WO2026073267A1 - Methods for treating traumatic brain injuries - Google Patents

Abstract

The embodiments herein provide for methods of treating traumatic brain injury, penetrating head trauma, surgically created cranial exposures, and cranial defects, comprising application of shape-transforming adsorbent composite particle preparations capable of transitioning from a shape-conforming state to a shape-retentive device. These devices are biocompatible and may be used as temporary covers, dural substitutes, protective implants, or plugs for cranial defects to be placed onto or into a subject in need thereof, and may comprise at least one pharmaceutical agent. The devices may provide hemostatic, anti-inflammatory, antimicrobial, or neuroprotective effects, and enable sustained release of therapeutic agents in situ. The embodiments described herein provide an advantageous approach to the treatment and management of open cranial injuries, cranial defects, and neurosurgical procedures requiring temporary dural or cranial coverage.

Description

Docket No. 89380.0005\WO

METHODS FOR TREATING TRAUMATIC BRAIN INJURIES

GOVERNMENT FUNDING

[0001] This invention was made with government support under Contracts No. HT942525P0002 and No. HT942525CE032 awarded by the United States Department of Defense, and a Cooperation and Research Development Agreement (CRADA) between the Walter Reed Army Research Institute (WRAIR) and Altrazeal Life Sciences Inc. 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 methods of treating traumatic brain injuries using shape-transforming adsorbent particle composites. More particularly, the embodiments relate to shape-transforming adsorbent particle composites that can function both as temporary dural covers and as controlled-release drug delivery’ devices. The invention addresses the unmet need for rapidly deployable, field-ready materials to stabilize brain tissue and neurological function in military’ and civilian emergency settings where exposed brain tissue requires protection and therapeutic support.

BACKGROUND

[0004] Traumatic brain injury (TBI) is a type of injury caused when an external force or foreign object impacts the skull with sufficient pressure and momentum to damage the brain, typically resulting in brain swelling. TBI from penetrating head trauma (PHT) is caused when an object pierces the skull, damaging skin, bone, meninges (the layers of membranes that protect the brain), and brain tissue. These injuries can be caused by blast injuries, gunshot wounds, stabbings, falls, vehicle crashes, and the like. Non-penetrating TBI is caused by an external force strong enough to move the brain within the skull. These injuries can be caused by falls, sports injuries, blast injury’, or being struck by an object. Even in the case of non-penetrating TBI, the skull of the TBI subject may require opening to treat swelling, intracranial pressure, intracranial bleeding, or other complications, thus exposing the brain tissue. Currently, there are few options for covering and treating brain tissue exposed within the dural cavity following TBI from trauma Docket No. 89380.0005\WO or surgical intervention. Current approaches rely primarily on dural substitutes (e.g., collagen matrices, synthetic polymer sheets), fibrin sealants and hemostats, which are designed for surgical settings rather than emergency or field deployment. These substitutes do not directly treat or protect exposed brain parenchyma, nor do they support localized drug delivery or longterm stabilization following craniotomy or decompressive surgical procedures. Beyond initial mechanical damage, secondary injury cascades — including neuroinflammation, oxidative stress, ischemia, excitotoxicity, and post-traumatic seizures — contribute substantially to morbidity and mortality. Accordingly, there is a critical need for rapidly deployable, biocompatible materials that both cover exposed brain tissue and provide site-directed delivery of therapeutic agents to prevent infection, reduce edema, and mitigate secondary neurological injury.

SUMMARY

[0005] The present embodiments provide methods for treating patients who have suffered traumatic brain injury (TB1) resulting in an exposed dural cavity, by applying biocompatible shape-transforming compositions (shape-conforming/shape-retentive compositions), specifically compositions comprising adsorbent composite polymer particles (ACP), that, upon contact with the exposed tissue surface, a physiological medium (wound exudate) or other medium of similar ionic strength, transform to shape-retentive devices. Various embodiments in accordance with the disclosure provide methods for using compositions, preparations, devices, pharmaceutical agent and medicinal drug deliver}', and therapeutic protocols that protect and stabilize TBI tissues. Methods of treating TBI as provided herein offer a practical and affordable method, advantageous in low-resource or remote environments. Further, once applied to exposed brain tissue, the biocompatible ACP compositions can be left in place for days with no adverse effects to provide a therapeutic dural cover. The ACP compositions can further be formulated or mixed w ith pharmaceutical agents, such as antibiotics, hemostats, and steroids, to deliver these therapeutic agents to the site of injury. Unlike current sealants or dural substitutes, these materials combine physical protection with pharmacological delivery, offering a dual mechanism of neuroprotection. The compositions offer a practical and affordable method, advantageous in low -resource, remote, or battlefield environments where the neurosurgical infrastructure is limited, yet rapid stabilization is critical.

[0006] The present embodiments provide for methods of treating a patient with TBI comprising applying directly to exposed brain tissue a composition comprising ACP. ACP compositions may be dry blended w ith other pharmaceutical agents prior to application. Alternatively, application of the ACP composition may be applied concurrently with sterile Docket No. 89380.0005\WO isotonic solutions (e.g., saline) that may further comprise a pharmaceutical agent. Upon hydration with body fluids, saline, or solutions comprising pharmaceutical agent(s), the shapetransforming composition transforms from a dry powder state to a wet, shape-conforming and shape-retentive matrix with a moisture content between 50% and 90% fluid by mass, forming a device that, for example, seals the surface of the interface between the brain cavity' and the outside environment. This device provides a dural closure, preventing foreign object or exogenous bacterial incorporation into the brain cavity. Further, the device comprising APC has anti-inflammatory and anti-biofilm properties and support a reduction in edema associated with TBI. The nature of the APC compositions allows for easy mixing with therapeutic agents at the time of application to the tissue, whereby the physical properties of the shape-retentive device extend the therapeutic efficacy of the agent. The sustained release properties of the hydrated matrix extend the therapeutic window of incorporated agents, reducing dosing frequency. The device is non-adhesive to neural tissue, allowing safe removal or replacement without damaging the underlying brain parenchyma.

[0007] In one embodiment, the TBI is caused by penetrating head trauma (PHT). In one embodiment, the TBI is caused by non-penetrating head trauma.

[0008] In at least one embodiment, the ACP composition for treating TBI comprises n-hydroxy-n-alkyl-m-methylprop-2-enoate polymers, wherein n and m range from 1 to 3. In at least one embodiment, the ACP composition comprises a polymer combination as represented in Table 2 herein. In at least one embodiment, the shape-transforming ACP compositions for treating TBI are prepared from a suspension of poly-2-hydroxyethyl-methacrylate (pHEMA) particles and poly-2-hydroxypropylmethacrylate (pHPMA) particles, for example at a weight ratio of pHEMA:pHPMA of about 80:20 to about 90: 10, inclusive and including ratios therebetween, such as about 85: 15. In one embodiment, the ACP are pHEMA particles and pHPMA particles present in a weightweight ratio of 85: 15 pHEMA:pHPMA. In at least one embodiment, the shape-transforming material is a lyophilized material prepared from a solution comprising 51% to 99.9% by weight (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 deoxy cholate.

[0009] In at least one embodiment, the shape-transforming materials used according to the present methods further comprise at least one pharmaceutical agent, thereby providing an in situ shape-retentive device that delivers a pharmaceutical agent from the device in contact with the exposed tissue surface. Accordingly, in at least one embodiment, the shape-transforming ACP composition comprises at least one pharmaceutical agent. In at least one embodiment, the ACP composition applied according to the present methods comprises at least one therapeutic Docket No. 89380.0005\WO pharmaceutical agent, such as a growth factor, neurotrophic growth factor, anti-in fl ammatory agent, pain-management agent, antioxidant, enzyme, antimicrobial agent, anti-seizure agent, hyperosmolar agent, biofilm-inhibiting/dispersal agent, hemostatic agent, nucleic acid, acetyl L-camitine, glyceryl tri-acetate, resveratrol tri -acetate, n-acetylcysteine, candesartan, or a combination of any of these. In an aspect of these embodiments, the method provides an environment that decreases the inflammatory response by signaling a proliferative rather than an inflammatory response. In at least one embodiment of the method, the shape-transforming material comprises both an antimicrobial agent and a hemostatic agent. In at least one embodiment of the method, the shape-transforming material comprises both an antimicrobial agent and a steroid. 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.

