. This material maintained the ability to be shape-transforming, and if exposed to a high ionic strength environment (including physiological fluids and simulated physiological fluids), the material retained the capability to transform from a shape-conforming to shape-retentive state. The gel material was studied both by injection from various orifices of syringes including needles and open syringes between 0.1Docket No. 89380.0006\WG mm and 5 mm. The gel material was also spread onto surfaces with a finger or spatula over sponges soaked with phosphate buffered saline at physiological pH and ionic strength that mimic a wound environment. The resulting gel was stable for at least several months without change in physical properties and showed uniform viscosity, flow, and shape-transforming properties.

[0104] Surprisingly, gel formulations attempted using bulk sieved pHEMA powder (formed by polymerizing pHEMA monomer with UV light) and bulk crushed, sieved pHPMA (formed by polymerizing pHPMA monomer with UV light) were incapable of being mixed into water to form a gel, and instead the material remained a separated mixture of powdered bulk hydrogel particles and water.Example 3. Preparation of shape-transforming gel comprising silica

[0105] A 500 mL beaker was charged with 8.9 g of 85: 15 (weightweight) pHEMA:pHPMA polymer particles (see Example 1), 2.0 g of fumed silica (average particle size: 0.2-0.3 micron, obtained from Sigma- Aldrich), and 89.1 mL of deionized water. Fumed silica was added as a strengthening agent. The materials were mixed with a propeller mixer sized for the beaker until the mixture was a translucent and uniform gel. The gel did not settle out and remained a uniform mixture that is capable of being injected into tunnels or spread over surfaces. The resulting gel was stored for several months without change in physical properties and shows uniform viscosity, flow, and shape conforming properties as in Example 2.Example 4. Preparation of shape-transforming gel comprising crosslinked polyacrylic acid

[0106] A 500 mL beaker was charged with 9.9 g of 85: 15 (weightweight) pHEMA:pHPMA polymer particles (see Example 1), 44.6 g of Carbopol 980 polymer (crosslinked polyacrylic acid, dry powder, Sigma-Aldrich) and 44.6 mL of deionized water. The materials were mixed with a propeller mixer-sized for the beaker until forming a translucent and uniform gel. The gel did not settle out and remained a uniform mixture capable of being injected into tunnels or spread over surfaces. The resulting gel can be stored for months without change in physical properties, and shows uniform viscosity, flow, and shape-transforming properties as in Example 2.Example 5. Preparation of shape-transforming planar material

[0107] A 1000 mL beaker was charged with 1.8 g of Pol oxamer 237 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol), available from Sigma- Aldrich), 3.5 g of 85: 15 (weightweight) pHEMA:pHPMA polymer particles suspension,Docket No. 89380.0006\WG and 0.27 g of glycerin (available from Sigma- Aldrich). 1000 mL of deionized water was then added, and the contents mixed to form a uniform solution of polymer, poloxamer, and glycerin. The solution was decanted into 3.5-inch petri dishes filled to a depth of 1 cm. The petri dishes were then frozen at -20°C, then the frozen petri dishes placed in a VirTis Genesis Lyophilizer (SP Scientific) and the contents dried. It should be noted that those skilled in the art appreciate that lyophilization may be carried out in a variety of conditions under which low temperature to freeze aqueous material and vacuum pulled on the material to be dried. Temperature, pressure, and time may be optimized but generally do not affect the resulting material. The resulting material was white, flexible pad that had the shape of the circular dishes, a thickness that corresponded to the depth of the pour (in this Example ~1 cm) and resisted catastrophic failure with bending, stretching, and rolling. In at least some instances, pressing the film composition enhanced the ability of the material to resist catastrophic failure upon bending, stretching, and rolling. This material was stable for at least several months and maintained its shapeconforming state until contacted with physiological fluid, whereupon it transformed to a shape- retentive state.

[0108] A similar planar material was made in which the poloxamer was Pluronic® F-127 (Sigma-Aldrich). This poloxamer has a higher molecular weight (12,700 Daltons), and affects the size of the hydrophilic and hydrophobic domains of the resulting material.

