WO2025014642A2 - Compositions, methods of making, and methods of using multi-functional antimicrobial polymers - Google Patents

Compositions, methods of making, and methods of using multi-functional antimicrobial polymers Download PDF

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WO2025014642A2
WO2025014642A2 PCT/US2024/035284 US2024035284W WO2025014642A2 WO 2025014642 A2 WO2025014642 A2 WO 2025014642A2 US 2024035284 W US2024035284 W US 2024035284W WO 2025014642 A2 WO2025014642 A2 WO 2025014642A2
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polymer
reaction mixture
construct according
alkyl
formula
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WO2025014642A3 (en
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Dae Won Park
Lucas DUNCAN
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University of Colorado System
University of Colorado Colorado Springs
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University of Colorado System
University of Colorado Colorado Springs
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02Polyamines
    • C08G73/0206Polyalkylene(poly)amines
    • C08G73/0213Preparatory process
    • C08G73/0226Quaternisation of polyalkylene(poly)amines
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02Polyamines
    • C08G73/024Polyamines containing oxygen in the form of ether bonds in the main chain

Definitions

  • Embodiments of the instant disclosure generally relate to multifunctional or multimodal polymers having one or more including, but not limited to, antimicrobial properties, wound healing properties, analgesic, and hemostatic properties.
  • constructs containing at least one of the multifunctional or multimodal polymers, methods of making the multifunctional or multimodal polymers, and methods of using the multifunctional or multimodal polymers are disclosed herein.
  • Traditional sterilization techniques primarily involve heat, chemical agents, radiation, or a combination of these methods.
  • Autoclaving a common heat-based sterilization method, effectively eliminates microorganisms but is not suitable for heat-sensitive materials or treating large surfaces.
  • Chemical disinfection methods including the use of disinfectants and liquid sterilants, are often limited by their compatibility with specific materials and potential toxic side effects.
  • Radiation-based sterilization such as gamma irradiation or electron beam irradiation, can be effective but may alter the properties of certain materials and require space and equipment to prevent exposure to those using such processes.
  • gamma irradiation or electron beam irradiation can be effective but may alter the properties of certain materials and require space and equipment to prevent exposure to those using such processes.
  • residual microorganisms can persist on surfaces and devices due to inadequate penetration or incomplete contact with the sterilizing agents. Microorganisms can also develop resistance to conventional disinfectants over time, diminishing their effectiveness. Additionally, repeated use of sterilization techniques can cause wear and tear on delicate medical devices, potentially compromising their functionality.
  • Embodiments of the present disclosure relate to constructs of multifunctional or multimodal polymers having at least one of antimicrobial, wound healing, analgesic, and/or hemostatic properties, methods of making the constructs, kits, and methods of using the constructs.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (I), (I); [0007] wherein R1, R2, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, a heterocycle, an aryl, and a heteroaryl, wherein the heterocycle, the aryl and the heteroaryl are each independently unsubstituted or are optionally, independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio; R3 can be a substituted or unsubstituted al
  • R 1 and R 2 can each be independently H, methyl, ethyl, propyl, butyl, pentyl, hydroxyl, or any combination thereof.
  • R 5 can be alkyl, aryl, or any combination thereof
  • R 3 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or any combinations thereof.
  • R6 can be hydrogen.
  • R 1 and R 2 can be methyl, R 5 can be methyl, R 6 can be hydrogen, n can be 1, and a can be 1.
  • R1, R2, and R6 can be hydrogen, n can be an integer from 1 to 5, and a can be 0.
  • R1 can be methyl
  • R2 and R6 can be hydrogen
  • n can be 1, and a can be 0.
  • R 1 can be hydroxyl
  • R 2 and R 6 can be hydrogen, n can be 1, and a can be 0.
  • R1 and R2 can be methyl, R5 can be phenyl, R6 can be hydrogen, n can be 1, and a can be 1.
  • R 1 , R 2 , and R 6 can be hydrogen, n can be 1, a can be 0, and r can be an integer between 1 and 150.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (II), (II); wherein R4 can be a substituted or unsubstituted alkyl and the polymer is a quaternized polymer.
  • R1 and R2 can be methyl, R3 can be octyl, R4 can be hexyl, R5 can be methyl, R6 can be hydrogen, n can be 1, and a can be 1.
  • R 1 and R 2 can be methyl, R 3 can be octyl, R 4 can be hexyl, R 5 can be methyl, R 6 can be imidazole-1-yl ethan-1-one, n can be 1, and a can be 1.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (III),
  • the polymer is a crosslinked polymer.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (IV), wherein the polymer is a zwitterionic polymer.
  • the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (V) or formula (VI),
  • the present disclosure provides methods of preparing the polymers in the construct.
  • the method of preparing the polymer includes a first reaction mixture of a first organocatalyst, a first solvent, a primary amine, and a terminal di- epoxide.
  • the method further includes performing a first heat treatment to the first reaction mixture for a time period sufficient to allow the formation of the polymer of formula (I)
  • the primary amine can be a compound of formula (VII) or (IX) and the terminal di-epoxide can a compound of formula (X), wherein R 1 , R 2 , R 5 , a, and n are as described previously; and p is an integer between 1 to 20.
  • the terminal di-epoxide can be neopentyl glycol diglycidyl ether, alkyl diglycidyl ethers, propylene glycol diglycidyl ether, glycerol diglycidyl ether, bisphenol A diglycidyl ether, and/or polyethylene glycol diglycidyl ether.
  • the first organocatalyst is 4-dimethylamino pyridine (DMAP) or optionally, triphenyl phosphate (TPP).
  • the first solvent is a polar solvent.
  • the first heat treatment includes heating the first reaction mixture to a first temperature.
  • the present disclosure provides methods of preparing polymers in the construct.
  • the method of preparing the polymer can include forming a second reaction mixture using the polymer of formula (I), an alkyl halide, a second solvent, and a bicarbonate salt.
  • the method further includes performing a second heat treatment to the second reaction mixture allowing formation of a quaternized polymer of formula (II).
  • the second solvent is a polar solvent.
  • the second reaction mixture is heated to a second temperature.
  • the present disclosure provides methods of preparing polymers in the construct.
  • the method of preparing the polymer includes forming a third reaction mixture using the quaternized polymer, a diglycidyl ether, and a third organocatalyst.
  • the method can include performing a third heat treatment to the third reaction mixture to form the crosslinked polymer of formula (III).
  • the third organocatalyst is a Lewis acid.
  • the third reaction mixture is heated to a third temperature.
  • the method can include forming a fourth reaction mixture using the polymer and a sultone forming the anionic quaternized polymer of formula (IV).
  • the method can include forming a fifth reaction mixture using the quaternized polymer and a coupling agent, performing a fourth heat treatment to the fifth reaction mixture to form a coupled-quaternized polymer, forming a sixth reaction mixture using the coupled-quaternized polymer and a peptide, and performing a fifth heat treatment to the sixth reaction mixture to form the peptide coupled-quaternized polymer of formulae (V) or (VI).
  • the present disclosure provides methods of preparing a substrate with antimicrobial activity, hemostatic activity, or both.
  • the method includes coating or spraying the substrate with the construct of formulae (I) to (VI).
  • the present disclosure provides methods of providing an antimicrobial agent to a subject, medical device, or surface, the method including applying to the subject, medical device, or surface a composition of at least one construct of formula (I).
  • the present disclosure provides a pharmaceutical composition.
  • the pharmaceutical composition can include the construct of formula (I) to (VI) and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition can include aqueous formulation, gelatinous formulation, a formulation on a pad, a patch, a gelatinous material or other wound dressing or a paste formulation.
  • the pharmaceutical composition can include a topical formulation.
  • kits can include one or more constructs disclosed herein and/or one or more anyone pharmaceutically-acceptable formulations disclosed herein and at least one container.
  • kits disclosed herein can be used for antimicrobial and hemostatic effect.
  • FIG. 1 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 1 ((poly(octyl neopentyl diglycidyl ether amine) or pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 2 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 2 (hexyl-poly(octyl neopentyl diglycidyl ether amine) or H-pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 1 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 1 ((poly(octyl neopentyl diglycidyl ether amine) or pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 2 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 2 (hexyl-poly(octyl neopenty
  • FIG. 3 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 3 in accordance with certain embodiments of the present disclosure.
  • FIG. 4 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 4 (propane sultone-poly(octyl neopentyl diglycidyl ether amine) or PS- pONDEA) in accordance with certain embodiments of the present disclosure.
  • FIG. 5 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 5 in accordance with certain embodiments of the present disclosure.
  • FIG. 6 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 6 in accordance with certain embodiments of the present disclosure.
  • FIG. 7 represents a schematic correlating properties and structure of multifunctional polymer constructs and certain applications of the constructs in accordance with certain embodiments of the present disclosure.
  • FIGS.8A-8D represent 1 H-NMR spectra of Polymer 1, Polymer 2, Polymer 4, and a hybrid polymer of Polymer 2 and Polymer 4 in accordance with certain embodiments of the present disclosure.
  • FIGS. 9A-9C represent data traces for thromboelastography (TEG) assay with untreated whole blood (FIG. 9A), kaolin treated blood (FIG. 9B), and Polymer 4 treated blood (FIG.9C) in accordance with certain embodiments of the present disclosure.