[0010] In at least one embodiment of the method, the shape-transforming ACP composition comprises at least one antibiotic or antimicrobial, such as ciprofloxacin, tobramycin, doxycycline, vancomycin, gentamicin, polyhexamethylene biguanide, minocy cline, ceftriaxone, trovafloxacin, or silver sulfadiazine. In at least one embodiment of the method, the ACP composition comprises a hemostatic agent such as collagen, chitosan, or tranexamic acid. In at least one embodiment of the method, the shape-transforming ACP composition comprises at least one anti-seizure/antiepileptic agent, such as phenytoin, levetiracetam, or valproate. In at least one embodiment of the method, the shape-transforming ACP composition comprises at least one agent to reverse anticoagulant or antiplatelet activities thereby effecting a decrease in clotting, such as unfractionated heparin, low⁷ molecular weight heparin, a Vitamin K antagonist such as warfarin, direct thrombin inhibitors, andexanet alfa, or ciraparantag. In at least one embodiment of the method, the shape-transforming ACP composition comprises at least one agent to decrease intracranial pressure, such as hyperosmolar agents, mannitol, or hypertonic concentrations of salt. In at least one embodiment, ACP compositions incorporate neurotrophic factors (e.g., BDNF, NGF, GDNF) or stem-cell-derived exosomes to promote neuronal survival and repair. In at least one embodiment, ACP compositions comprise at least one imaging agent such as radiopaque compounds or fluorescent tracers are included to facilitate intraoperative visualization and post-operative monitoring. In at least one embodiment of the method, the shape-transforming ACP composition comprises at least one agent to reduce inflammation or edema, such as corticosteroids, dexamethasone, betamethasone, methylprednisone, or triamcinolone. In at least one embodiment of the method, the shape-transforming ACP composition comprises a combination of at least one antibiotic and at least one agent to reduce edema, such as a combination of ciprofloxacin and dexamethasone. By combining Docket No. 89380.0005\WO antimicrobials with anti-inflammatory agents or antiepileptics, ACP matrices address multiple secondary injury pathways simultaneously.

[0011] Accordingly, the present embodiments provide methods that allow a medical provider, such as a provider of first aid or clinician at a medical faci li ty, to treat a patient who presents with a TBI resulting in open trauma within the dural cavity, wherein the method of treatment is capable of providing a dural closure, thereby limiting cerebrospinal fluid loss, and may release at least one pharmaceutical agent to the injury to facilitate neurostabilization or neuroprotection, especially when immediate neurological intervention is not available. The temporary cover also reduces risk of exposed brain tissue infection and mechanical trauma during transport.

[0012] The present embodiments also provide methods allowing a medical provider (e.g., a first aid provider or clinician at a medical facility) to treat a patient with a TBI that can provide dural closure, limiting cerebrospinal fluid loss and may release at least one pharmaceutical agent, including agents suitable for improving clotting or slowing and stopping traumatic bleeding into the brain cavity. In at least one embodiment, the pharmaceutical agent for improving clotting or slowing traumatic bleeding into the brain cavity is, for example, tranexamic acid, chitosan, or collagen. The matrix’s shape-retentive nature maintains local concentration of hemostatic agents at the wound site, prolonging antifibrinolytic effect and reducing re-bleeding risk.

[0013] The present embodiments also provide methods allowing a medical provider to treat a patient with a TBI that can provide a dural closure, limiting cerebrospinal fluid loss and may release at least one pharmaceutical agent including agents suitable as antiepileptics to limit seizures. Such antiepileptics for use according to these embodiments include, for example, phenytoin, levetiracetam, or valproate. Localized delivery of antiepileptics reduces systemic exposure and side effects while mitigating the risk of early post-traumatic seizures.

[0014] The present embodiments also provide methods allowing a medical provider (e.g., a first aid provider or a clinician in a surgical situation) to treat a patient with a TBI that can provide a dural closure, thereby limiting cerebrospinal fluid loss and release at least one pharmaceutical agent including agents suitable for reversal of anticoagulants or antiplatelets to decrease clotting. In at least one embodiment, the pharmaceutical agent suitable for reversal decreased clotting caused by anticoagulant- or antiplatelet- treatment is, for example, unfractionated heparin, low molecular weight heparin, a Vitamin K antagonist such as warfarin, direct thrombin inhibitors, andexanet alfa. or ciraparantag to decrease clotting. Local reversal of anticoagulant effect may reduce or eliminate the need for systemic reversal, balancing hemostasis without affecting systemic thrombotic risk. Docket No. 89380.0005\WO

[0015] The present embodiments also provide methods allowing a medical provider to treat a patient with a TBI that can provide a dural closure, limiting cerebrospinal fluid loss and may release at least one pharmaceutical agent including hyperosmolar agents to reduce intracranial pressure. In at least one embodiment, the agents to decrease intracranial pressure include, for example, hyperosmolar agents, mannitol, or hypertonic concentrations of salt. In some embodiments, the ACP matrix itself exerts osmotic modulation, synergizing with hyperosmolar agents to lower intracranial pressure.

[0016] The present embodiments also provide methods allowing a medical provider to treat a patient with a TBI that can provide a dural closure, limiting cerebrospinal fluid loss and may release at least one pharmaceutical agent including antimicrobials or antibiotics to reduce bacterial loads in contaminated injuries. Such antimicrobials or antibiotics include, for example, ciprofloxacin, minocycline, doxycycline, vancomycin, tobramycin, ceftriaxone, gentamicin, polyhexamethylene biguanide, silver sulfadiazine or trovafloxacin, to reduce bacterial loads with contamination. By maintaining high local concentrations of antimicrobials directly at the site of contamination, the compositions reduce bacterial load and biofilm formation, which are major contributors to sustained infection in penetrating TBI.

[0017] The present embodiments also provide methods allowing a medical provider to treat a patient with a TBI that can provide a dural closure, limiting cerebrospinal fluid loss and may release at least one active pharmaceutical agent including corticosteroids to reduce edema. Such agents to reduce edema include, for example, corticosteroids, dexamethasone, betamethasone, methylprednisone, or triamcinolone.

[0018] The present embodiments also provide methods allowing a medical provider to treat a patient with a TBI that can provide a dural closure, limiting cerebrospinal fluid loss and may release at least one active pharmaceutical agent including a combination of antibiotic and therapeutic agent for the reduction of edema, such as, for example, a combination of ciprofloxacin and dexamethasone. Sustained release of corticosteroids at the site of injury reduces local edema and inflammation while minimizing systemic side effects associated with high-dose steroid therapy.

[0019] In additional embodiments, multiple classes of agents - for example, antimicrobials, anti-edema agents, and antiepileptics - are co-loaded to simultaneously address infection, swelling, and seizure risk. This multimodal capability distinguishes ACP matrices from existing single-function hemostatic dressings or dural sealants. Accordingly, these methods provide a practical, affordable, and multifunctional approach to treating traumatic brain injury, bridging the gap between emergency stabilization and advanced neurosurgical care. Docket No. 89380.0005\WO

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows two graphs comparing mean intercranial pressure (ICP - top panel) and cerebral perfusion pressure (CPP -bottom panel) recordings after controlled cortical impact (CCI) brain injury with and without shape-retentive material. Measurements were documented prior to CCI and then following CCI with or without application of an embodiment of shapetransforming material to the brain injury site. Y-axis: ICP (mmHg); X-axis: time (minutes); black symbols: CCI with application shape-retentive material; gray symbols: no treatment control. Outliers were identified using the ROUT method and one-way ANOVA used to determine statistically significant differences (bars).

[0021] FIG. 2A-FIG. 2C are a series of bar graphs comparing cerebral edema formation in sectioned brain regions of a control group that received CCI without treatment versus CCI and treatment with an embodiment of a shape-transforming material. Y-axis: brain water content (%); gray = CCI control; black = CCI with shape-retentive material. FIG. 2A shows results for the brain water content (%) of the ipsilateral (injured) brain hemisphere over time after TBI for each brain region: anterior (A), medial (M), and posterior (P). FIG. 2B shows brain water content (%) of the medial brain regions (contra = contralateral; ipsi = ipsilateral), which contain the injury site, over time after TBI (X-axis: hours or day). FIG. 2C shows brain water content (%) of the anterior brain sections (contra = contralateral; ipsi = ipsilateral) over time after TBI (X-axis: hours or day). Mean and standard error bars (SEM) shown.

[0022] FIG. 3A is a bar graph comparing the TBI lesion size with or without treatment with an embodiment of a shape-transforming material. For analysis, fixed brain tissue was sectioned, stained with hematoxylin and eosin, and then region of interest (lesion) was manually traced by blinded individuals using scientific image analysis software for quantification. Mean lesion volumes are shown for CCI (gray bars) or CCI with shape-retentive material (black bars). Y-axis: lesion volume (mm³); X-axis: time post-injury (72 hour or 7 day); T tests were used to assess statistical significance and standard error means (SEMs) are shown.

[0023] FIG. 3B and FIG. 3C show quantification of the protein marker Iba-1, indicating microglial activation or an inflammatory response in the hippocampal (FIG. 3B) and cortex brain (FIG. 3C) regions of both the ipsilateral (Ipsi) (injured) and contralateral (Contra) brain hemispheres. Y-axis: mean pixel intensity; X-axis: time post-TBI; gray bars: CCI control; black bars: CCI with shape-retentive material. Outliers were evaluated using the ROUT method and statistical significance was determined by one-way ANOVA with Tukey post hoc tests as applicable and SEM are shown. Docket No. 89380.0005\WO

DETAILED DESCRIPTION

[0024] It should be understood that this invention is not limited to the particular embodiments, methodology, protocols, and reagents, etc., described herein and as such may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. The invention is further illustrated by examples herein, which are not intended to limit the scope of the claims.

[0025] 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.

[0026] 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 more other non-stated integers or groups of integers. The term “or” is inclusive unless modified, for example, by “either.” Thus, unless context indicates otherwise, the word “or” means any one member of a particular list and also includes any combination of members of that list.