[0109] Surprisingly, planar (sheet / pad) formulations attempted without the inclusion of a poloxamer resulted in a white cake of freeze dried material that when handled disintegrated into polymer flakes that could not be reformed into a pad or sheet formulation after that failure.Example 6. Hydration and aggregation rates of gel and sheet preparations

[0110] The gel and sheet formulations described herein transform from a shapeconforming to a shape-retentive state by aggregation of the polymer particles within each preparation. It is surprising that a stable gel or stable sheet formulation can be prepared and maintain the desired properties without aggregation. Primary testing of physical attributes of hydration and aggregation (transformation to a final shape-retentive state) was performed by adding an excess amount of phosphate buffered saline (PBS) (120 mmol / L chloride concentration, pH=7.4) to a mass (100 mg) of each material, then determining the total percent of PBS solution adsorbed at steady state when the mass no longer changed, as well as the total time taken to reach such steady state. By way of comparison, the gel and sheet materials were compared with loose powder of lyophilized particles as described in Example 1 (85: 15 pHEMA:pHPMA). Results are shown in Table 7:Docket No. 89380.0006\WG

[0111] Note that skin has a water content of between 60% and 70%, and both the sheet and gel devices achieve skin-like hydration despite their disparate formulations. The sheet material required a longer time to reach a steady state (i.e., no longer changing state) with maximum strength than did the powder comparator. The gel materials (due to their high level of original moisture content) initially experienced a loss in mass and eventually adsorbed PBS to the requisite levels, but did so much more slowly than the sheet material. Hydration rates remained consistent within each material type regardless of the type of active ingredient added thereto (see additional Examples).Example 7. Preparation and characteristics of antimicrobial gel and sheet materials

[0112] Gel formulations were prepared as in Examples 2 and 3, but with the addition of antimicrobials (doxycycline hyclate, gentamycin sulfate, or vancomycin at 0.05% wt or0.1% wt) into the liquid mixture to provide a homogenous gel. Sheet formulations were prepared as in Example 5, but with the addition of antimicrobials (doxycycline hyclate, gentamycin sulfate, or vancomycin at 0.05% wt or 0.1% wt) into the liquid mixture to provide a homogenous solution prior to freeze-drying. Physical attributes of 100 mg samples were characterized as in Example 6, and the results shown in Table 8.Docket No. 89380.0006\WOExample 8. Release of antibiotics from antimicrobial gel and sheet materials.

[0113] Gel and sheet materials were prepared as described in Example 7. Note that the low concentrations of API were chosen to “stress test” the release at lower doses. Sustained release studies were performed using a modified Franz cell in which a 5 cm diameter disc of material that had been hydrated with phosphate buffered saline to provide sufficient shape- retentive state for handling was clamped into a holder which also served as the lid to the sample chamber. A 125 mL volume of phosphate buffered saline (to mimic physiological fluids such as wound fluid) was added to the sample, which was then allowed to remain undisturbed. Samples(0.5 mL each) were analyzed, and a makeup PBS solution was added back to keep the volume constant. Samples pulled from the vial at intervals were analyzed and compared to a standard curve. Doxycycline and vancomycin were detected using UV Visible and gentamicin sulfate was detected using an indirect complex formed of Ninhydrin with Gentamicin Sulfate where the complex was detected with UV Visible. Results are shown in FIG. 1 to FIG. 3.

[0114] These data show that some embodiments exhibit sustained release of API for more than 72 hours. The tested APIs have different solubility constants and different interactions between the gel or sheet 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 doxycycline and vancomycin. These data show that the releaseDocket No. 89380.0006\WG 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 gel or sheet formulations by considering API, hydration / aggregation profiles, surface areas of material / subject (e.g., type of wound), and subject / health provider need.Example 9. Preparation and characteristics of hemostatic gels and sheets

[0115] Gel formulations were prepared as in Examples 2 and 3, but with the addition of collagen or tranexamic acid (0.05% wt or 0.1% wt) into the liquid mixture to provide a homogenous gel. Sheet formulations were prepared as in Example 5, but with the addition of collagen or tranexamic acid (0.05% wt or 0.1% wt) into the liquid mixture to provide a homogenous solution prior to freezing. Physical attributes of 100 mg samples were characterized as in Example 6, and the results shown in Table 9.Docket No. 89380.0006\WOExample 10. Chitosan-Loaded Gels

[0116] Gels are formulated according to Table 10:

[0117] Gels are created using a suspension of polymer particles of 85: 15 pHEMA:pHPMA (see Example 1) combined with the materials in either Formulation 1 or Formulation 2. In addition to the formulations above, 0.1 weight percent of chitosan powder is dissolved into the gel mixture. Chitosan acts as a potent hemostat when applied to a bleeding wound. The resulting gel has a viscosity above water and can be forced through a narrow orifice approximately 2 mm in diameter. When the gel is injected into phosphate buffered saline, the materials gradually transform over a 2-hour to 3- hour period from a viscous gel to a shape- retentive material that resists deformation and retains its initial dimensions and shape.Example 11. Hemostasis testing