  • FIGS.10A-10C represent cytotoxicity results of Polymer 4 using AlamarBlue Assay on L929 cells in accordance with certain embodiments of the present disclosure.
  • DEFINITIONS can mean relative to the recited value, e.g., amount, dose, temperature, time, percentage, etc., ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, or ⁇ 1%.
  • an analog refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • isomers refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • alkyl refers to a saturated aliphatic hydrocarbon group including C1- C20 straight chain and branched chain groups.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, I-ethyl propyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4- methylhexyl,
  • An alkyl group can be a lower alkyl having 1 to 6 carbon atoms.
  • Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and etc.
  • the alkyl group can be substituted or unsubstituted.
  • the substituent group(s) can have one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio, carbonyl, carboxy or carboxylic ester.
  • cycloalkyl refers to saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group and have 3 to 20 carbon atoms.
  • monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl etc.
  • a polycyclic cycloalkyl can include the cycloalkyl having Spiro ring, fused ring, and bridged ring.
  • the substituent group(s) can be one or more groups independently selected from of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio, carbonyl, carboxy or carboxylic ester.
  • hydroxyl refers to an —OH group.
  • hydroxyalkyl refers to -alkyl-OH, wherein alkyl as defined above.
  • halo or “halogen” refers to fluoro, chloro, bromo, or iodo.
  • thiol refers to an organosulfur compound according to the form R ⁇ SH, where R represents an alkyl or other organic substituent.
  • carbonyl refers to —C( ⁇ O)—.
  • nitro refers to —NO2.
  • cyano refers to —CN.
  • amino refers to —NH2.
  • “carboxy” refers to —C( ⁇ O)OH.
  • “carboxylic ester” refers to —C( ⁇ O)O-alkyl.
  • “optionally substituted” indicates that a group can be unsubstituted or can be substituted with one or more substituents as provided herein or known in the art.
  • substituted in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced.
  • substituted includes the provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (e.g. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination).
  • a single atom can be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • Suitable substituents are defined herein for each substituted or optionally substituted group.
  • polymers can be in liquid form, and can be applied to a subject, medical device, or surface as a suspension (e.g., alcohol suspension or other aqueous suspension).
  • Anti- microbial activity of the polymer can be beneficial in preventing pathogenic microbial infections in healthcare settings among other uses.
  • polymers disclosed herein can provide active bactericidal activity, minimizing the risk of any incidentally introduced bacteria or eliminating any existing bacterial contaminants.
  • materials disclosed herein can be non-cytotoxic, biocompatible, and biodegradable. Unlike traditional sterilization methods, the antimicrobial polymers disclosed herein provide continuous and broad-spectrum antimicrobial activity, ensuring immediate elimination of any contaminants and sustained anti-bacterial protection over time.
  • application methods used for distributing these compositions can permit even coverage on various surfaces and complex-shaped devices, overcoming the limitations of penetration and accessibility and improving accessibility for improved sterility.
  • the polymer coating is compatible with a wide range of substrates, including heat-sensitive materials, enabling its application in diverse settings (e.g., medical, military, for surfaces susceptible to contamination, etc.).
  • Some embodiments disclosed herein concern agents, methods, and processes of use in preparing the disclosed constructs and compositions containing constructs disclosed herein. It is understood that combinations, subsets, interactions, agents disclosed herein where specific reference of each individual and collective combinations and permutation of these constructs cannot be explicitly disclosed, each is contemplated. Additional embodiments of the disclosure are described below. I.
  • the present disclosure provides anti-microbial constructs in the form of polymers for eliminating microbes and providing protection from pathogenic microbes on surfaces and to treat, prevent, or ameliorate a microbial infection in a subject in need thereof (e.g., a wound).
  • the different elements of the polymer can be modified to increase or decrease hydrophobicity for tailored use for a given purpose.
  • a polymer can include a construct according to formula (I), ( ); an analog, an isomer, a pharmaceutically acceptable salt, and/or a prodrug thereof, and/or formulation thereof; wherein R 1 , R 2 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, a heterocycle, an aryl, and a heteroaryl.
  • the heterocycle, the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio;
  • R 3 can include a substituted or unsubstituted alkyl; n is independently an integer from 1 to 15; or from 1 to 12; a is independently 0 or an integer from 1 to 5; r is independently an integer from 1 to 150; or from 1 to 135; and m is independently an integer from 10 to 200 [0071]
  • R1 and R2 are each independently H,
  • R 5 is alkyl, aryl, or any combination thereof.
  • R 3 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or any combinations thereof.
  • R 6 can be hydrogen.
  • R 1 and R 2 are methyl, R 5 is methyl, R 6 is hydrogen, n is 1, and a is 1.
  • R1, R2, and R6 can be hydrogen, n can be an integer from 1 to 5, and a can be 0.
  • R 1 is methyl, R 2 and R 6 are hydrogen, n is 1, and a is 0. In some embodiments, R 1 is hydroxyl, R 2 and R 6 are hydrogen, n is 1, and a is 0. In yet other embodiments, R1 and R2 are methyl, R5 is phenyl, R6 is hydrogen, n is 1, and a is 1. In some embodiments, R1, R2, and R6 are hydrogen, n is 1, a is 0, and r is an integer between 1 and 150. [0073] In some embodiments, polymers of the present disclosure can include Formula (XI), wherein m can range [0074] In some embodiments, the polymer can include Formula (II), wherein R 4 is a aryl.
  • Linear polymeric units can also be crosslinked to form gels of varying mechanical properties, which can be delivered via syringe to fill a three-dimensional space.
  • the polymer can include Formula (III), wherein the [0078]
  • the polymer can include zwitterionic groups, which can enhance hemostatic abilities and/or biocompatibility.
  • the polymer can include Formula (IV), wherein the [0079]
  • polymers of the present disclosure can include Formula (XIII),
  • polymers of the present disclosure can include Formula (XV), ; wherein m can [0082] In some embodiments, polymers of the present disclosure can include Formula (XVI),
  • constructs of the present disclosure can be in the form of a pharmaceutically acceptable salt.
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt it is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • a salt can refer to a salt, which can be formed when a polymer herein has an acidic group such as carboxyl or a basic group such as amino or imino.
  • a salt of a polymer disclosed herein can be formed with an acidic group, can include, but is not limited to alkali metal salts such as a sodium salt, potassium salt or lithium salt, alkaline earth metal salts such as a calcium salt or magnesium salt, metal salts such as an aluminum salt or iron salt; amine salts, e.g., inorganic salts such as an ammonium salt and organic salts such as a t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N′-dibenzy
  • polymers of the present disclosure can be in a crystalline form or a crystalline and amorphous form combination or mixture.
  • polymers in a solid state can exist in a crystalline, powder, or non-crystalline form, or as a mixture thereof.
  • polymers disclosed herein in crystalline form can be used to form acceptable solvates. A skilled artisan can appreciate that acceptable solvates can be formed where solvent molecules are incorporated into the crystalline lattice during crystallization.
  • solvates for uses disclosed herein can include nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or they can include water as the solvent incorporated into the crystalline lattice.
  • Solvates where water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates can include stoichiometric hydrates as well as compositions containing variable amounts of water. The present disclosure encompasses all such solvates known in the art.
  • polymers of the present disclosure can exist in crystalline form, including various solvates thereof, and can exhibit polymorphism (e.g., the capacity to occur in different crystalline structures). These different crystalline forms are referred to herein as "polymorphs.” Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and/or other descriptive properties of the crystalline solid state. Polymorphs, therefore, can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X- ray powder diffraction patterns, NMR signatures, which can be used for identification. In certain embodiments, polymers of the present disclosure can be polymorphs.
  • FIG.7 is a schematic illustration of a multimodal composition contemplated herein.
  • Polymer systems known in the art can either be impregnated with bactericidal agents that are gradually released into the surrounding environment or can include bactericidal agents bound to the polymer backbone that do not leech into the environment.
  • Agent leaching coatings have a limited lifetime for bactericidal activity as the active agent is removed from the coating and must be regenerated via subsequent bactericide treatments for continued activity.
  • non- leeching leaching polymeric systems such as poly(quaternary ammonium) compounds (QAC) can possess bactericidal activity almost indefinitely without release of agents into the environment.
  • QAC poly(quaternary ammonium) compounds
  • the antimicrobial action of QACs is mostly attributed to their ability to increase cell permeability and disrupt the cell membrane.
  • the structure should possess a long alkyl chain to provide a hydrophobic segment.
  • the cationic sites of the QACs bind to anionic sites of the cell-wall surface by electrostatic interaction. Subsequently, the long alkyl chains disrupt the cytoplasmic membrane, leading to the death of the cells. Alkyl chain lengths between C6 and C8 could kill various strains of Gram-negative and Gram- positive bacteria, and even viruses.
  • polyQACs with a long alkyl chain can provide reliable anti-microbial properties against a variety of pathogens causing disease in humans and other mammals.
  • Bacteria and other cells commonly exhibit an anionic or net negative charge, due to surface protein charge and ion exchange across the membrane.
  • bacteria In contrast to mammalian cells, bacteria exhibit a significantly higher density of negatively charged phospholipid head groups, enhancing their susceptibility to electrostatic interactions.
  • Cell membranes of bacteria are selectively permeable, with embedded channels that control the flow of ions, metabolites, and other substances across the membrane. The ability of bacteria to control and expel contents of the cytoplasm are important to resisting effects of antibiotics.