[0027] 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%.

[0028] 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. Docket No. 89380.0005\WO

[0029] As used herein, the term ‘‘shape-conforming” means that a material will take the shape of its container. In applications in wound healing, the shape-conforming material may start as a powder or fine flakes and will conform to a wound surface or wound shape.

[0030] As used herein, the term “shape-retentive” means that a material retains a shape as a fixed material and will generally not conform to a different shape.

[0031] As used herein, the term “shape-transforming” refers to a property of a material that allows the material to initially act as shape-conforming material but then transform to a shape-retentive material. Accordingly, the adsorbent polymer particle materials are shapeconforming. After a transformation by contact with physiological fluids, the material aggregates and becomes shape-retentive. In wound care, the shape-conforming powder is applied to a wound of an irregular, undefined shape, the material conforms to the wound surface and then transforms to a shape-retentive material that retains the shape of the wound surface.

[0032] As used herein, the term “gel” refers to a three-dimensional structure comprising adsorbent composite particles prepared as a shape-conforming material that, after contact with a physiological surface, transitions to a shape-retentive state. In some embodiments, the shapetransforming adsorbent composite particles may adopt a gel-like consistency during preparation or aggregation, or may retain gel-like characteristics in the shape-retentive state.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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 Docket No. 89380.0005\WO 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.

[0037] As used herein, the term "plurality" refers to more than one, i.e., two or more.

[0038] As used herein the term "dry weight'’ means the weight of particles without the weight of any polar liquid(s).

[0039] 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, adiopaque agents, contrast agents, fluorescent tracers, and nanoparticles for intraoperative or postoperative imaging), and is not limited to therapeutic agents. Small molecule compounds include, without limitation, hemostatic agents, antimicrobials, antibiotics, antivirals, chemotherapeutics (in particular platinum compounds and taxol and its derivatives), analgesics, antidepressants, antibiotics, antimicrobials, anti-allergenics, anti-rejection agents such as immunosuppressive or tolerance-inducing agents, debriding agents, antiarrhythmics, anti-inflammatory compounds, CNS stimulants, sedatives, anti-chohnergics. anti- arteriosclerotics, and the like. Macromolecular compounds include, without limitation, monoclonal antibodies (mAbs), Fabs, proteins, peptides, cells, antigens, nucleic acids, genes, proteins, growth factors, antigens, polypeptides, nucleic acids (e.g., DNA, RNA), ribozymes, enzymes, growth factors, and the like. A pharmaceutically active agent may be intended for topical or systemic use. Examples of pharmaceutically active agents include, without limitation, biomedical agents and biologically active substances such as hemostatic agents, antibiotics, polypeptides or proteins, growth factors, monoclonal antibodies or portions thereof, and antigens or immunogens, as well as stem cells, stem-cell derived secretome fractions, extracellular vesicles, or exosomes, including those derived from mesenchymal stem cells or neural progenitors. 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 (USP) standards. Dosing of pharmaceutically active or therapeutic agents may be determined based on existing therapeutic dosage levels, with upper and lower ranges adjusted according to clinical need, while remaining within non-toxic limits as established by FDA or equivalent pharmacopeial standards.

[0040] “Therapy” refers to treatment intended to relieve or heal a disorder in a subject. Docket No. 89380.0005\WO

[0041] 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.

[0042] 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.

[0043] 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 -COO . Another example is the amino (-NH2) group, which, in an acidic environment, will form an ammonium (-NH3 ) ion.

[0044] In general, an “excipient” or “pharmaceutically acceptable excipient” refers to an inert substance added to a therapeutic composition to facilitate its administration. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars (e.g., glucose and dextrose), types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. A “pharmaceutically acceptable excipient” does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound (pharmaceutical or therapeutic agent). The term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical carriers, such as a phosphate buffered saline, water, emulsions, and various types of wetting agents. Excipients can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see REMINGTON’S PHARMA. SCI. 15th Ed. (Mack Publ. Co., Easton, Penn. 1975).

[0045] 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 wi th 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.

[0046] As used herein, the term “occlude” has the meaning generally understood by those skilled in the chemical art, that is, to absorb and retain a substance for a period of time. Docket No. 89380.0005\WO

Regarding the embodiments provided herein, substances may be absorbed by and retained in, i.e., occluded by. the APC compositions of the present embodiments during their manufacture, preparation, or upon mixing in situ.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] Aspects of the present embodiments provide for methods for the stabilization or treatment of TBI resulting in open trauma within the dural cavity, and systems, formulations, compositions, and devices for such treatments. TBI resulting in open trauma within the dural cavity may result from PHT and non-PHT injuries. PHT with accompanying TBI is a type of injury where a foreign object or external force impacts a skull with sufficient pressure and momentum to damage skin, bone, meninges (the layers of membranes that protect the brain) and brain tissue. In some cases, decompressive craniectomy for severe swelling similarly results in intentional exposure of the dura or brain parenchyma, creating management challenges comparable to traumatic exposures. Causes of PHT can include gunshot wounds, falls, vehicle crashes, stabbings, blast trauma and other incidents involving blunt or sharp objects that impact the head with enough force to penetrate the skull and open the protective envelope to expose meninges or brain tissue to the outside environment. In military or austere environments, blast injuries are particularly frequent, often combining blunt and penetrating mechanisms with complex bacterial contamination. TBI may also occur without PHT when the skull is impacted with sufficient traumatic force to injure the brain. Causes of non-PHT TBI include falls, accidents, blast trauma, or blows to the head. Non-PHT TBI may induce significant swelling or bleeding in the brain, necessitating surgical intervention to open the skull and the protective envelope and thereby to expose meninges or brain tissue to the outside environment. The cranium or skull protects the brain as a protective enclosure. The cranium bones include the Docket No. 89380.0005\WO frontal, temporal, occipital, sphenoid and ethmoid bones each with different locations, shapes and thickness. Rhoton. CRANIA ANATOMY & SURGICAL APPROACHES (Walters Klover Neurosurgery Publications, 5th ed., 2023). Beneath the bones of the cranium are the meninges which are membranes that are divided into three layers: (a) the dura matter is a spongy fluid filled layer beneath the skull (b) beneath the dura matter is the arachnoid layer which is filled with he cerebrospinal fluid and acts as the interface between blood and brain tissue, and (c) the pia matter is the layer that is directly in contact with the brain tissue and adheres to the outermost layer of the brain tissue. Accordingly, materials that can rapidly conform to and cover irregular anatomical structures and optionally deliver therapeutic agents address a significant unmet need in both surgical and field settings.

[0052] As noted. PHT occurs when a foreign body or forceful pressure, such as a blast pressure wave, breaches the skull and affects the meninges and brain. Vakil & Singh, 24 Emergency Radiol., 301 (2017). For head injuries, PHT is the most lethal and debilitating form of head trauma with between 70-90% of patients dying before reaching hospital care and 50% of patients dying after reaching operative care facilities, van Rein et al., 154 JAMA Surg. 421 (2019). Treatment algorithms from the American Association of Neuropathic Surgeons and Brain Trauma Foundation respectively for patients with PHT provide general guidelines for emergency management including stabilization, transfer to a trauma center and imaging with surgical preparation. 51 J. Trauma & Acute Care Surg., Suppl. (2001). Current guidelines are based on military emergency protocols for stabilization of PHT patients during evacuation from conflict. Argwalla et al., 28 Neurosurg. Focus, El (2010). However, these protocols largely rely on access to neurosurgical facilities, and do not specify materials suitable for prolonged intracranial coverage in prehospital or battlefield care. In the general protocols, a first responder is recommended to assess the size of the injury and if possible ascertain if the inner ear has a hemotympanum with accumulated blood. PHT can also introduce contaminants or foreign materials in the brain which increases infection risk. Meister et al., 95 J. Trauma Acute Care Surg. S72-S78 (2023). Soil, metallic fragments, and fabric debris from helmets or uniforms are frequently embedded, compounding the challenge of infection control. Secondary injury mechanisms including ischemia, increased intracranial pressure, oxidative stress, cytotoxicity, and metabolic diseases can occur in the hours following trauma, his secondary cascade underscores the importance of early local intervention not only to seal and protect but also to deliver therapeutic agents directly to the injury' site. Following evaluation of the patient for more critical life-threatening injuries and stabilization of breathing and blood pressure, the PHT injury should be evaluated for foreign bodies, loss of blood at the penetrating injury, presence of cerebrospinal fluid at the injury site. Follow ing these steps, the management of forward Docket No. 89380.0005\WO treatment of PHT in the prehospital setting should focus on stopping bleeding and preventing infection by ensuring dural coverage at the injured site.

[0053] Ensuring survival through primary emergency first responder care is key to the downstream survivability of a PHT. Since the era of the Israeli-Lebanon conflict in thel980s, the first responder treatment protocols for patients wi th PHT have included: Stabilization of patient; Cessation of bleeding; Formation of a watertight dura-sealing of the PHT with a barrier that prevents loss of cerebrospinal fluid; and Administration of antibacterial agents. These experiences highlighted that even rudimentary dural coverage could significantly improve outcomes during delayed evacuation. However, conventional field dressings and dural substitutes were not designed for intracranial application, are not biocompatible for extended placement, and do not provide localized delivery of antimicrobials, hemostatic agents, or antiepileptics. This gap underscores the need for next-generation materials that can combine barrier protection with therapeutic delivery.