[0118] Preliminary clotting studies were conducted with sheet materials containing chitosan, collagen, or TXA as provided in Example 9, and compared to QuikClot® gauze (Teleflex Inc., Wayne, Penn.) and powders (see Example 1). More specifically, bovine blood was added to a 100 mg sample of a sheet material and allowed to form a clot for 2 min, then 50 mL of phosphate buffered saline was added. The solutions were then viewed to determine qualitatively if the clot remained intact or blood seeped out into the solution after a period of 10 min. Clotting occurred with no significant loss in the integrity of the clot.Example 12. Antimicrobial properties

[0119] Antimicrobial efficacy of sample sheet preparations was tested and validated by pre-populating 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. After the full colony was formed, a 1 cm piece of antibiotic-loadedDocket No. 89380.0006\WD shape-conforming sheet material was added to the surface of the “carpet.” (Powder formulations were pre-aggregated in a 1 cm mold.) 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 sheet 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. The gels described in Examples 7 and 8 were not tested due to their relatively slower aggregation times (i.e., time to transform into a shape-retentive form) and release rates relative to the sheet material. 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 up to 72 hours even at the lowest dosage levels (0.05-0.1%). FIG. 4 provides the zone of inhibition data of the various sheetantibiotic combinations over 72 hr while stacking the combined zones of inhibition for each 24- hour period, and comparing these data with that of powder formulations. Dressings 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 sheet material that can provide inhibition of these bacteria strains for up to 72 hr, provide a dose response, and release antimicrobial agents over a longer period of time.Example 13. Release of low to high molecular weight molecules from sheet formulations.

[0120] The sustained release of fluorescein-labeled dextran molecules was studied to model the effect of API size on controlled release. Each sheet was formulated as above, to contain 0.001 weight percent (10 mg active / gram of sheet). The soluble fluorescein-labeled dextrans were dissolved into the suspension of particles, glycerin, poloxamer and water at the following ratios:

[0121] When the above suspensions were freeze dried into 3 -inch petri dishes, the resulting discs were approximately 5 mm deep and had a pale-yellow color. The resulting materials had roughly 0.01 % labeled dextran (or 10 mg of labeled dextran per gram of disc). 100 mg samples of each disc were cut and were added to 100 mL of PBS and allowed to hydrate and the dextrans were allowed to release. 100 microliter samples were pulled from the controlledDocket No. 89380.0006\WG release study samples, and the amount of fluorescein-dextran released was calculated at the time points in Table 12:

[0122] These data show the sustained release for each different molecular weight from sheet materials composed of 85: 15pHEMA:pHPMA with Pluronic and glycerin in 100 mL PBS. The release profiles show that the molecular weight affects the release rate from a given formulation. The lower molecular weight dextrans are smaller and come out of the aggregate at a much faster rate than the higher molecular weight, larger dextrans.Example 14. Shape-transforming devices comprising antibiotic and hemostatic agents

[0123] Shape-transforming sheet and gel devices comprising both an antibiotic and a hemostatic agent were prepared. The antibiotics doxycycline hyclate, gentamicin sulfate, and vancomycin were selected because each has known dosage curves and activities. The hemostats bovine collagen, chitosan, and tranexamic acid (TXA) were selected because these have been commercialized as clotting agents.

[0124] Gel materials were manufactured by forming the gel polymer suspension first and then mixing the suspension with antibiotic and clotting agent. Two concentrations of each antibiotic were prepared, and a single concentration of clotting agent was added to each sample. For gel materials comprising silica, the general preparation of the gel was as follows: To a 120 mL sample vial, 1 g of 85: 15 pHEMA:pHPMA particles and 300 mg of fumed-silica was added. 100 mL distilled H2O was added. The dry ingredients were mixed with water using a spatula until a uniform gel was formed over a period of approximately 5 minutes. Samples of gel were transferred in 10 gram-aliquots into 20 mL labeled sample vials. For gel materials comprising Carbopol, the general preparation of the gel was as follows: To a 120 mL sample vial, 1 g of 85: 15 pHEMA:pHPMA particles and 200 mg of Carbopol 940 was added. 100 mLDocket No. 89380.0006\WO distilled H2O was added. The dry ingredients were mixed with water using a spatula until a uniform gel was formed over a period of approximately 5 minutes. Samples of gel were transferred in 10 gram aliquots into 20 mL labeled sample vials.