  • quaternized polymers as disclosed herein can have anti- microbial properties.
  • an anionic cell surface can be electrostatically attracted to the positively charged quaternized nitrogen atoms on the polymer.
  • hydrophobic acyl chains can penetrate bacterial cell membranes, lysing the bacterium and killing the bacteria.
  • one advantage of polymer constructs disclosed herein, and other polymeric based microbicides is their non-reliance on uptake into the bacterial envelope in order to function. Adaptation of membrane channels and improved elimination of bactericidally active compounds from within the bacteria is a main mechanism for antibacterial resistance.
  • the mechanism utilized by cationic, hydrophobic polymers is such that the material does not rely on uptake into the bacterial interior, and thus, bypasses any sort of bacterial resistance mechanism.
  • antibacterial function of the polymer constructs disclosed herein can also operate partly upon this principle, providing a strong attraction and lysing bacterial cells.
  • Hemostasis describes the natural ability of blood to clot, thereby preventing uncontrolled hemorrhage.
  • a variety of mechanisms can be responsible for adjunct mediated hemostasis. Common to all hemostatic materials is the catalytic effect on the coagulation cascade, an enzymatically mediated process which facilitates clot formation and the beginning of the wound healing process. For some materials, this can be a simple mechanism such as fluid absorption leading to a concentration of proteins and cells, to biologically active factors such as thrombin that are direct factors in the coagulation cascade.
  • Cationic polymers initially support this process by the electrostatic attraction mechanism, which leads to the aggregation of cellular components of whole blood, including red blood cells and platelets. This supports the coagulation cascade with activation of platelets and concentration of coagulation factors. While effective, interactions with exclusively cationic polymers can be cytotoxic, through the same membrane disruption mechanism that is effective against bacterial cells. Therefore, to achieve the results of effective hemostasis while preserving biocompatibility and bactericidal action, the material’s design must be tuned. [0096] In contrast with cationic polymers, zwitterionic materials contain a balance of negatively and positively charged functional groups. These materials are well characterized as biocompatible, and non-inflammatory.
  • Positively charged polymeric materials can accelerate hemostasis by electrostatic interaction between positively charged groups and negatively charged red blood cell membranes, which result in a formation of a strong hemostatic plug at the injury sites. In addition, they facilitate platelet adhesion, activation, and agglomeration by increasing the glycoprotein complex.
  • Some biologically-derived materials such as chitosan, collagen, and keratin have shown hemostatic properties. Although these materials are readily available, there are risks of disease transmission and toxicity associated with the use of those materials. Based on these facts, synthetic-based positively charged materials can be a good alternative hemostatic material.
  • quaternized polymers functionalized with peptides or other agents disclosed herein can have hemostatic properties.
  • analgesic agent Although the precise molecular mechanisms of analgesic agent action remain elusive, clinical studies report that the administration of analgesic agents at a dose of about 1.0 mg/kg to about 3.0 mg/kg reduces different types of pain including but not limited to neuropathic pain, diabetic neuropathy, peripheral nerve injury, chronic regional pain, and central pain.
  • FDA approved analgesic agents such as lidocaine jelly product to control local pain.
  • An analgesic strategy can be to develop a system capable of sustained and local delivery of analgesic agents such as lidocaine.
  • polymer constructs disclosed herein can be used as a vehicle for sustained delivery of analgesic agents such as lidocaine.
  • compositions of the instant disclosure include at least one polymer according to the instant disclosure for use to treat, prevent, or ameliorate a microbial infection in a subject in need thereof.
  • the polymer can be, for example as described in Section I.
  • pharmaceutical compositions can include at least one polymer disclosed herein and at least one pharmaceutically acceptable carrier.
  • pharmaceutical compositions can include pharmaceutically acceptable carriers, excipients, and/or stabilizers are nontoxic to recipients at dosages and/or concentrations used to practice the methods disclosed herein.
  • the pharmaceutically acceptable excipient can include, but is not limited to a diluent, a binder, a filler, a buffering agent, a pH modifying agent, a disintegrant, a dispersant, a preservative, a lubricant, or a coloring agent.
  • concentrations and types of excipients utilized to form pharmaceutical compositions disclosed herein and contemplated herein can be selected according to known principles of pharmaceutical science and knowledge in the art.
  • the excipient can be a diluent.
  • the diluent can be compressible (i.e., plastically deformable) or abrasively brittle.
  • Non-limiting examples of suitable compressible diluents can include, but are not limited to, microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, dextran, and trehalose or the like.
  • MCC microcrystalline cellulose
  • cellulose derivatives i.e., acetate
  • Non-limiting examples of suitable abrasively brittle diluents include dibasic calcium phosphate (anhydrous or dihydrate), calcium phosphate tribasic, calcium carbonate, and magnesium carbonate.
  • the excipient can be a binder.
  • Suitable binders include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C 12 -C 18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
  • the excipient can be a filler.
  • Suitable fillers include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone.
  • the filler can be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.
  • the excipient can be a buffering agent.
  • Suitable buffering agents include, but are not limited to, phosphates, carbonates, citrates, tris buffers, polysaccharide buffers, and buffered saline salts (e.g., Tris buffered saline, or phosphate buffered saline).
  • the excipient can be a pH modifier.
  • the pH modifying agent can be sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid.
  • the excipient can be a disintegrant. The disintegrant can be non-effervescent or effervescent.
  • non- effervescent disintegrants include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro- crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth.
  • suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid.
  • the excipient can be a dispersant or dispersing enhancing agent.
  • Suitable dispersants can include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isomorphous silicate, and microcrystalline cellulose.
  • the excipient can be a preservative.
  • suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol.
  • the excipient can be a lubricant.
  • suitable lubricants include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate, or stearic acid.
  • the excipient can be a coloring agent. Suitable color additives include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).
  • Other pharmaceutically acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or ly
  • the present disclosure provides anti-microbial compositions. In some embodiments, the present disclosure provides anti-microbial and hemostatic compositions. In some embodiments, the present disclosure provides for constructs having at least one of anti- microbial, hemostatic, and wound healing compositions. In some embodiments, the present disclosure provides multimodal compositions including any one or more of anti-microbial compositions, hemostatic compositions, wound healing compositions, analgesic compositions, or compositions of any combinations thereof.
  • anti-microbial polymers disclosed herein provide a diverse range of forms and applications to combat microbial growth and to eliminate existing contaminations.
  • these compositions can manifest as sprays, enabling convenient and efficient disinfection of various surfaces and objects.
  • sprays disclosed herein can be applied to a wound and can cure into a layer or uniform layer that can protect the wound.
  • Sprayable compositions can be easily applied relative to surgical incision drapes that require labor intensive placement to avoid bubble and wrinkles.
  • these polymers can also take the form of foams, providing a versatile means of targeting specific areas or achieving controlled coverage.
  • anti- microbial polymers can be incorporated to offer enhanced hygiene benefits during handwashing or body cleansing routines. Additionally, these compositions can be found in gels, creams, and ointments, providing localized anti-microbial properties for skincare or wound care applications. Overall, the versatility of anti-microbial polymer compositions allows for their integration into numerous products, enabling effective microbial control across a wide range of settings.
  • the polymers of the instant disclosure can include, but is not limited to, suspensions in organic solvents. In some embodiments, the solvent is a protic solvent.
  • protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof.
  • protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof.
  • the method of preparing the polymer includes a first reaction mixture of a first organocatalyst, a first solvent, a primary amine, and a terminal di- epoxide.
  • the method further includes performing a first heat treatment to the first reaction mixture for a period of time sufficient to allow the formation of the polymer of formula (I)
  • the primary amine can be a polymer of formula (VII) or (IX) and the terminal di-epoxide can be a polymer of formula (X), wherein R 1 , R 2 , R 5 , a, and n are as described previously; and p is an integer between 1 to 20.
  • the terminal di-epoxide can include a structure selected from the group including, but not limited to: [00119] In some embodiments, the terminal di-epoxide can be neopentyl glycol diglycidyl ether, alkyl diglycidyl ethers, propylene glycol diglycidyl ether, glycerol diglycidyl ether, bisphenol A diglycidyl ether, and/or polyethylene glycol diglycidyl ether. [00120] In some embodiments, the first organocatalyst is triphenyl phosphine (TPP).
  • TPP triphenyl phosphine
  • the first organocatalyst is 4-dimethylaminopyridine (DMAP); optionally where the first organocatalyst is triphenyl phosphine (TPP ).
  • the first solvent is a polar solvent.
  • the first heat treatment includes heating the first reaction mixture to a first temperature.
  • the present disclosure provides methods of preparing polymers in the construct. The method of preparing the polymer can include forming a second reaction mixture using the polymer of formula (I), an alkyl halide, a second solvent, and a bicarbonate salt.
  • the method further includes performing a second heat treatment to the second reaction mixture allowing formation of a quaternized polymer of formula (II).
  • a quaternized polymer can have antibacterial properties.
  • the second solvent is a polar solvent.
  • the second reaction mixture is heated to a second temperature.
  • the present disclosure provides methods of preparing polymers in the construct.
  • the method of preparing the polymer includes forming a third reaction mixture using the quaternized polymer, a diglycidyl ether, and a third organocatalyst.