[0054] Dural closure is a crucial component of emergency treatment for PHT injuries, as well as treatment for non-PHT TBI where the skull has been opened, e.g., to release pressure. Studies of dural closure in surgical procedures related to PHT have shown that prevention of cerebrospinal fluid loss is key to patient survival. In addition, the prevention of bacterial infection has been show n to be a critical component of survival after 72 hours. Accordingly, there is a need for intracranial materials that can provide mechanical protection, resist bacterial colonization, and optionally deliver antimicrobial agents in situ, thereby addressing both CSF containment and infection risk simultaneously. Because PHT is by definition an injury where the protective barrier for the brain is breached and the penetrating object is external and typically carries bacteria into the brain cavity and tissue, there is an assumption that all PHT patients present with bacterial contamination within the cranium. Patients receiving surgical intervention in non-PHT TBI are similarly at risk for bacterial infection.

[0055] Presently, most approaches to cover exposed brain tissues in TBI settings simply involve placing skin over the open dural cavity. Administration of oral or intravenous (IV) antibiotics are components of treatment during first aid with stabilization of patients, there remains a need for a treatment that provides a system to cover, seal, protect, and administer antimicrobial agents or other active pharmaceutical agents during the management or treatment of TBI resulting in open trauma within the dural cavity. Current commercial coverings can not be left internally or be used for extended periods - they must be changed daily or multiple times a week causing repeat trauma at the point of injury and exposing the area to infection. They are also susceptible to bioburden growth (and reduces formation of biofilms), do not deliver drugs, and can generate excessive inflammatory response or trap moisture at the injury site. In contrast, Docket No. 89380.0005\WO the methods of treating TBI provided herein comprise the application shape-transforming ACP compositions that conform to the contours of the injury and can safely be left in place within the brain as a shape-retentive dural covering device for days or even weeks, providing therapy for an extended period of time, avoiding repeated trauma and risk of exposure to infection. This approach is applicable in remote settings as well as clinical settings following decompressive craniectomy, where leaving a protective, biocompatible dural cover in situ reduces the risk of secondary complications while awaiting definitive closure. The ACP composition itself has been found to have anti-biofilm, anti-inflammatory, and hemostatic properties. The hemostatic properties of the shape-retentive ACP composition are especially advantageous in preventing rebleeding in TBI patients where blood-thinners have been implicated. Moreover, the shape- retentive ACP devices described herein can be used to provide sustained release of antibiotics, steroids, or other pharmaceutical agents, and increase the efficacy of such agents in situ.

[0056] The present embodiments provides methods for treating TBI, more particularly, for use of compositions, devices, medicaments, and techniques for treating patients w ho have suffered TBI resulting in exposed brain tissue. Specifically, various embodiments provide use of shape-transforming materials and protocols that protect and stabilize the brain in TBI contexts. This approach provides methods that allow a medical provider, such as a provider of first aid, to treat a TBI patient with a system comprising shape-conforming/shape-retentive ACP compositions as described herein that can be applied as a pow der - enabling rapid use in prehospital, battlefield, or other resource-limited settings without specialized neurosurgical tools - optionally concurrent or sequentially with a pharmaceutically acceptable liquid, such as saline, or a pharmaceutically acceptable liquid that comprises at least one pharmaceutical agent, as described herein, directly to the brain surface and safely provide contact to the dura or brain tissue. In surgical settings such as decompressive craniectomy or cranial defects, the material may be placed directly over exposed parenchyma and closed beneath the scalp, functioning as a temporary or semi-permanent dural substitute. This system provides a dural closure device that may be left exposed or covered with skin and removed after a suitable time, or in some indications be left as a biocompatible implant for at least a period of days or weeks. Unlike conventional dural sealants, which are designed for short-term intraoperative use, ACP compositions can function as both protective barriers and sustained-release therapeutic devices, extending their uti 1 i ty across acute and sub-acute phases of care.

[0057] An aspect of the present embodiments provides for use of compositions comprising shape-transforming ACP compositions as described herein, that may be formulated or mixed with one or more active agents to treat subjects with TBI as a primary cover to form a dural closure or beneath a surgically created bone flap following decompressive craniectomy, Docket No. 89380.0005\WO and can release at least one pharmaceutical agent, such as a therapeutic agent, that improves traumatic conditions associated with TBI.

[0058] In at least one embodiment, the composition comprising ACP in a method of treating TBI is in the form of a shape-conforming powder that hydrates and transforms into a shape-retentive solid, moist, flexible material that forms a dural closure device at the site of open trauma within the dural cavity or beneath a surgically created bone flap following decompressive craniectomy or in cranial defects. In at least one embodiment, the powder is applied concurrently (e.g., immediately before or after) with a pharmaceutically acceptable liquid, such as saline, to fully hydrate the powder and prevent powder granules from flowing freely internally. In at least one embodiment, the pharmaceutically acceptable liquid comprises at least one pharmaceutical agent. In at least one embodiment, at least one pharmaceutical agent is applied to the brain tissue in liquid form, and the powder is applied over it. In at least one embodiment, the powder is applied to the brain tissue and at least one pharmaceutical agent is applied in liquid form over the powder. In at least one embodiment, the steps of applying powder and liquid may be performed in any order, and may be repeated to provide the desired therapeutic device.

[0059] As provided herein, the composition applied according to the methods herein is a shape-transforming preparation of adsorbent composite polymer particles (ACP) prepared from the synthetic family of n-hydroxy-n-alkyl-m-methylprop-2-enoate polymers where n and m can range from 1-3 and alkyl can be methyl, ethyl, or propyl. In at least one embodiment, the ACP composition is composed of one or more polymers from the synthetic family of polymers of n- hydroxy-n-alkyl-m-methylprop-2-enoate polymers where n and m can range from 1-3. Alkyl can be, for example, methyl, ethyl, butyl or propyl. In at least one embodiment, the ACP comprises the polymers described in Table 1 and Table 2 herein. These polymer combinations are selected to ensure rapid transformation from shape-conforming to shape-retentive states upon contact with physiological fluids, enabling safe intracranial application. Selection among these variations provides tunable physical properties, such as tensile strength, elasticity, fluid absorption and retention, and rate of shape transformation, which can be optimized for different clinical applications.

[0060] In at least one embodiment, the ACP composition comprises at least one pharmaceutical agent or pharmaceutically acceptable excipient. In at least one embodiment, at least one pharmaceutical agent is mixed with polymers during production of adsorbent composite particles. In at least one embodiment, at least one pharmaceutical agent is mixed (dry blended) with the adsorbent composite particles. In at least one embodiment, at least one pharmaceutical agent is provided as a solution and contacted with the ACP composition at the Docket No. 89380.0005\WO time of application to the injury. In at least one embodiment, at least two pharmaceutical agents are provided as a solution or suspension and contacted with the ACP composition at the time of application to the injury, thereby enabling combination therapy at the site of injury.

[0061] In at least one embodiment, the ACP composition hydrates with a liquid that contains at least one pharmaceutical agent suspended or dissolved in the liquid so that the composition adsorbs the liquid containing the suspended or dissolved pharmaceutical agent as the composition transforms and occludes the agent in the shape-transforming matrix. This mechanism enables localized loading and sustained release of therapeutic agents directly at the site of application.

[0062] In at least one embodiment, the shape-retentive (transformed) ACP composition provides that after hydration and occluding of at least one pharmaceutical agent, the at least one agent is released from the composition into tissue over time in a predetermined, sustained, or controlled release profile. The release profile can be tailored by adjusting polymer composition, particle size, or agent concentration.

[0063] In at least one embodiment, the ACP composition provides sustained release properties of at least one pharmaceutical agent to optimize therapeutic effect in brain tissue, and those sustained release properties are based on ACP polymer composition. In certain embodiments, polymer ratios, crosslinking density, or hydrophilicity may be varied to modulate release kinetics.

[0064] Accordingly, to manage the risk of the secondary sequelae of TBI resulting in open trauma within the dural cavity by facilitating point of injury stabilization, the ACP composition can be formulated with anti-inflammatory agents (reduce TBI-induced ICP/edema), hemostatic agents (reduce surface bleeding), antimicrobial agents (reduce infection risk), or combinations of such agents, thereby delivering a comprehensive kit of topical therapeutics that optimize the material’s performance in TBI injuries that require prolonged care. The composition may be easily combined with the requisite agents by dry-blending with their powdered forms or by hydrating with their liquid forms that are easily available in the market in the form of ophthalmic or ear droppers (lower doses) and IV injections (higher doses). An object of this aspect provides a comprehensive kit that combines selective, safe, and well-accepted, cost-effective, FDA-approved and commercially available agents with the various embodiments of shape-retentive materials described herein. The combinations expand the material’s capability' for use in diverse environments. Such environments include prehospital, prolonged field care, and resource-limited civilian or military facilities where repeated surgical intervention is not feasible. In surgical settings, the compositions may be applied intraoperatively as temporary or semi-permanent dural covers, or beneath cranial defects following decompressive craniectomy, Docket No. 89380.0005\WO reducing the need for repeated dressing changes and lowering infection risk until definitive closure or reconstruction is performed. When aggregates form, covalent crosslinking of the methacrylate backbone occludes the active agents within the heterogeneous polymer network and ensure a sustained drug release. This entrapment mechanism slows diffusion, allowing predictable, tunable release kinetics over hours to days. Production methods may be adapted to vary sequencing and timing of release of actives. Various dose ranges are 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 TBI. The various dosages are tested for absolute and relative performance to select the dosage level with the most clinically optimal release profde.