[0125] For devices comprising sheet materials with antibiotic and hemostat, sheet materials were formed by preparing suspensions of 85: 15 pHEMA:pHPMA particles and purifying them by Tangential Flow Filtration as described above. To the suspension was added 20 weight percent Pluronic F87 and 1 weight percent glycerine, calculated as the percent of solids in the water. 25 mL of suspensions were combined with one antibiotic and one clotting agent so that the solids content was a total of 6.4 percent at the ratios shown in Table 9. Following mixing of the suspensions, the liquids were decanted into 3-inch petri dishes to a depth of roughly 2 cm and frozen. The samples were then freeze-dried under vacuum until all water had sublimed, leaving behind shape-transforming sheets.Docket No. 89380.0006\WODocket No. 89380.0006\WO

[0126] Each sample was 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 15. Application to wound therapy

[0127] 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.Docket No. 89380.0006\WO

[0128] 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, antimicrobial properties, and 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 overextended periods of time while bringing comfort to the patient by providing pain relief and unrestricted movement. Additionally, the device should be capable of delivering active ingredients, sometimes for extended periods of time, so that their efficacy is maintained in cases of prolonged need.

[0129] 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.”

[0130] For antibiotic and infection studies, gel or sheet 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 positive 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 (MRSA). 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 sheet or gel preparations.

[0131] As an example of hemostatic screening, partial thickness wounds (1 cm2) are treated in experimental groups. Each group will have wounds for pharmaceutic agents (e.g.,Docket No. 89380.0006\WO collagen, TXA low, TXA high, or chitosan), a negative control (no treatment), and a positive 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 semi -quantitatively assessed using the modified fibrin plate method. This study may also be repeated and extended to 14 days for the most efficacious sheet or gel formulations.Example 16. Porcine studies of antibiotic-loaded shape-transforming sheet formulations

[0132] An animal study was undertaken to confirm that the sustained release of antibiotic from shape-transforming materials described herein provided efficacy against bacterial infection for an extended period of time.

[0133] Porcine wound healing studies were performed on Yorkshire Cross pigs under IACUC and ACURO approval for the ethical treatment of animals. Pigs were weighed and anesthetized then prepped for surgery with shaving and cleaning the surgical area with antibacterial soap and sterile water. Animals received forty-four full-thickness, punch biopsy wounds using a 10-mm round biopsy punch. Wounds were arranged in grids on each test animal’s back. Wounds were each separated by 15-20 mm of skin without cuts or wounds. Four un-infected control and four infected un-treated control wounds were included on opposite ends of the test treatment grids. Wounds were designed for inoculation with a volume of bacteria corresponding to 1 x 106colony forming units (CFU) of either Pseudomonas aeruginosa (PA) or methicillin-resistant Staphylococcus aureus (MRSA) and allowed to rest for 15 minutes before treatment with test preparation.

[0134] Test devices were prepared as described herein. Sheet formulations were either pre-loaded with antibiotic or were loaded with antibiotic at the time of application to the wound. In the latter instance, sheet materials were contacted with the wound surface and immediately hydrated with a solution containing the antibiotic. Ciprofloxacin solution was obtained as Ciprofloxacin Ophthalmic Solution USP 0.3% as base, sterile, 5 mL, from Leading Pharma. Vancomycin Hydrochloride for Injection USP, 1 g per vial, for intravenous use, as sterile lyophilized powder was obtained from Slate Run Pharmaceuticals, and solution was prepared using sterile saline. Sheet formulations transformed from shape-conforming devices to shape- retentive devices upon contact with wound exudate.Docket No. 89380.0006\WO

[0135] Results are presented in Table 14, and show that antibiotic-loaded sheet preparations were effective in controlling bacterial infection for at least 7 days in this pre- clinical model.Example 17. Preparation of Lyophilized Composite Cake

[0136] A lyophilized cake of composite pHEMA / pHPMA particles was prepared according to Example 1, except that the solid was retained intact without sieving.Hydration studies were conducted by exposing cake fragments (n=3) to phosphate-buffered saline (PBS) at room temperature. The lyophilized cake adsorbed PBS corresponding to -85% of its aggregate mass, producing a hydrated, pliable matrix. The hydrated material exhibited conformability and mechanical integrity consistent with shape-transforming behavior but transformed slower while adsorbing greater amount of fluid than its powder forms.Example 18. Preparation of Lyophilized Composite Cake with Sponge Backing