  • the method can include performing a third heat treatment to the third reaction mixture to form the crosslinked polymer of formula (III).
  • the third organocatalyst is a Lewis acid.
  • the third reaction mixture is heated to a third temperature.
  • the method can include forming a fourth reaction mixture using the polymer and a sultone forming the anionic quaternized polymer of formula (IV).
  • the anionic quaternized polymer can have antibacterial and wound healing properties.
  • the method can include forming a fifth reaction mixture using the quaternized polymer and a coupling agent, performing a fourth heat treatment to the fifth reaction mixture to form a coupled-quaternized polymer, forming a sixth reaction mixture using the coupled-quaternized polymer and a peptide, and performing a fifth heat treatment to the sixth reaction mixture to form the peptide coupled-quaternized polymer of formulae (V) or (VI).
  • the peptide coupled-quaternized polymer can have both antibacterial and hemostatic properties. IV.
  • the present disclosure provides methods of providing an antimicrobial agent to a subject, medical device, or surface such as a table or military items or other surfaces for quick and rapid elimination of bacterial contamination and prevention of future contamination, these methods can include applying to the subject, medical device, or surface a composition of at least one construct of formula (I).
  • the pharmaceutical composition can include an aqueous formulation, gelatinous formulation, a sprayable formulation, a wipeable formulation, a formulation on a pad or other wound dressing or a paste formulation, or any applicable formulation.
  • the present disclosure encompasses methods of preparing a substrate with antimicrobial activity, hemostatic activity, or both using a polymer of the instant disclosure.
  • the polymers can be as described in Section (I) herein above.
  • the method includes coating or spraying the substrate with the construct of formulae (I) to (VI).
  • Coating a substrate with an antimicrobial polymer can include applying a specially formulated polymer solution onto the substrate to provide antimicrobial properties. This process is particularly useful in medical facilities, kitchens, industrial food facilities, and other settings where controlling the growth and spread of harmful microorganisms is crucial.
  • the method can include spraying a liquid form of the polymer onto a substrate to provide an antimicrobial coating to the substrate.
  • methods of the instant disclosure can include preparing the polymers of the instant disclosure in a sprayable liquid suspension, allowing for easy application and effective dispersion of the active antimicrobial agents.
  • the composition and nature of the polymer can vary depending on the specific requirements and desired performance characteristics.
  • the liquid form of the polymer can include a suspension of the polymer in a buffer or solution (e.g., alcohol, for example for quick drying).
  • a gel form of the polymer can be formulated to be syringable and able to be injected via a syringe.
  • the polymer(s) can be a viscous fluid or a spreadable fluid.
  • the polymer can be formulated as a firm gel that can be placed or cut and used as needed.
  • methods can include applying to an affected area a therapeutically effective amount of a polymer according to the instant disclosure alone or as combination therapies in treating, reducing onset or ameliorating the health condition in the subject in need thereof.
  • the polymer can be in the form of a therapeutic composition including at least one polymer according to the instant disclosure. Certain embodiments of the method and health conditions are described below. Disclosed polymers and therapeutic compositions and formulations are described herein, for example, in Sections I and II. Kits [00138] In some embodiments, the present disclosure provides kits for harboring or storing any of the constructs and/or compositions and for practicing any of the methods disclosed herein.
  • kits can include one or more polymers disclosed herein and/or one or more anyone pharmaceutically-acceptable formulations disclosed herein and at least one container. In some embodiments, kits disclosed herein can be used for antimicrobial and hemostatic effect. [00139] In certain embodiments, kits are provided herein for use in providing an antimicrobial agent to a subject, medical device, or surface, the method including applying to the subject, medical device, or surface a composition of at least one construct of formula (I). In some embodiments, the pharmaceutical composition can include aqueous formulation, gelatinous formulation, a formulation on a pad or other wound dressing or a paste formulation.
  • the kit can include at least one polymer or composition containing at least one polymer disclosed herein, and at least one container.
  • the kit can include instructions for use in accordance with any of the methods described herein.
  • instructions can include a description for applying to a surface or administering at least one polymer and/or pharmaceutical composition disclosed herein to a subject.
  • kits can include instructions that provide information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • kits disclosed herein can include at least one container.
  • containers can be any container capable of storing at least one polymer or at least one composition containing at least one polymer disclosed herein such as spray bottles, tubes, vials, bottles, syringe, such as unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses.
  • Instructions supplied in the kits of the invention can be written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine- readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the label or package insert indicates that the composition is used for treating, delaying the onset and/or alleviating onset of a health condition or disease contemplated herein.
  • kits disclosed herein can include suitable packaging.
  • suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like.
  • packages for use in combination with a specific device such as an inhaler, nasal administration device (e.g., an atomizer), patch or an infusion device such as a minipump.
  • a kit can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits can optionally provide additional components such as buffers and interpretive information. Normally, the kit includes a container and a label or package insert(s) on or associated with the container. In some embodiments, the invention provides articles of manufacture including contents of the kits described above. EXAMPLES [00144] The following examples are included to illustrate certain embodiments.
  • Example 1 Synthesis of Polymer 1 (pONDEA) [00145]
  • poly(octyl neopentyl diglycidyl ether amine) or pONDEA (Polymer 1) was synthesized.
  • FIG.1 illustrates the chemical reaction equation for synthesis of Polymer 1.
  • pONDEA Polymer 1(6670 mg or mL), 1-bromohexane (0.5 mL, 2.57 mmol), and sodium carbonate (100 mg) were dissolved in dry dimethylformamide (DMF) (0.5 mL). The resulting mixture was stirred at 120 °C for 24 hrs forming H-pONDEA (Polymer 2)in an inert nitrogen atmosphere. The reaction was stopped by cooling to room temperature. The resulting polymer was purified by washing in hexane three times to remove unreacted reagents. The resulting polymer was obtained by roto-evaporating the residual hexane and DMF.
  • FIG.3 illustrates the chemical reaction equation for synthesis of Polymer 3.
  • Polymer 2 144 mg
  • polyethylene glycol diglycidyl ether Mn 526, 72 mg
  • catalytic amount of boron trifluoride diethyl etherate 55.8 ⁇ l
  • the reaction was stopped by cooling to room temperature.
  • the resulting polymer was purified by washing in hexane three times to remove unreacted reagents.
  • Example 4 Synthesis of Polymer 4 (poly sultone-pONDEA) – Zwitterionic functionalization
  • Polymer 4 PS-pONDEA
  • FIG. 4 illustrates the chemical reaction equation for synthesis of Polymer 4.
  • Polymer 1 and 1,2-oxathiolane 2,2-dioxide (1.5x to 5x molar excess) were reacted at 70 °C for 24 hrs. The reaction was stopped by cooling to room temperature. A resulting polymer was purified by washing in diethyl ether to remove unreacted reagents.
  • a solution of N-hexyl-N-(2-hydroxy-3-(3-(2-hydroxybutoxy)-2,2- dimethylpropoxy)propyl)-N-(2-hydroxypropyl)octan-1-aminium and di(2H-1 ⁇ 4 -imidazol-1- yl)methanone in DMF will be stirred at 60 °C for 3 hrs forming N-(3-(3-(2-((2H-1 ⁇ 4 -imidazole- 1-carbonyl)oxy)butoxy)-2,2-dimethylpropoxy)-2-hydroxypropyl)-N-hexyl-N-(2- hydroxypropyl)nonan-1-a
  • Example 6 Peptide conjugation II [00156] In one exemplary method, 1,6-diamino-12-carboxy-16-ethyl-N-hexyl-24-hydroxy-N- (2-hydroxypropyl)-1-imino-20,20-dimethyl-N-nonyl-7,10,14-trioxo-15,18,22-trioxa-2,8,11- triazapentacosan-25-aminium (Polymer 6) was synthesized.
  • FIG. 6 illustrates the chemical reaction equation for synthesis of Polymer 6.
  • Example 7 Characterization of Polymers 1, 2, and 4 by Gel Permeation Chromatography
  • GPC Gel Permeation Chromatography
  • a size exclusion column filled with porous beads to separate molecules of different size. Smaller molecules enter the pores and take longer to elute, while larger molecules bypass these pores and elute more quickly. This technique is used primarily to determine the molecular weight distribution of the resultant polymer.
  • GPC was used to determine how the polymers changed during course of the reaction.
  • GPC was used to determine the range of polymer sizes (molecular weight) and polydispersity to determine the distribution of molecular weights of the synthesized polymers.
  • a 30 mg/ml sample of polymer was prepared using chromatography grade Dimethyl Formamide (DMF) as a solvent. This sample was placed into a sampling vial, which was loaded into a Malvern Viscotek GPCmax sampling rack. A 100 ⁇ l aliquot was pulled and run through the GPC column at a flow rate of 1 ml/min. The column separates the resultant sample, and contents are analyzed with laser light scattering to determine the dwell time, and therefore size, of the sample contents. Polymer Mn Mw PD unit mw Mn units Mw units an lar weight, consists of 45 repeating units.
  • DMF Dimethyl Formamide
  • FIGS.8A-8D show NMR spectra and analysis of the NMR spectra of the synthesized polymers. Analysis of the NMR spectra determined that the reaction resulted in the predicted backbone polymer, in the case of non-functionalized pONDEA. Spectra of the functionalized polymers confirmed the presence of a quaternized ammonia, as well as successful functionalization reactions with propane sultone. The data further demonstrates that the backbone polymer can be modified with both propane sultone and hexyl bromide, to customize the charge balance of functional groups.