[0065] In at least one embodiment, the ACP composition further comprises an antiinflammatory agent. In one embodiment, the anti-inflammatory agent is dexamethasone. TBI induced brain swelling and increased ICP are life-threatening. Steroids have been and continue to be used widely to decrease inflammation and swelling. Systemic steroid use has not shown a great benefit in the treatment of TBI, however, as systemic steroid use affects both injured and non-injured brain tissue and has other deleterious systemic complications. Topical steroid use reduces the risk of adverse systemic effects by localizing the therapy to the affected site. Dexamethasone is a potent synthetic corticosteroid with low mineralocorticoid, androgenic or estrogenic effects. It has been used extensively for its high anti-inflammatory and low saltretaining properties and is administered orally and via IV. IM, and IP injections, as well as topically in several pharmaceutical forms. Like other corticosteroids, dexamethasone has shortterm decreased vasodilation and permeability effects on capillaries and decreased leukocyte migration to sites of inflammation. Upon binding to the glucocorticoid receptor, dexamethasone elicits gene expression modulations that translate into numerous transient downstream effects including the inhibition of neutrophil apoptosis, phospholipase A2, the formation of arachidonic acid derivatives, NF-kappa B, and other inflammatory transcription factors, in addition to enhancing the expression of anti-inflammatory genes like interleukin- 10. The mineral effects of glucocorticoids occurring at extended use of high doses and resulting in raised sodium and lowered potassium levels are uniquely minimal for dexamethasone which induces its antiinflammatory effect at low' doses while maintaining the immunosuppressive effects at high doses. Dexamethasone’s effect will be enhanced by the protective and moisture-retaining barrier properties of the shape-transforming adsorbent composite particles that w ere shown to be beneficial in open brain procedures. These properties also enhance local drug residence time, reduce washout from CSF circulation, and ensure sustained therapeutic concentrations at the injury interface. A combination of dexamethasone with the ACP compositions described here Docket No. 89380.0005\WO enables the use of corticosteroids topically on the brain to maximize the advantages of their therapeutic properties over a sustained period while bringing the medication's adverse systemic effects to a minimum. In remote pre-hospital locations including PFC, early intervention with a long-lasting shape-retentive dexamethasone-loaded ACP application provides an opportunity to use direct application of steroids to the brain to decrease the penumbra of injury and reclaim the brain tissue that is vulnerable, leading to better outcomes. Where surgical interventions are feasible, this composition may also be used intraoperatively in decompressive craniectomies or other cranial defect repair, a frequent treatment strategy for these conditions where protecting the brain from exposure to damaging environmental elements is paramount. The dexamethasone-loaded ACP device delivers dexamethasone effectively at intended concentrations to mitigate brain swelling and any underlying inflammatory conditions.

[0066] In at least one embodiment, the ACP composition further comprises a hemostatic agent. In one embodiment, the hemostatic agent is tranexamic acid (TXA). Open brain injury or brain injury' requiring craniectomy to control swelling may also present with raw surface bleeding. This bleeding may be difficult to control using traditional options due to the inherent limitations of traditional methods in a PFC environment. TXA is a potent antifibrinolytic synthetic derivative of lysine. It has been indicated orally for the treatment of fibrinolysis disorders including cyclic heavy menstrual bleeding in premenopausal females. Intravenously, TXA is used for short periods to prevent and decrease bleeding in dental procedures in individuals with hemophilia as well as to help reduce swelling associated with hereditary angioedema. The high potency of TXA is attributed to its tight binding of plasminogen at the strong and weak affinity receptor sites leading to the strong inhibition of the plasminogen activation to plasmin. Formation of the latter is necessary for the activation of the first complement protein (Cl) which is involved in edema development as documented in angioedema attacks. Importantly, the binding to the high affinity receptors of plasminogen competes and prevents binding of plasminogen to fibrin which is a required interaction for fibrinolysis and dissolution of fibrin. The addition of TXA may provide a mechanism to control raw surface punctate bleeding which is not amenable to cautery or other conventional methodologies by stabilizing blood clots and preventing hemorrhage. This is especially important in the neurosurgical setting, where diffuse parenchymal oozing is common and traditional cautery can risk further tissue damage. Accordingly, TXA-loaded ACP compositions can be used effectively to deliver small doses of TXA to prevent bleeding in the brain and ameliorate secondary bleeding problems. In surgical interventions, TXA-loaded ACP can be applied intraoperatively beneath bone flaps or within cranial defects to secure hemostasis prior to closure. In PFC and first-aid, point of injury scenarios, topical TXA within ACP offers a Docket No. 89380.0005\WO deployable alternative where cautery' and transfusion are not available. The high potency of TXA and direct delivery to micro and macro wounds protect patients from intravascular clot formation while TXA is applied at very small doses topically to the brain surface. Combining with the ACP compositions provides oxygen permeable, non-toxic matrix device that generates a favorable microenvironment and provides the added benefit of covering and protecting the brain with a biocompatible dural cover.

[0067] In at least one embodiment, the ACP composition further comprises an antimicrobial agent. In one embodiment, the antimicrobial agent is ciprofloxacin. Open TBI is vulnerable to infection. Studies have shown that peripheral infections appear in up to 28% of patients, often associated with biofilm formation on exposed dura or bone edges. Utilizing an ACP composition as a drug delivery system facilitates sustained local topical antimicrobial release leading to a decrease in local biofilm formation and infection in open TBI. In neurosurgical settings, Ciprofloxacin-loaded ACP can be applied intraoperatively to dural edges, cranial defects, or beneath bone flaps to provide sustained prophylaxis against surgical site infection. In PFC and field environments, topical delivery with ACP offers immediate antimicrobial coverage where systemic delivery may be delayed. Ciprofloxacin is a second- generation fluoroquinolone used to treat a wide range of susceptible bacteria from gram-positive and negative clades. The germicidal effect is due to binding to bacterial DNA gyrase with a 100- fold stronger affinity than its interaction with that of mammalians, making its effect highly specific and potent. Because fluoroquinolones have no cross-resistance with other antibiotic classes, ciprofloxacin is clinically important in patients infected with resistant bacterial strains. Although ciprofloxacin has poor solubility' in w ater it has been successfully formulated into oral suspensions and intravenous injections for many indications. It can be found in the market as an ophthalmic or otic solution or suspension mixed with corticosteroids such as hydrocortisone and dexamethasone for the treatment of otitis externa among many other diseases in pediatric patients. Antibiotics, such as ciprofloxacin are frequently used prophylactically in neurosurgery when there is a risk of post-operative infections. Advantageously, ciprofloxacin can be used in ophthalmic or otic forms, which are sterile, FDA-approved and easily dispensed in dropper bottles for rapid and easy application with the ACP composition directly on to the injury.

[0068] In at least one embodiment, the ACP composition comprises both an antimicrobial agent and an anti-inflammatory agent. In one embodiment, the composition comprises ciprofloxacin and dexamethasone. This provides a multifunctional neuroprotective device. Otic and ophthalmic drops combining dexamethasone and ciprofloxacin are FDA- approved and commercially available for use in steroid responsive inflammatory conditions when bacterial infections or risk of bacterial infections exist. The ability to use existing Docket No. 89380.0005\WO ophthalmic and otic solutions in combination with the ACP compositions at the time of application greatly eases treatment steps in any application setting and provides a shape- retentive, sustained release drug delivery device and the site of brain injury. This dual-loaded ACP composition therefore provides simultaneous infection prophylaxis and neuroinflammation control in a single sustained-release dural covering.

[0069] The compositions provided herein enable provision of a comprehensive kit with anti-inflammatory, hemostatic, and antimicrobial agents to provide neuroprotection and restoration in penetrating TBI and open skull injuries during PFC. The hypothesis is that sustained release of these therapeutic agents will provide protection for at least 72 hours when occluded in ACP compositions - a biocompatible delivery medium that simultaneously covers and protects the brain. The agents may be used individually or sequentially depending on the situation. For example, in case with surface bleeding, TXA-loaded ACP provides the necessary support to control the bleeding and prevent hemorrhage, a vital first step. Once the bleeding stops, the shape-retentive device may be easily removed atraumatically (because ACP compositions do not integrate into tissue) or alternatively left in situ beneath surgical closure as a temporary or semi-permanent, and dexamethasone-ACP or dexamethasone-ciprofloxacin-ACP compositions (in case of high risk of infection) may then be applied to prevent neuroinflammation and secondary⁷ infections. Upon hydration, these embodiments maintain their ability' to absorb sufficient moisture and form contiguous, homogeneous aggregate devices necessary’ for dural coverage. The moisture vapor transmission rate (MVTR) of hydrated prototype aggregates is sufficient to help wick away exudate from the surface. These combinations provide not only sustained release of the active agents, but retention of active agents at the site of treatment and the extension of efficacy over a prolonged period of care, for example for about 72 hours to about 14 days.