[0137] A suspension of poly-2-hydroxyethyl-methacrylate (pHEMA) and poly-2- hydroxypropyl-methacrylate (pHPMA) particles was prepared as per Example 1 and introduced over a porous foam substrate in a mold prior to freeze drying. During freeze-drying, the lyophilized cake formed in intimate contact with the porous sponge structure, resulting in a bonded bilayer construct. This process produced a reinforced composite in which the polymerDocket No. 89380.0006\WO network was attached to the sponge, providing structural stability and enhanced handling characteristics.

[0138] This example demonstrates that the composite powders may be combined with supporting scaffolds or backing materials, such as foams, sponges, or meshes, and processed via lyophilization to generate mechanically stable formats that maintain the shape-transforming properties of the base polymer particle upon hydration

[0139] 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. 89380.0006\WOCLAIMSWe claim:

1. A shape-transforming device comprising a planar adsorbent material comprising about 60% to about 70% (w / w) of a preparation comprising poly-2-hydroxyethyl-methacrylate (pHEMA) and poly-2-hydroxypropylmethacrylate (pHPMA) adsorbent composite particles, about 25% to about 30% (w / w) pol oxamer, about 2% to about 7% (w / w) glycerin, and, optionally, at least one pharmaceutical agent; wherein the planar material is a sheet, film, foam, or pad; and wherein upon contact with a physiological fluid or other fluid of similar ionic strength, the shape-transforming polymer planar material transforms from a shape-conforming state to shape-retentive state.

2. A shape-transforming device comprising an adsorbent gel material comprising about 8% to about 10% of a powdered preparation comprising poly-2-hydroxy ethyl -methacrylate (pHEMA) and poly-2-hydroxypropylmethacrylate (pHPMA) adsorbent composite particles, about 45% to about 92% water, and, optionally, about 2% fumed silica or about 45% to about 50% polyacrylic acid, and, optionally, at least one pharmaceutical agent; wherein upon contact with a physiological fluid or other fluid of similar ionic strength, the shape-transforming adsorbent gel material transforms from a shape-conforming state to shape-retentive state.

3. A shape-transforming device comprising a lyophilized solid cake, slab, layered structure, or block consisting essentially of poly-2-hydroxyethyl-methacrylate (pHEMA), poly- 2-hydroxypropyl-methacrylate (pHPMA), a-hydroxy olefinic methacrylate polymers, copolymers thereof, or mixtures thereof, optionally comprising at least one pharmaceutical agent, wherein upon hydration with a physiological fluid or biocompatible liquid carrier, the solid form transforms from a shape-conforming to a shape-retentive state and provides sustained release and extended coverage at a biological site, wherein the solid form further functions as a temporary implant providing stabilization, coverage, or localized delivery before resorption or removal and wherein the lyophilized solid form may be prepared as a single mass or by sequential freezing and lyophilization of multiple suspensions of polymer particles to produce discrete stacked layers differing in concentration, ratio, or pharmaceutical agent, thereby enabling staged or multimodal release.

4. The shape-transforming device of any one of claims 1, 2, or 3, wherein the preparation of pHEMA and pHPMA adsorbent composite particles is 85: 15 pHEMA:pHPMA by weight.Docket No. 89380.0006\WO5. The shape-transforming device of cany one of claims 1, 2, or 3, wherein the at least one pharmaceutical agent is selected from a regenerative agent, debriding agent, antiinflammatory agent, pain-management agent, enzyme, antimicrobial agent, biofilm-inhibiting agent, or hemostatic agent.

6. The shape-transforming device of cany one of claims 1, 2, or 3, wherein the device is configured for sequential, stacked, or simultaneous application with powders, liquids, gels, or other planar or cake devices to provide multimodal or staged release.

7. The shape-transforming device of any one of the preceding claims, wherein the rate of sustained release has been modified by changing polymer composition, excipient content, pharmaceutical loading, or stacking / sequencing of components to achieve a desired therapeutic profile.

8. Use of the shape-transforming device of any one of the preceding claims for treatment of a wound in a subject in need thereof.

9. A method of treatment comprising contacting the shape-transforming device of any one of claims 1 to 6 with a tissue, defect, bone, tendon, ligament, joint, surgical exposure, or organ surface in a subject in need thereof, wherein the device provides coverage, sustained release of pharmaceutical agents, and optionally functions as a temporary implant for stabilization or repair.