  • Example 9 Solubility of synthesized polymers
  • Polymer 1 poly(octyl neopentyl diglycidyl ether amine) (pONDEA) consists of several hydrophobic elements, with a relatively high density of hydroxyl groups. In its basic form, Polymer 1 is a highly viscous amber liquid. This liquid polymer was readily solubilized in alcohols, such as isopropyl alcohol, for use. Dimethyl formamide was used in the synthesis and further functionalization of the polymer, due to the high boiling point and good solubility with the polymer, monomers, and constituent elements.
  • the base polymer was soluble in diethyl ether, so hexanes were used to wash the polymer of unreacted monomers and catalyst materials.
  • the resultant polymer was insoluble in diethyl ether. This insolubility is diethyl ether was because of the ionic nature.
  • Polymer 2 was functionalized with alkyl halides. Polymer 2 forms the cationic quaternary ammonium salt form of the Polymer 1. Polymer 2 was highly hydrophobic and very insoluble in water.
  • Polymer 4 was zwitterionic and displays some ability to be hydrated. This form of the polymer was water miscible up to around 30% water by weight, at which point separation of water from the polymer phase was observed.
  • Example 10 Blood clotting properties
  • TAG thromboelastography
  • Thromboelastography is a viscoelastic analysis technique, wherein coagulation of blood is monitored under the conditions to assess changes to the clotting process. This technique is used clinically to rapidly evaluate the presence of coagulopathy in trauma patients, and simply characterizes the clotting characteristics of the blood samples.
  • the blood was mixed with either kaolin or polymer sample.
  • the sample was placed in a disposable cup, which oscillates through a 4.75 degree arc around a fixed plastic pin. As a clot forms in the blood, the pin is torqued, with the relative levels of deflection related to clot formation and strength.
  • Table 2 shows variables and values associated with thromboelastography readings. Table 2. Variables and values associated with thromboelastography readings.
  • test method defines several options for evaluation, of which the extraction method was used. Briefly, this method consists of extracting a polymer sample with cell growth media, then culturing cells using the extracted media and assessing cell viability and growth compared to an untreated control culture. [00178] Two concentrations, 2 mg/ml and 10 mg/ml Polymer 4 (PS-pONDEA in 3T3 cell growth media) were selected for testing. Polymer 4 was selected as a test material, as this was functionalized to serve as the baseline high-biocompatibility material, due to the presence of sulfonate functional groups.
  • concentration selections was determined by the high end of what was observed in publications (2 mg/ml), and a significant challenge to those conditions (10 mg/ml). Each sample was extracted in the 3T3 cell growth media for 24 hours at 37°C. The resulting media was filtered using a 0.45 ⁇ m filter to remove any particulate.
  • L929 mouse fibroblasts were selected, based on the similarity to cell types in the relevant treatment environment. The plates were seeded at a rate of 10,000 cells/well of a 24 well plate. The cells were incubated in control media, 2mg/ml extract media, or 10mg/ml extract media. Each two days after incubation, up to day 6, an Alamar Blue assay was performed to identify cell viability.
  • This assay utilizes a cell permeable, non-toxic compound to identify living cells.
  • the compound is blue in color, but upon absorption to a living cell, is reduced to a red compound.
  • the assay can be assessed by detection in an absorbance or fluorescence-based plate reader.
  • the cell viability of the test groups can easily be compared to the control groups to determine if any cytotoxic effect is observed.
  • Each group was incubated with 1 ml of 10% Alamar Blue solution for 2 hours at 37 °C, then assessed by microplate reader.
  • FIGS. 10 A-C illustrate cytoxicity of Polymer 4 (PS-pondea) at two different concentrations using the AlamarBlue Assay. These results depict each day of testing, grouped by test group.
  • compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods have been described in terms of embodiments, it is apparent to those of skill in the art that variations can be applied to the compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope herein. More specifically, certain agents that are both chemically and physiologically related can be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept as defined by the appended claims.

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Abstract

Embodiments of the instant disclosure relate to novel constructs including constructs having antimicrobial applications, hemostatic applications, wound healing applications, analgesic activity, or a combination thereof and compositions, and methods for making and using the same. In certain embodiments, the present disclosure provides methods of providing an antimicrobial agent to a subject, medical device, or surface, the method including applying to the subject, medical device, or surface a composition of at least one construct of disclosed herein.

Description

COMPOSITIONS, METHODS OF MAKING, AND METHODS OF USING MULTI- FUNCTIONAL ANTIMICROBIAL POLYMERS PRIORITY [0001] This International Application claims priority to U.S. Provisional Application No. 63/526,336 filed July 12, 2023. This provisional application is incorporated herein by reference in its entirety for all purposes. FIELD [0002] Embodiments of the instant disclosure generally relate to multifunctional or multimodal polymers having one or more including, but not limited to, antimicrobial properties, wound healing properties, analgesic, and hemostatic properties. In certain embodiments, constructs containing at least one of the multifunctional or multimodal polymers, methods of making the multifunctional or multimodal polymers, and methods of using the multifunctional or multimodal polymers are disclosed herein. BACKGROUND [0003] Traditional sterilization techniques primarily involve heat, chemical agents, radiation, or a combination of these methods. Autoclaving, a common heat-based sterilization method, effectively eliminates microorganisms but is not suitable for heat-sensitive materials or treating large surfaces. Chemical disinfection methods, including the use of disinfectants and liquid sterilants, are often limited by their compatibility with specific materials and potential toxic side effects. Radiation-based sterilization, such as gamma irradiation or electron beam irradiation, can be effective but may alter the properties of certain materials and require space and equipment to prevent exposure to those using such processes. [0004] Despite these methods, residual microorganisms can persist on surfaces and devices due to inadequate penetration or incomplete contact with the sterilizing agents. Microorganisms can also develop resistance to conventional disinfectants over time, diminishing their effectiveness. Additionally, repeated use of sterilization techniques can cause wear and tear on delicate medical devices, potentially compromising their functionality. [0005] Accordingly, there is a need for antimicrobials and sterilants that can provide quick, continuous, and broad-spectrum antimicrobial effects, ensuring protection or, that can allow for even coverage on various surfaces and complex-shaped devices, and that is compatible with a wide range of substrates and surfaces, enabling its application in diverse settings. SUMMARY [0006] Embodiments of the present disclosure relate to constructs of multifunctional or multimodal polymers having at least one of antimicrobial, wound healing, analgesic, and/or hemostatic properties, methods of making the constructs, kits, and methods of using the constructs. In certain embodiments, the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (I),
Figure imgf000003_0001
(I); [0007] wherein R1, R2, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, a heterocycle, an aryl, and a heteroaryl, wherein the heterocycle, the aryl and the heteroaryl are each independently unsubstituted or are optionally, independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio; R3 can be a substituted or unsubstituted alkyl; n is independently an integer from 1 to 15; a is independently 0 or an integer from 1 to 5; r is independently an integer from 1 to 150; and m is independently an integer from 10 to 200. [0008] In some embodiments, R1 and R2 can each be independently H, methyl, ethyl, propyl, butyl, pentyl, hydroxyl, or any combination thereof. [0009] In some embodiments, R5 can be alkyl, aryl, or any combination thereof [0010] In some embodiments, R3 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or any combinations thereof. [0011] In some embodiments, R6 can be hydrogen. [0012] In some embodiments, R1 and R2 can be methyl, R5 can be methyl, R6 can be hydrogen, n can be 1, and a can be 1. [0013] In some embodiments, R1, R2, and R6 can be hydrogen, n can be an integer from 1 to 5, and a can be 0. [0014] In some embodiments, R1 can be methyl, R2 and R6 can be hydrogen, n can be 1, and a can be 0. [0015] In some embodiments, R1 can be hydroxyl, R2 and R6 can be hydrogen, n can be 1, and a can be 0. [0016] In some embodiments, R1 and R2 can be methyl, R5 can be phenyl, R6 can be hydrogen, n can be 1, and a can be 1. [0017] In some embodiments, R1, R2, and R6 can be hydrogen, n can be 1, a can be 0, and r can be an integer between 1 and 150. [0018] In certain embodiments, the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (II),
Figure imgf000004_0001
(II); wherein R4 can be a substituted or unsubstituted alkyl and the polymer is a quaternized polymer. [0019] In some embodiments, R1 and R2 can be methyl, R3 can be octyl, R4 can be hexyl, R5 can be methyl, R6 can be hydrogen, n can be 1, and a can be 1. [0020] In some embodiments, R1 and R2 can be methyl, R3 can be octyl, R4 can be hexyl, R5 can be methyl, R6 can be imidazole-1-yl ethan-1-one, n can be 1, and a can be 1. [0021] In certain embodiments, the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (III),
[0022] wherein the polymer is a crosslinked polymer. [0023] In certain embodiments, the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (IV),
Figure imgf000005_0001
wherein the polymer is a zwitterionic polymer. [0024] In certain embodiments, the present disclosure provides constructs containing a polymer having a formula as illustrated in formula (V) or formula (VI),