[0070] As noted, PHT injuries that incorporate TBI are an open wound where the scalp, connective tissue between the scalp and the skull, and the skull is breached into the brain cavity. The dura mater may or may not be broken, however, the interior of the skull cavity' has been breached and the injury typically has an associated TBI. First responders working to stabilize a patient in this condition have straightforward protocols designed to stabilize the wound and prevent further contamination while minimizing the loss of cerebrospinal fluid. In addition, any foreign body penetrating the skull could remain in the injured area as removal of this without surgical staff could prove dangerous or fatal to the patient. A PHT will present with a random shape that could be irregular and sealing the injury above and around the dura mater is one of the principal requirements for stabilization before evacuation to secondary trauma care. In other embodiments, the same method may be used intraoperatively, for example following Docket No. 89380.0005\WO decompressive craniectomy, to conform to irregular cranial defects and provide a temporary- dural seal. The materials described herein would be applied to the PHT through the opening in the scalp. The ACP composition may be applied from a sterile dispensing package that may include a molded tip, syringe, or ampoule to facilitate application of the powder to precise areas within the injury-. As the ACP composition is applied, fluid including blood and serum hydrate the ACP composition. As the composition hydrates, the ionic strength of the body fluids causes an irreversible aggregation of the composition forming a uniform, shape-retentive mass. This mass eventually becomes a film that having conformed to the injury shape, now covers the injury' and transforms into a shape-retentive barrier covering the brain matter, bone, dura mater, and, importantly, further sealing around any penetrating foreign body. This sealing property reduces cerebrospinal fluid leakage and limits ingress of contaminants along the retained foreign body.

[0071] The ability of the ACP compositions described herein to transform around a foreign body that remains embedded in the wound and still seal is a key feature of the material that is not known to exist in any other device used in treating PHT with TBI. This property is especially advantageous in preventing cerebrospinal fluid leakage and infection risk at the injured site. In at least one embodiment, the shape-transforming APC composition is applied concurrently (immediately before or after, optionally repeated) with a liquid such that the composition is hydrated quickly and does not disperse away from the injury- site as it seals around the penetrating foreign body. This ACP composition then hydrates with fluid that may include blood and or serum. The ionic strength of the wound fluid causes the ACP material to irreversibly aggregate, forming a shape-retentive device that seals the wound surface from edge to edge, and, importantly, around a penetrating foreign body. If required, the shape-retentive device can be removed, typically by moistening the area with saline and lifting off with forceps. In surgical settings, the device may alternatively be left in situ beneath a bone flap or within a cranial defect until definitive closure is performed.

[0072] As noted, shape-transforming ACP compositions 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. These materials have numerous applications, one of which is application to PHT and non-PHT TBI. In the treatments contexts herein, the shape-transforming materials are shape-conforming until contacted with 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, these materials contain at least one active therapeutic agent that is released (e.g., diffuses) from the material over time. In the context of a treatment of TBI, the therapeutic agent is passively Docket No. 89380.0005\WO delivered from the shape-retentive state (device) to the injury. In surgical contexts, the material may also be placed beneath a dural substitute or bone flap, where its non-resorbable, shape- retentive state maintains wound sealing and supports sustained local drug delivery.

[0073] The shape-transforming APC compositions presented herein, which change from a shape-conforming state to a shape-retentive state, are substantially different in composition from conventional commercial sheet, gel, or woven pad materials. In particular, when a shapetransforming material of the present embodiments is placed in contact with a brain tissue surface or is placed in a surgical or PHT wound cavity, it assumes the shape of the tissue surface, 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. Advantageously, the shape-retentive material may be removed from the site of injury, for example with forceps or tweezers, if desired by medical personnel. In at least one embodiment, the shape-retentive APC device may be left in contact with the treated brain tissue for about 1 hour to about 24 hours, at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, or at least 14 days. In at least one embodiment, the shape-retentive APC device may be left in contact with the treated brain tissue for about 1 to about 14 days, such as about 1 to about 7 days. The shape-retentive APC device has been observed to cause no adverse effects in subjects in which the shape-retentive APC device has been left in contact with brain tissue for about 7 days.

[0074] As noted, other conventional/commercial materials exhibit high w ater uptake and pure shape-conforming properties with very⁷ low' strenglh-to-w ater-absorption 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 state have low er water absorption properties, ty pically 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, the shape-retentive materials provided 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 causing fluid accumulation, decreasing temperature as the w ater vapor is driven off and producing a slight negative pressure between the aggregate material and the tissue surface which helps in the adhesion and has also been shown to facilitate healing. These properties are particularly advantageous in neurosurgical applications where fluid accumulation can worsen intracranial pressure and impair outcomes. Docket No. 89380.0005\WO

[0075] Desirable properties for the shape-retentive materials that form irreversibly after aggregation include rate of aggregation, tensile strength, bulk modulus, elastic modulus, percent moisture/water, physical dimensions, and volume change with aggregation, sustained release rates that can be tuned for a given therapeutic index, and, optionally, ease in removing the material from the site of placement. Alternatively, because the ACP compositions are nonabsorbable, they may be used as plugs or implants for skull fractures or cranial defects. In such applications, the material not only provides structural filling but also serves as a localized drug delivery matrix to prevent infection or inflammation at the defect site.

[0076] In at least one embodiment, methods of treatment described herein provide application of adsorbent composite polymer particles 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® transforming powder (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. Additional adsorbent polymer particles may be prepared using 2-alkenoic acid, a hydroxy (2C-4C) alkyl 2-alkenoate, dihydroxy (2C-4C) alkyd 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. Selection and ratios of monomers can be tuned to adjust swelling, tensile strength, and drug release kinetics for specific neurosurgical indications. 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. Such powders may be composed of ratios of poly-a- hydroxy olefinic methacrylate polymers formed as suspensions, that can be one component or mixed components, purified, and freeze dried. These materials are selected to ensure that the transformation occurs from a shape-conforming state to a shape-retentive state when the material contacts wound fluid or aqueous solutions of physiological pH and ionic strength. These polymers have a long history of safe biomedical use, including in ophthalmic and intracranial contexts, supporting their suitability for brain-contacting applications. These materials may Docket No. 89380.0005\WO further incorporate at least one pharmaceutical agent. In at least one embodiment of treatment, the ultimate shape-retentive states are biocompatible and not quickly biodegradable - thus retaining their shape after aggregation and functioning as removable, biocompatible devices. In one embodiment, the ACP composition comprises pHEMA particles and pHPMA particles present at a weightweight ratio of 85: 15 pHEMA:pHPMA.

[0077] As noted, the methods described herein provide for application of shapetransforming preparations that may include at least one active pharmaceutical agent or therapeutic molecule selected for their desired effects, for example on the managing infections and hemorrhage to facilitate healing. For example, 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 provide an antibioticreleasing shape-transforming device. There are a variety of broad-spectrum and more targeted antibiotics that can be effective topical agents. Non-limiting examples include vancomycin, gentamicin sulfate, doxycycline hyclate. ciprofloxacin, tobramycin, and analogs and derivatives thereof. As another example, the treatments of the present embodiments may include incorporation with the shape-transforming material of 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 shape-transforming preparation for treating TBI. Different combinations of active agents can be utilized in order to customize treatments depending on the type of bacterial strain being targeted and patient resistance. The antibiotic-loaded ACP compositions extends the efficacy of the antibiotic, thereby enabling reduced dosing, which in turn reduces resources required and may reduce drug resistance development, as well as reduce origination of new bacterial mutant ty pes, n surgical settings, these antibiotic- or antiseptic-loaded ACP devices can also be applied intraoperatively following debridement or craniectomy, reducing the need for systemic antibiotic administration.

[0078] In at least one embodiment, the APC composition comprises a hemostatic agent. Examples of hemostatic agents that may be incorporated into the present embodiments include tranexamic acid, chitosan, collagen, or other 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 Docket No. 89380.0005\WO 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 lnt’1 J. Pharma. 217 (2002). Additionally, chitosan is a glycosaminoglycan (GAG) having natural abi 1 i ty 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). Collagen, and analogs and derivatives thereof, can also be included in the APC compositions used 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). In neurosurgical or trauma settings, incorporation of chitosan or collagen within ACP compositions not only enhances hemostasis but also provides a biologically familiar matrix that may reduce inflammatory responses and support tissue integration.

[0079] 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 shape-transforming materials described herein to deliver both active agents for treatment of TBI 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 local delivery of those active agents to a site in need thereof. Indeed, the technology described herein has the potential for many drug combinations to treat TBI that require more than one active agent for clinical improvement. For example, an ACP composition may be formulated with ciprofloxacin and tranexamic acid to provide simultaneous antimicrobial protection and hemorrhage control, or with dexamethasone and collagen to reduce edema while supporting dural coverage.