10. The method of treatment as in claim 9, wherein the tissue comprises a wet wound, bleeding, or surgically exposed hard or soft tissue site or surgical or organ exposure.

11. A pre-loaded syringe having a 2 mm opening at the distal end pre-loaded with the gel material of claim 2.

12. A kit comprising the pre-loaded syringe of claim 11.

13. A kit comprising the device of any one of claims 1-4, and optionally instructions for use.Docket No. 89380.0006\WO14.. The kit of claim 13, further comprising at least one solution comprising at least one pharmaceutical agent, wherein the solution is applied sequentially or simultaneously to the site and where the same solution can be reapplied to the site or another solution with a different agent can be applied to the same site.

15. A device comprising a dry, shape-transforming planar material comprising pHEMA:pHPMA particles, glycerin, poloxamer, and, optionally, a pharmaceutically active agent, wherein said material when contacted with a physiological fluid transforms from a shapeconforming state to a shape-retentive state in about 2 hours in vitro.

16. The device of claim 15, comprising about 62.8% (wt.) pHEMA:pHPMA particles, about 32.3% (wt.) poloxamer, and about 4.8% (wt.) glycerin.

17. The device of claim 16, wherein the ratio of pHEMA:pHPMA is 85: 15 (by weight).

18. A device comprising a hydrated shape-transforming gel comprising pHEMA:pHPMA adsorbent composite particles, optionally a strengthening agent, and, optionally, a pharmaceutically active agent, wherein said gel material when contacted with a physiological fluid transforms from a shape-conforming state to a shape-retentive state in about 48-56 hours in vitro.

19. The device of claim 18, comprising about 9.0% (wt.) pHEMA:pHPMA particles and about 90.0% (wt.) water.

20. The device of claim 18 comprising about 8.9% (wt.) pHEMA:pHPMA particles, about 89.1% (wt.) water, and about 2.0% fumed silica.

21. The device of claim 18, comprising about 9.9% (wt.) pHEMA:pHPMA particles, about 45% water, and about 45% polyacrylic acid.

22. A layered therapeutic device of any one of claims 1 to 4, applied in contact with one another in or on a subject in need thereof.

23. The shape-transforming device of any one of claims 1 to 4, wherein said device comprises two pharmaceutical agents that perform separate functions.Docket No. 89380.0006\WO24. The shape-transforming device comprising a planar adsorbent material of claim 1, wherein the material has been pressed and is capable of being bent or rolled without breaking.25 . The shape-transforming device comprising an adsorbent gel material of claim 2, wherein a large volume of the aggregated, shape-retentive gel is capable of being pulled from a small orifice without breaking.

26. A layered or stacked therapeutic device comprising any combination of the planar device of claim 1, the gel device of claim 2, the lyophilized cake device of claim 3, and / or a backed device of claim 4, applied sequentially, simultaneously, or in stacked arrangements at a biological site to provide extended coverage and staged or multimodal therapeutic release.

27. A shape-transforming device comprising a lyophilized solid cake or slab of adsorbent composite polymer particles, wherein the solid form is configured to be used directly as a device or is mechanically crushable, fragmentable, or millable into particles immediately prior to or at the time of application.

28. The device of claim 27, wherein upon hydration the intact cake or fragments hydrate to form a conforming, shape-retentive device that provides physical coverage and sustained release of at least one pharmaceutical agent.

29. A kit comprising the device of claim 27 or claim 28, wherein the lyophilized solid cake or slab is provided in sterile packaging and is configured to be applied intact or mechanically reduced into particles prior to use.

30. The kit of claim 29, further comprising a tool, applicator, or packaging feature configured to facilitate crushing, fragmenting, or milling of the lyophilized cake into particles at the point of care.

31. A method of treating a biological site selected from tissue injuries, bone or joint defects, tendon or ligament repairs, or surgical or organ exposures, comprising applying the device of claim 27 or claim 29, wherein the lyophilized cake is either (a) applied intact to the site or (b) crushed into particles prior to hydration to form a conforming, shape-retentive device in situ.Docket No. 89380.0006\WO32. The shape-transforming device of any one of claims 1 to 7, further comprising a backing layer, scaffold, or porous support selected from collagen sponges, gelatin foams, alginate sheets, polymer meshes, woven textiles, or composite laminates, wherein the backing enhances mechanical stability, handling, or anatomical placement.

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