[0080] Regarding preparation of shape-transforming adsorbent composite polymer particle preparations, 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 1) hydroxyl-terminated methacrylate monomers and ratios by percentage of the above monomer concentrations in solution can be combined to make polymer particles through free radical initiation. These ratios can be adjusted to change the desired physical properties (e.g., time to aggregation, device Docket No. 89380.0005\WO strength, sustained release characteristic) of the ACP composition. In certain embodiments, the ratio selection may also be tailored to optimize properties specifically for neurosurgical use, such as minimizing swelling pressure against brain tissue, improving flexibility for dural coverage, or extending drug release duration in situ. Docket No. 89380.0005\WO

[0081] Further, within the polymers and copolymers noted above, 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 an APC composition. The ratios in Table 2 provide representative examples of polymer particle ratio compositions that can be designed for desired characteristics such as strength, hydration, aggregation, or sustained/controlled release of active agents. These ratios are illustrative and not limiting, and other combinations may be used to achieve desired properties. Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WO Docket No. 89380.0005\WQ

[0082] As noted, the shape-transforming materials 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 materials to provide a device tuned for different release profiles within a desired therapeutic range. For example, faster release may be desirable for rapid infection control in contaminated penetrating injuries, while slower release profiles may be selected for prolonged anti -infl ammatory or anti-edema therapy following decompressive craniectomy.

EXAMPLES

Example 1. Polymer particles for use in methods of treating TBI

[0083] 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, USA). These particles are sterile, odorless, crystalline, white powder composed of a mixture of lyophilized poly-2-hydroxyethyl-methacrylate (pHEMA) and poly-2- hydroxypropyl-methacrylate (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 Docket No. 89380.0005\WO 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 to 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 know n size ranges. Such particles may also be mixed with at least one pharmaceutical agent prior to the lyophilization process, be dry-mixed with at least one pharmaceutical agent after lyophilization, or remain as therapeutic/drug-free powders for on-demand mixing with at least one pharmaceutical agent at the point of care.

[0084] 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.

[0085] The above polymer particles are collectively called "polymer particles” and may be in suspension form or be lyophilized form. These represent the form of polymers that remain stable and useful in the shape-transforming ACP composition systems described herein.

Example 2. Application of ACP materials to PHT wounds

[0086] Anesthetized Sprague-Dawley rats underwent moderate/severe controlled cortical impact (CCI) that induced a TBI. Briefly, the animals were placed in a vented anesthesia chamber for 60 seconds and induce anesthesia with inspired isoflurane (IsoFlo, Abbott Laboratories. North Chicago, IL) at a concentration of 4% in 2: 1 N2O:O2. Animals were Docket No. 89380.0005\WO intubated mechanically ventilated throughout the surgical procedure. Each animal was treated to protect eyes per IUCAC requirements. The animal scalp was shaved with an animal hair trimmer and the exposed skin was scrubbed with betadine. A stenle drape was placed over the restraining frame with an opening for the exposed scalp. A 20 mm midline incision was created. The muscle and skull was separated using a periosteal elevator in combination with forceps. Skin was retracted and fascia was retracted to expose the underlying skull. A craniectomy was performed creating an opening approximately 6 mm in diameter that encircles the bregma and lambda and falls between the sagittal suture and the coronal ridge using a dental drill. The resulting bone flap was detached carefully to avoid disruption of the dura mater. The impact shaft was lowered centered above the craniotomy with contact on the dura mater. The piston was retracted and used to impact the tissue 2.8 mm of total distance at a velocity of 4m/second to produce a moderately severe injury. The dura mater was then incised and pulled away to expose the brain tissue at the craniotomy site. After 15 minutes, roughly 100 mg of shape- conforming/shape-retentive ACP composition was added with a spatula to the wound site. The material was allowed to hydrate or hydrated with saline above the brain matter and care was taken to ensure that the ACP composition formed an intact mass (device) across the wound, forming a fully closed hydrated surface that sealed along the margins of the craniotomy along the dura and above the brain matter. This example also demonstrates use as a temporary intracranial dural cover beneath a closed cranial flap, mimicking human neurosurgical postcraniectomy management. The cranial flap was closed over the shape-retentive ACP device for post-surgical care because rodents are known to scratch and gnaw at open wounds. (It should be noted that when the shape-transforming materials described herein are applied to human injuries, the wound would be covered as indicated by medical professional standard of care, but would not necessarily require closure as provided in this example.) Animals were sacrificed at 24 hours, 3 days, and 14 days. Brains were excised and lesion size, edema neuroinflammation, biomarkers were assessed.

[0087] Further regarding Intercranial Pressure (ICP) and Mean Arterial Blood Pressure (MAP): Under anesthesia, the right femoral artery and vein were cannulated for MAP monitoring. Animals were positioned in a stereotaxic frame under anesthesia where ICP was measured using the Codman ICP Express (Johnson & Johnson). Following placement and stabilization of the ICP probe, a 10 minute baseline recording was taken and then followed by CCI and immediate administration of ACP to the injured brain tissue. All physiological parameters were recorded using PowerLabs data acquisition system and analyzed using LabChart v7 (ADInstruments). Outliers were identified and removed. N=12 per group. Results are shown in FIG. 1: Preliminary analysis based on a 2-way ANOVA with Sadik post hoc Docket No. 89380.0005\WO method indicated that the presence of shape-transforming material on the injured brain after injun’ did not exacerbate the TBI induced ICP increase and cerebral perfusion pressure (CPP) over time after injury. Importantly, ICP and CPP values remained within physiologically acceptable ranges, supporting feasibility for translation into surgical or point of injury stabilization settings.

[0088] Further regarding edema, cerebral edema was evaluated (wet-dry method) as follows. Isolated brains were placed into a brain matrix on ice for dissection. Brains were sectioned into ipsilateral (ipsi) and contralateral (contra) to injury hemispheres and then anterior (A), medial (M), and posterior (P) sections (injury' site is in the medial section). All sections were immediately transferred to pre-weighed tubes and tissue weights were obtained (wet weight). The tubes were opened, and tissues were incubated at 60°C for 7 days. The tissues were then re-weighed (dry weight). Brain water content percentage was determined as (wet weight - dry weight)/wet weight x 100. N=8-I5 per group per time point and compared for injuries treated with ACP versus CCI controls. These findings support the potential of ACP compositions to reduce secondary brain swelling, a key determinant of neurological outcome following TBI. Results are shown in FIG. 2. More specifically, as shown in FIG. 2A. at Day 7 post-TBI, there was a significant decrease in the brain water content of the ipsilateral anterior brain section for ACP-treated animals suggesting ACP-specific reduction in edema at a subchronic stage. As shown in FIG. 2B, a direct comparison of the medial sections (lesion site region) of the ipsilateral and contra hemispheres over time confirmed edema formation over the acute 72-hour post-TBI period. ACP did not show' a significant acute effect in this model. As shown in FIG. 2C, comparison of anterior (to lesion) sections of the ipsilateral and contra hemispheres over time. At Day 7 post-TBI, the injured ipsilateral anterior had significantly less water content than matching sections of CCI controls. Outliers were determined by the ROUT method and one-way ANOVA with Tukey post hoc tests as appropriate was used to determine statistically significant differences. In all, application of the shape-retentive material onto the brain injury' site after TBI, did not affect acute cerebral edema formation. By 7 days post-TBI, there was a significant decrease in brain water content in the ipsilateral anterior brain section to the TBI injury site with the shape-retentive material application compared to the CCI only control group.

[0089] Analysis of Intracranial pressure and cerebral perfusion pressure on ACP-treated rats showed that the material w as well tolerated and did not increase pressure either intracranially or within perfusion as measured over 5 hours. This indicates that the ACP powder materials w ere well tolerated in an initial study for the protection of brain tissue in a relevant animal model of a traumatic brain injury' with penetrating head trauma. Intracranial pressure and Docket No. 89380.0005\WO cerebral perfusion pressure over time are shown for the ACP and control rats with the same injun’ but no treatment in FIG. 1. It should be noted that foreign bodies such as cotton gauze or polymer films may result in foreign body responses with increased pressure.

[0090] A further analysis compared TBI lesion size with or without treatment with a shape-retentive material as described herein. For analysis, fixed brain tissue was sectioned, stained with hematoxylin and eosin (H&E), and then region of interest (lesion) was manually- traced by blinded individuals using scientific image analysis software for quantification. T tests were used to assess statistical significance. The results are shown in FIG. 3 A, showing mean lesion volumes and standard error means (SEMs) for CCI (gray bars) or CCI treated with shape- retentive material (black bars). Although there was a significant difference at 72 hours post-TBI between the two groups, there was no difference by 7 days post-TBI. This indicates that ACP compositions do not exacerbate lesion expansion and may provide early neuroprotection without interfering with the natural course of lesion resolution.

[0091] An additional study provided quantification of the protein marker Iba-1, w hich indicates microglial activation or an inflammatory response in the hippocampal and cortex brain regions of both the ipsilateral (injured) and contralateral brain hemispheres. The results are shown in FIG. 3B and FIG. 3C. Mean pixel intensity and SEM are shown with gray bars indicating the CCI control, and black bars showing the CCI shape-retentive material. Outliers were evaluated using the ROUT method and statistical significance w as determined by one-way ANOVA with Tukey post hoc tests as applicable. In all. there were no significant differences in microglial inflammatory responses in the brain hippocampus and cortex regions with the application of the shape-retentive material compared to the control group. This lack of excess inflammatory- activation is advantageous compared to conventional foreign body materials, which often exacerbate gliosis or scarring.

[0092] These analyses showed that application of a shape-retentive material as described herein o the injured brain following TBI did not exacerbate the TBI lesion or microglia (inflammatory-) response. Together, these studies demonstrate that ACP-based shapetransforming materials are biocompatible, safe for intracranial use, and effective as temporary dural coverings capable of delivering localized therapy.

[0093] 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 w ill be apparent to those skilled in the art to which the disclosure pertains.

Claims

Docket No. 89380.0005\WO CLAIMS We claim:

1. A method of treating a subject having exposed brain tissue or dura resulting from traumatic brain injury (TBI), penetrating head trauma (PHT), decompressive craniectomy, cranial defect, or other neurosurgical procedure, comprising applying to a brain injury a covering, protecting, formation of a dural device comprising a shape-transforming composition comprising adsorbent composite particles of n-hydroxy-n-alkyl-m-methylprop-2-enoate polymers, wherein where n and m can range from 1 to 3.

2. The method of claim 1, wherein the polymers of the adsorbent composite particles are selected from those in Table 1.

3. The method of claim 1, wherein the polymers of the adsorbent composite particles are selected from those in Table 2.

4. The method of claim 1, wherein the polymers are 2-hydroxypropylmethacrylate and 2 day droxy ethylmethacrylate polymers.

5. The method of any one of claims 1 to 4. wherein the polymers are present in the amount of 1 %: 99% to 99%: 1% for the polymers by mass.

6. The method of any one of claims 1 to 5, wherein the applying is to an area of brain injury’, cranial defect, or surgically exposed brain tissue.

7. The method of claim 6, wherein upon applying the adsorbent composite particles composition adsorbs body fluid, hydrates, and forms a shape-conforming matrix.

8. The method of claim 7, wherein the body fluid is blood, serum, or cerebrospinal fluid.

9. The method of any one of claims 1 to 6, further comprising the step of applying saline, wherein the adsorbent composite particles composition adsorbs the saline, hydrates, and forms shape-conforming matrix. Docket No. 89380.0005\WO

10. The method of any one of claims 7-9, wherein the adsorbent composite particles of the shape-conforming matrix aggregate and the matrix transforms from a shape-conforming matrix to a hydrated shape-retentive device.

11. The method of claim 10, wherein the hydrated shape-retentive device contains fluid.

12. The method of claim 11, wherein the fluid within the hydrated shape-retentive device is between 20% and 80% of the shape retentive composition by weight.

13. The method of any one of claims 10-12, wherein the hydrated shape-retentive device covers injured, defective, or surgically exposed area in contact with brain tissue, dura, or bone.

14. The method of claim 13, wherein the hydrated shape-retentive device is in contact with the dura tissue in the brain cavity.

15. The method of claim 13. wherein the hydrated shape retentive device is in contact with bone tissue within the brain cavity.

16. The method of claim 13, wherein the hydrated shape-retentive device is in contact with brain tissue within the brain cavity.

17. The method of claim 10, wherein the hydrated shape-retentive device acts as a barrier to prevent dirt and debris from contacting brain tissue in the injury.

18. The method of claim 10, wherein the hydrated shape-retentive device acts as a barrier to prevent exogenous bacteria from contacting brain tissue in the injury.

19. The method of claim 10, further comprising the step of covering the hydrated shape- retentive device with skin.

20. The method of claim 10, further comprising the step of removing the hydrated shape- retentive device from the site of the injury, cranial defect, or surgical exposure site.

21. The method of claim 20, wherein the removing step is conducted after 1 minute to 60 minutes, after 1 hour to 24 hours, after 1 day to 14 days, after 1 day, after 2 days, after 3 days, Docket No. 89380.0005\WO after 4 days, after 5 days, after 6 days, after 7 days, after 8 days, after 9 days, after 10 days, after 11 days, after 12 days, after 13 days, or after 14 days.

22. The method of claim 1, wherein the covering, protecting, formation of a dural device comprising a shape-transforming composition comprising adsorbent composite particles further comprises at least one pharmaceutical agent.

23. The method of claim 1 , further comprising the step of applying to the injury, cranial defect, or surgical site exposure, a solution comprising at least one pharmaceutical agent currently with (immediately before, during or after) applying the covering, protecting, formation of a dural device comprising a shape-transforming composition comprising adsorbent composite particles, whereby the solution comprising at least one pharmaceutical agent is adsorbed by the shape-transforming composition comprising adsorbent composite particles to form a shape- retentive device comprising the at least one pharmaceutical agent.

24. The method of claim 23. wherein the at least one pharmaceutical agent is occluded within the shape-retentive device.

25. The method of any one of claim 22 to 23, wherein the at least one pharmaceutical agent is released from the dural device comprising a shape-transforming composition comprising adsorbent composite particles over time.

26. The method of any one of claims 22 to 24, wherein the at least one pharmaceutical agent is a growth factor, neurotrophic growth factor, anti-inflammatory agent, pain-management agent, antioxidant, enzyme, antimicrobial agent, anti-seizure agent, hyperosmolar agent, biofilm- inhibiting/dispersal agent, hemostatic agent, nucleic acid, acetyl L-camitine, glyceryl tri-acetate, resveratrol tri-acetate, n-acetylcysteine, candesartan, or a combination of any of these.

27. The method of claim 26, wherein the at least one pharmaceutical agent is a combination of hemostatic agent and antibiotic.

28. The method of claim 26, wherein the at least one pharmaceutical agent is a combination of antibiotic and anti-inflammatory agent. Docket No. 89380.0005\WO

29. The method of claim 26, wherein the at least one pharmaceutical agent is: an antibiotic or antimicrobial, such as ciprofloxacin, tobramycin, doxycycline, vancomycin, gentamicin, polyhexamethylene biguanide, minocycline, ceftriaxone, trovafloxacin, or silver sulfadiazine; a hemostatic agent such as collagen, chitosan, or tranexamic acid; an anti-seizure/antiepileptic agent, such as phenytoin, levetiracetam, or valproate; an agent to reverse anticoagulant or antiplatelet activities thereby effecting a decrease in clotting, such as unfractionated heparin, low molecular weight heparin, a Vitamin K antagonist such as warfarin, direct thrombin inhibitors, andexanet alfa, or ciparantag; an agent to decrease intracranial pressure, such as hyperosmolar agents, mannitol, or hypertonic concentrations of salt; an anti-inflammatory agent, such as corticosteroid, dexamethasone, betamethasone, methylprednisone, or triamcinolone; or any combination of any of these.

30. The method of claim 29. wherein the at least one pharmaceutical agent is a combination of ciprofloxacin and dexamethasone.

31. The method of any one of claims 26 to 30, wherein the pharmaceutical agent is present at a concentration range of about 0.01% by weight to about 10.0% by weight of the shape-transforming composition comprising adsorbent composite particles.

32. The method of claim 1. wherein the dural device comprising a shape-transforming composition comprising adsorbent composite particles provides at least one of antiinflammatory, hemostatic, anti-biofilm, anti-edema/anti-swelling therapeutic benefits in the subject suffering from the injury.

33. The method of any one of claims 22 to 32, wherein at least one pharmaceutical agent is selected from any therapeutic, prophylactic, or diagnostic agent capable of being delivered locally or sustained-release from the shape-transforming composition, including small molecules, peptides, proteins, nucleic acids, biologies, antibodies, cells, or combinations thereof.

34. The method of any one of claims 1 to 33, wherein the hydrated shape-retentive device is used as a temporary dural substitute or graft cover during a neurosurgical procedure. Docket No. 89380.0005\WO

35. The method of any one of claims 1 to 33, wherein the hydrated shape-retentive device is used to cover or protect a cranial defect or bone flap site following decompressive craniectomy or other surgical exposure.

36. The method of any one of claims 1 to 33, wherein the hydrated shape-retentive device is used as a temporary implant to maintain brain protection until definitive surgical closure.

37. A method of treating a subject having exposed brain tissue or dura resulting from traumatic brain injury' (TBI), penetrating head trauma (PHT), decompressive craniectomy, cranial defect, or other neurosurgical procedure, comprising applying to the exposed site a shape-transforming composition comprising adsorbent composite particles of n-hydroxy-n- alkyl-m-methylprop-2-enoate polymers, wherein n and m can range from 1 to 3, thereby forming a protective dural-covering device in contact with brain tissue, dura, or bone, optionally providing localized delivery of at least one pharmaceutical agent, wherein the method is performed in a prehospital, battlefield, civilian emergency', or surgical or other care setting.

38. The method of any one of the preceding claims, wherein the adsorbent composite particles are a mixture of lyophilized poly-2-hydroxyethyl-methacrylate (pHEMA) and poly-2- hydroxypropyl-methacrylate (pHPMA) particles combined in a ratio of 85: 15.