(VI); wherein the polymer is a peptide-conjugated polymer. [0025] In certain embodiments, the present disclosure provides methods of preparing the polymers in the construct. In some embodiments, the method of preparing the polymer includes a first reaction mixture of a first organocatalyst, a first solvent, a primary amine, and a terminal di- epoxide. The method further includes performing a first heat treatment to the first reaction mixture for a time period sufficient to allow the formation of the polymer of formula (I) [0026] In some embodiments, the primary amine can be a compound of formula (VII) or (IX) and the terminal di-epoxide can a compound of formula (X), wherein R1, R2, R5, a, and n are as described previously; and p is an integer between 1 to 20. [0027] In some embodiments, the terminal di-epoxide can be neopentyl glycol diglycidyl ether, alkyl diglycidyl ethers, propylene glycol diglycidyl ether, glycerol diglycidyl ether, bisphenol A diglycidyl ether, and/or polyethylene glycol diglycidyl ether. [0028] In some embodiments, the first organocatalyst is 4-dimethylamino pyridine (DMAP) or optionally, triphenyl phosphate (TPP). [0029] In some embodiments, the first solvent is a polar solvent. [0030] In some embodiments, the first heat treatment includes heating the first reaction mixture to a first temperature. [0031] In certain embodiments, the present disclosure provides methods of preparing polymers in the construct. The method of preparing the polymer can include forming a second reaction mixture using the polymer of formula (I), an alkyl halide, a second solvent, and a bicarbonate salt. The method further includes performing a second heat treatment to the second reaction mixture allowing formation of a quaternized polymer of formula (II). [0032] In some embodiments, the second solvent is a polar solvent. [0033] In some embodiments, during the second heat treatment the second reaction mixture is heated to a second temperature. [0034] In certain embodiments, the present disclosure provides methods of preparing polymers in the construct. In certain embodiments, the method of preparing the polymer includes forming a third reaction mixture using the quaternized polymer, a diglycidyl ether, and a third organocatalyst. The method can include performing a third heat treatment to the third reaction mixture to form the crosslinked polymer of formula (III). [0035] In some embodiments, the third organocatalyst is a Lewis acid. [0036] In some embodiments, during the third heat treatment the third reaction mixture is heated to a third temperature. [0037] In certain embodiments, the method can include forming a fourth reaction mixture using the polymer and a sultone forming the anionic quaternized polymer of formula (IV). [0038] In certain embodiments, the method can include forming a fifth reaction mixture using the quaternized polymer and a coupling agent, performing a fourth heat treatment to the fifth reaction mixture to form a coupled-quaternized polymer, forming a sixth reaction mixture using the coupled-quaternized polymer and a peptide, and performing a fifth heat treatment to the sixth reaction mixture to form the peptide coupled-quaternized polymer of formulae (V) or (VI). [0039] In other embodiments, the present disclosure provides methods of preparing a substrate with antimicrobial activity, hemostatic activity, or both. In certain embodiments, the method includes coating or spraying the substrate with the construct of formulae (I) to (VI). [0040] In certain embodiments, the present disclosure provides methods of providing an antimicrobial agent to a subject, medical device, or surface, the method including applying to the subject, medical device, or surface a composition of at least one construct of formula (I). [0041] In certain embodiments, the present disclosure provides a pharmaceutical composition. The pharmaceutical composition can include the construct of formula (I) to (VI) and at least one pharmaceutically acceptable excipient. [0042] In some embodiments, the pharmaceutical composition can include aqueous formulation, gelatinous formulation, a formulation on a pad, a patch, a gelatinous material or other wound dressing or a paste formulation. [0043] In some embodiments, the pharmaceutical composition can include a topical formulation. In some embodiments, the topical formulation is a cream, gel, powder, or would dressing. In some embodiments, the wound dressing is a pad. [0044] In some embodiments, the present disclosure provides kits for harboring or storing any of the constructs and/or compositions and for practicing any of the methods disclosed herein. In some embodiments, kits can include one or more constructs disclosed herein and/or one or more anyone pharmaceutically-acceptable formulations disclosed herein and at least one container. In some embodiments, kits disclosed herein can be used for antimicrobial and hemostatic effect. BRIEF DESCRIPTION OF THE DRAWINGS [0045] The following drawings form part of the present specification and are included to further demonstrate certain embodiments of the present disclosure. Certain embodiments can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [0046] FIG. 1 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 1 ((poly(octyl neopentyl diglycidyl ether amine) or pONDEA) in accordance with certain embodiments of the present disclosure. [0047] FIG. 2 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 2 (hexyl-poly(octyl neopentyl diglycidyl ether amine) or H-pONDEA) in accordance with certain embodiments of the present disclosure. [0048] FIG. 3 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 3 in accordance with certain embodiments of the present disclosure. [0049] FIG. 4 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 4 (propane sultone-poly(octyl neopentyl diglycidyl ether amine) or PS- pONDEA) in accordance with certain embodiments of the present disclosure. [0050] FIG. 5 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 5 in accordance with certain embodiments of the present disclosure. [0051] FIG. 6 represents an exemplary experiment illustrating a chemical reaction equation for synthesis of Polymer 6 in accordance with certain embodiments of the present disclosure. [0052] FIG. 7 represents a schematic correlating properties and structure of multifunctional polymer constructs and certain applications of the constructs in accordance with certain embodiments of the present disclosure. [0053] FIGS.8A-8D represent 1H-NMR spectra of Polymer 1, Polymer 2, Polymer 4, and a hybrid polymer of Polymer 2 and Polymer 4 in accordance with certain embodiments of the present disclosure. [0054] FIGS. 9A-9C represent data traces for thromboelastography (TEG) assay with untreated whole blood (FIG. 9A), kaolin treated blood (FIG. 9B), and Polymer 4 treated blood (FIG.9C) in accordance with certain embodiments of the present disclosure. [0055] FIGS.10A-10C represent cytotoxicity results of Polymer 4 using AlamarBlue Assay on L929 cells in accordance with certain embodiments of the present disclosure. DEFINITIONS [0056] As used herein, the term “about,” can mean relative to the recited value, e.g., amount, dose, temperature, time, percentage, etc., ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%. [0057] As used herein, “analog,” refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound. [0058] As used herein, “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms. [0059] As used herein, “alkyl” refers to a saturated aliphatic hydrocarbon group including C1- C20 straight chain and branched chain groups. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, I-ethyl propyl, 2-methylbutyl, 3- methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4- methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3- dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5- dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3- ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2- ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the isomers of branched chain thereof. An alkyl group can be a lower alkyl having 1 to 6 carbon atoms. Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl and etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can have one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio, carbonyl, carboxy or carboxylic ester. [0060] As used herein, “cycloalkyl” refers to saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group and have 3 to 20 carbon atoms. Representative examples of monocyclic cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl etc. A polycyclic cycloalkyl can include the cycloalkyl having Spiro ring, fused ring, and bridged ring. [0061] As used herein, “heteroaryl” refers to an 5-14 membered aryl having 1 to 4 heteroatoms selected from O, S, and N as ring atoms, the remaining ring atoms being C. Examples of heteroaryl groups are furan, thiophene, pyridine, pyrrole, N-alkyl pyrrole, pyrimidine, pyrazine, imidazole, tetrazolyl, and the like. Heteroaryl herein can be fused to aryl, heterocyclic alkyl or cycloalkyl, wherein the ring connected with parent structure is heteroaryl. Heteroaryls herein can be substituted or unsubstituted. When substituted, the substituent group(s) can be one or more groups independently selected from of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio, carbonyl, carboxy or carboxylic ester. [0062] As used herein, “hydroxyl” refers to an —OH group. As used herein, “hydroxyalkyl” refers to -alkyl-OH, wherein alkyl as defined above. As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo. As used herein, “thiol” refers to an organosulfur compound according to the form R−SH, where R represents an alkyl or other organic substituent. As used herein, “carbonyl” refers to —C(═O)—. As used herein, “nitro” refers to —NO2. As used herein, “cyano” refers to —CN. As used herein, “amino” refers to —NH2. As used herein, “carboxy” refers to —C(═O)OH. As used herein, “carboxylic ester” refers to —C(═O)O-alkyl. [0063] As used herein, "optionally substituted" indicates that a group can be unsubstituted or can be substituted with one or more substituents as provided herein or known in the art. As used herein, "substituted" in reference to a group indicates that a hydrogen atom attached to a member atom within a group is replaced. It should be understood that the term "substituted" includes the provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (e.g. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination). In certain embodiments, a single atom can be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group. [0064] As used herein, “individual”, “subject”, “host”, and “patient” can be used interchangeably and refer to any subject or any mammalian regarding treatment, prophylaxis or therapy as desired; for example, humans (e.g., adults, adolescents, toddlers, senior adults, children, infants and a fetus), companion animals (e.g., pets, horses), livestock, or other animals. [0065] As used herein, “multifunctional polymer” and “multimodal polymer” can be used interchangeably and can refer to any polymer disclosed herein having one or more antimicrobial, wound healing, and analgesic hemostatic properties. DETAILED DESCRIPTION [0066] In the following sections, certain exemplary compositions and methods are described to detail certain embodiments of the invention. It will be obvious to one skilled in the art that practicing the certain embodiments does not require the employment of all or even some of the specific details outlined herein, but rather that concentrations, times, and other specific details can be modified through routine experimentation. In some cases, well known methods, or components have not been included in the description. [0067] Embodiments disclosed herein relate to constructs having any one of antimicrobial, wound healing, analgesic hemostatic properties, or any combination thereof. In accordance with these embodiments, polymers can be in liquid form, and can be applied to a subject, medical device, or surface as a suspension (e.g., alcohol suspension or other aqueous suspension). Anti- microbial activity of the polymer can be beneficial in preventing pathogenic microbial infections in healthcare settings among other uses. In some embodiments, polymers disclosed herein can provide active bactericidal activity, minimizing the risk of any incidentally introduced bacteria or eliminating any existing bacterial contaminants. In some embodiments, materials disclosed herein can be non-cytotoxic, biocompatible, and biodegradable. Unlike traditional sterilization methods, the antimicrobial polymers disclosed herein provide continuous and broad-spectrum antimicrobial activity, ensuring immediate elimination of any contaminants and sustained anti-bacterial protection over time. In some embodiments, application methods used for distributing these compositions can permit even coverage on various surfaces and complex-shaped devices, overcoming the limitations of penetration and accessibility and improving accessibility for improved sterility. Furthermore, the polymer coating is compatible with a wide range of substrates, including heat-sensitive materials, enabling its application in diverse settings (e.g., medical, military, for surfaces susceptible to contamination, etc.). [0068] Some embodiments disclosed herein concern agents, methods, and processes of use in preparing the disclosed constructs and compositions containing constructs disclosed herein. It is understood that combinations, subsets, interactions, agents disclosed herein where specific reference of each individual and collective combinations and permutation of these constructs cannot be explicitly disclosed, each is contemplated. Additional embodiments of the disclosure are described below. I. Polymers/Constructs [0069] In certain embodiments, the present disclosure provides anti-microbial constructs in the form of polymers for eliminating microbes and providing protection from pathogenic microbes on surfaces and to treat, prevent, or ameliorate a microbial infection in a subject in need thereof (e.g., a wound). The different elements of the polymer can be modified to increase or decrease hydrophobicity for tailored use for a given purpose. [0070] In some embodiments, a polymer can include a construct according to formula (I), ( ); an analog, an isomer, a pharmaceutically acceptable salt, and/or a prodrug thereof, and/or formulation thereof; wherein R1, R2, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, a heterocycle, an aryl, and a heteroaryl. In some embodiments, the heterocycle, the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio; R3 can include a substituted or unsubstituted alkyl; n is independently an integer from 1 to 15; or from 1 to 12; a is independently 0 or an integer from 1 to 5; r is independently an integer from 1 to 150; or from 1 to 135; and m is independently an integer from 10 to 200 [0071] In some embodiments R1 and R2 are each independently H, methyl, ethyl, propyl, butyl, pentyl, hydroxyl, or any combination thereof. In some embodiments, R5 is alkyl, aryl, or any combination thereof. In some embodiments, R3 can be methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or any combinations thereof. In some embodiments, R6 can be hydrogen. [0072] In some embodiments, R1 and R2 are methyl, R5 is methyl, R6 is hydrogen, n is 1, and a is 1. In other embodiments, R1, R2, and R6 can be hydrogen, n can be an integer from 1 to 5, and a can be 0. In some embodiments, R1 is methyl, R2 and R6 are hydrogen, n is 1, and a is 0. In some embodiments, R1 is hydroxyl, R2 and R6 are hydrogen, n is 1, and a is 0. In yet other embodiments, R1 and R2 are methyl, R5 is phenyl, R6 is hydrogen, n is 1, and a is 1. In some embodiments, R1, R2, and R6 are hydrogen, n is 1, a is 0, and r is an integer between 1 and 150. [0073] In some embodiments, polymers of the present disclosure can include Formula (XI), wherein m can range
Figure imgf000015_0001
[0074] In some embodiments, the polymer can include Formula (II), wherein R4 is a
Figure imgf000015_0002
aryl. [0075] In other embodiments, R1 and R2 are methyl, R3 is octyl, R4 is hexyl, R5 is methyl, R6 is hydrogen, n is 1, and a is 1. In other embodiments, R1 and R2 are methyl, R3 is octyl, R4 is hexyl, R5 is methyl, R6 is imidazole-1-yl ethan-1-one, n is 1, and a is 1. [0076] In certain embodiments, the polymers can be functionalized to include cationic quaternary ammonium, which can have well defined bactericidal action. In some embodiments, polymers of the present disclosure can include Formula (XII),
wherein m can range from about 10 to about 200. [0077] Linear polymeric units can also be crosslinked to form gels of varying mechanical properties, which can be delivered via syringe to fill a three-dimensional space. In some embodiments, the polymer can include Formula (III), wherein the
Figure imgf000016_0001
[0078] In some embodiments, the polymer can include zwitterionic groups, which can enhance hemostatic abilities and/or biocompatibility. In other embodiments, the polymer can include Formula (IV), wherein the
Figure imgf000016_0002
[0079] In some embodiments, polymers of the present disclosure can include Formula (XIII),
; wherein m can range fro [0080] In certain embodiments, polymers of the present disclosure can also be functionalized with peptides or other agents including but not limited to hyaluronic acid or similar agents that can promote the hemostatic process. Examples of peptides with hemostatic properties include, but are not limited to, von Willebrand factor peptides, fibrinogen-mimetic peptides, fibrin-binding single- domain variable fragment antibodies, collagen peptides, or similar peptides. In other embodiments of the instant disclosure, the polymer can include Formula (V),
Figure imgf000017_0001
(V); or Formula (VI)
; (VI); wherein the polymer is a peptide-conjugated polymer. [0081] In some embodiments, polymers of the present disclosure can include Formula (XV), ; wherein m can
Figure imgf000018_0001
[0082] In some embodiments, polymers of the present disclosure can include Formula (XVI),
; (XVI); wherein m can range from about 10 to about 200. [0083] In some embodiments, polymers of the present disclosure can include Formula (XIV),
Figure imgf000019_0001
; (XIV); wherein m can range from about 10 to about 200. [0084] In certain embodiments, constructs of the present disclosure can be in the form of a pharmaceutically acceptable salt. In some embodiments, the salt is a pharmaceutically acceptable salt. By “pharmaceutically acceptable salt”, it is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. A salt can refer to a salt, which can be formed when a polymer herein has an acidic group such as carboxyl or a basic group such as amino or imino. In some embodiments, a salt of a polymer disclosed herein can be formed with an acidic group, can include, but is not limited to alkali metal salts such as a sodium salt, potassium salt or lithium salt, alkaline earth metal salts such as a calcium salt or magnesium salt, metal salts such as an aluminum salt or iron salt; amine salts, e.g., inorganic salts such as an ammonium salt and organic salts such as a t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxymethyl)aminomethane salt; and amino acid salts such as a glycine salt, lysine salt, arginine salt, ornithine salt, glutamate or aspartate. In some embodiments, a salt derivative of a polymer disclosed herein formed with a basic group can include, but is not limited to, hydro-halides such as a hydrofluoride, hydrochloride, hydrobromide or hydroiodide, inorganic acid salts such as a nitrate, perchlorate, sulfate or phosphate; lower alkanesulfonates such as a methanesulfonate, trifluoromethanesulfonate or ethanesulfonate, arylsulfonates such as a benzenesulfonate or p-toluenesulfonate, organic acid salts such as an acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; and amino acid salts such as a glycine salt, lysine salt, arginine salt, histidine salt, ornithine salt, glutamate or aspartate. [0085] In certain embodiments, constructs of the present disclosure can include, but are not limited to, polymers in a solid or a liquid form or state. When in a liquid form, the polymers of the instant disclosure can include, but is not limited to, suspensions in organic solvents. In some embodiments, the solvent is a protic solvent. Suitable examples of protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t- butanol, formic acid, acetic acid, water, and combinations thereof. [0086] In other embodiments, constructs of the present disclosure can be in an amorphous form. In other embodiments, polymers of the present disclosure can be in a crystalline form or a crystalline and amorphous form combination or mixture. In accordance with some embodiments disclosed herein, polymers in a solid state can exist in a crystalline, powder, or non-crystalline form, or as a mixture thereof. In some embodiments, polymers disclosed herein in crystalline form can be used to form acceptable solvates. A skilled artisan can appreciate that acceptable solvates can be formed where solvent molecules are incorporated into the crystalline lattice during crystallization. In accordance with some embodiments, solvates for uses disclosed herein can include nonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or they can include water as the solvent incorporated into the crystalline lattice. Solvates where water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates can include stoichiometric hydrates as well as compositions containing variable amounts of water. The present disclosure encompasses all such solvates known in the art. [0087] In certain embodiments, polymers of the present disclosure can exist in crystalline form, including various solvates thereof, and can exhibit polymorphism (e.g., the capacity to occur in different crystalline structures). These different crystalline forms are referred to herein as "polymorphs." Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and/or other descriptive properties of the crystalline solid state. Polymorphs, therefore, can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X- ray powder diffraction patterns, NMR signatures, which can be used for identification. In certain embodiments, polymers of the present disclosure can be polymorphs. In certain embodiments, polymers of the present disclosure can be polymorphs that are identified by their melting points, IR spectra, X-ray powder diffraction patterns, NMR signatures, or any combination thereof. In some embodiments, different polymorphs of polymers herein can be produced by changing and/or adjusting the reaction conditions and/or reagents, used in making the polymer. For example (but not limited to), changes in temperature, pressure, or solvent can result in polymorphs. In some embodiments, different polymorphs of polymers disclosed herein can spontaneously convert to another polymorph. II. Multimodal Compositions [0088] In certain embodiments, polymers of the instant disclosure have at least one of antimicrobial, wound healing, analgesic, and hemostatic properties, or any combination thereof. FIG.7 is a schematic illustration of a multimodal composition contemplated herein. [0089] Polymer systems known in the art can either be impregnated with bactericidal agents that are gradually released into the surrounding environment or can include bactericidal agents bound to the polymer backbone that do not leech into the environment. Agent leaching coatings have a limited lifetime for bactericidal activity as the active agent is removed from the coating and must be regenerated via subsequent bactericide treatments for continued activity. In contrast, non- leeching leaching polymeric systems such as poly(quaternary ammonium) compounds (QAC) can possess bactericidal activity almost indefinitely without release of agents into the environment. The antimicrobial action of QACs is mostly attributed to their ability to increase cell permeability and disrupt the cell membrane. For QACs to be compatible with the bilayer of the outer cell membranes, the structure should possess a long alkyl chain to provide a hydrophobic segment. The cationic sites of the QACs bind to anionic sites of the cell-wall surface by electrostatic interaction. Subsequently, the long alkyl chains disrupt the cytoplasmic membrane, leading to the death of the cells. Alkyl chain lengths between C6 and C8 could kill various strains of Gram-negative and Gram- positive bacteria, and even viruses. In this example, polyQACs with a long alkyl chain (C6 to C8) can provide reliable anti-microbial properties against a variety of pathogens causing disease in humans and other mammals. [0090] Bacteria and other cells commonly exhibit an anionic or net negative charge, due to surface protein charge and ion exchange across the membrane. In contrast to mammalian cells, bacteria exhibit a significantly higher density of negatively charged phospholipid head groups, enhancing their susceptibility to electrostatic interactions. Cell membranes of bacteria are selectively permeable, with embedded channels that control the flow of ions, metabolites, and other substances across the membrane. The ability of bacteria to control and expel contents of the cytoplasm are important to resisting effects of antibiotics. Commonly used antibiotics and bactericidal compounds pass into the cytoplasm, where they can disrupt bacterial processes. Resistance mechanisms can arise as bacteria develop adaptations to eliminate these compounds from their interior envelope making antibiotics less useful and in certain cases useless to attack bacteria and reduce bacterial infections. [0091] In some embodiments, quaternized polymers as disclosed herein can have anti- microbial properties. In accordance with these embodiments, an anionic cell surface can be electrostatically attracted to the positively charged quaternized nitrogen atoms on the polymer. In this example, hydrophobic acyl chains can penetrate bacterial cell membranes, lysing the bacterium and killing the bacteria. [0092] In certain embodiments, polymer constructs disclosed herein can achieve their antibacterial functionality through inclusion of cationic quaternary amines, and hydrophobic functional groups. In accordance with these embodiments, cationic charge of a quaternary amine group provides an electrostatic attraction to the bacteria. Further, hydrophobic elements, including, for example, an alkyl chain extending from the amine, and additional hydrophobic groups of the polymer, serve to enhance compatibility with the bacterial membrane. In this example, the alkyl chain then is able to penetrate the bacterial outer membrane, leading to disruption of the membrane and lysis of the bacteria. This mechanism has been demonstrated previously, using fluorescence techniques where treated bacteria display disrupted membrane integrity. Further, these treated bacteria are now inviable, confirming that this mechanism is bactericidal as opposed to antibiotics and other agents which are bacteriostatic. In addition, this mechanism is effective against gram positive, gram negative, and antibiotic resistant strains in similar approaches by killing the bacteria. [0093] In other embodiments, one advantage of polymer constructs disclosed herein, and other polymeric based microbicides is their non-reliance on uptake into the bacterial envelope in order to function. Adaptation of membrane channels and improved elimination of bactericidally active compounds from within the bacteria is a main mechanism for antibacterial resistance. The mechanism utilized by cationic, hydrophobic polymers is such that the material does not rely on uptake into the bacterial interior, and thus, bypasses any sort of bacterial resistance mechanism. Further, although these functionalities enable a powerful biocide against bacteria, this polymer system can be adjusted to enhance compatibility with human cells. With a sufficiently hydrophobic material, this mechanism can disrupt human cell membranes, so care must be taken to ensure that cationic and hydrophobic segments are balanced at a ratio that selectively kills bacteria without effects on human cells. Embodiments disclosed herein take this into consideration. [0094] In certain embodiments, for effective hemostasis, rapid coagulation and subsequent activation of clotting cascade are known in the art as being a primary consideration. Biological cells, including those composing whole blood, and to a greater extent, bacteria, commonly exhibit a net negative membrane charge. Cationic, or positively charged, polymers can interact with cells and other negatively charged biological substances through electrostatic interactions. In some embodiments, antibacterial function of the polymer constructs disclosed herein can also operate partly upon this principle, providing a strong attraction and lysing bacterial cells. Hemostasis describes the natural ability of blood to clot, thereby preventing uncontrolled hemorrhage. A variety of mechanisms can be responsible for adjunct mediated hemostasis. Common to all hemostatic materials is the catalytic effect on the coagulation cascade, an enzymatically mediated process which facilitates clot formation and the beginning of the wound healing process. For some materials, this can be a simple mechanism such as fluid absorption leading to a concentration of proteins and cells, to biologically active factors such as thrombin that are direct factors in the coagulation cascade. [0095] Cationic polymers initially support this process by the electrostatic attraction mechanism, which leads to the aggregation of cellular components of whole blood, including red blood cells and platelets. This supports the coagulation cascade with activation of platelets and concentration of coagulation factors. While effective, interactions with exclusively cationic polymers can be cytotoxic, through the same membrane disruption mechanism that is effective against bacterial cells. Therefore, to achieve the results of effective hemostasis while preserving biocompatibility and bactericidal action, the material’s design must be tuned. [0096] In contrast with cationic polymers, zwitterionic materials contain a balance of negatively and positively charged functional groups. These materials are well characterized as biocompatible, and non-inflammatory. By mixing cationic and zwitterionic moieties in the disclosed polymer construct, certain desired effects of hemostasis and antibacterial action can be achieved, while enhancing the biocompatibility of the disclosed polymer construct. These cationic moieties can be achieved by a quaternization reaction on a tertiary amine in the polymer backbone. Similarly, zwitterionic functional groups can be achieved by reacting the tertiary amine with propane sultone, resulting in a cationic quaternary ammonium and anionic sulfonate groups. [0097] Positively charged polymeric materials can accelerate hemostasis by electrostatic interaction between positively charged groups and negatively charged red blood cell membranes, which result in a formation of a strong hemostatic plug at the injury sites. In addition, they facilitate platelet adhesion, activation, and agglomeration by increasing the glycoprotein complex. Some biologically-derived materials such as chitosan, collagen, and keratin have shown hemostatic properties. Although these materials are readily available, there are risks of disease transmission and toxicity associated with the use of those materials. Based on these facts, synthetic-based positively charged materials can be a good alternative hemostatic material. In some embodiments, quaternized polymers functionalized with peptides or other agents disclosed herein can have hemostatic properties. [0098] In other embodiments, for wound healing, materials such as bandages, gauges, and pads have been utilized with primary functions of the absorption of wound exudate. However, bandages, gauges, and pads become more adhesive to the wound after the exudate fluid solidifies, resulting in aches and pains. Moreover, they can tear the newly generated tissue when the solidified dressing is removed. Zwitterionic materials have attracted significant attention as wound healing materials. Zwitterionic units contains one positive charge and one negative charge. The balance in charge can lead to macroscopic neutrality while exhibiting an ability to absorb water by ionic solvation. Zwitterionic materials show strong hydration characteristic, facilitating the rehydration of dry necrotic tissue. This promotes autolytic debridement and further re-epithelialization in wound healing. Incorporating zwitterionic unit in a polymer structure can introduce wound healing capabilities. In some embodiments, zwitterionic polymers as disclosed can have hemostatic properties. [0099] In other embodiments, for analgesic treatment, administration of local analgesic agents such as lidocaine is known to be antinociceptive in both acute and chronic pain states. Although the precise molecular mechanisms of analgesic agent action remain elusive, clinical studies report that the administration of analgesic agents at a dose of about 1.0 mg/kg to about 3.0 mg/kg reduces different types of pain including but not limited to neuropathic pain, diabetic neuropathy, peripheral nerve injury, chronic regional pain, and central pain. In addition, FDA approved analgesic agents such as lidocaine jelly product to control local pain. An analgesic strategy can be to develop a system capable of sustained and local delivery of analgesic agents such as lidocaine. In some embodiments, polymer constructs disclosed herein can be used as a vehicle for sustained delivery of analgesic agents such as lidocaine. [00100] In certain embodiments, polymers of the present disclosure can be applied to incisions, wounds such as chronic infected wounds, or other surfaces of a subject where there is a desired antimicrobial and hemostatic effect. In accordance with these embodiments, the polymers can be used in aqueous form as a sprayable or paintable material, to form a coating to the applied surface. Linear polymeric units can also be crosslinked to form gels of varying mechanical properties, which can be delivered via a syringe to fill a three-dimensional space or applied to a wound salve, gel, pad, or other material for application to the surface of a subject. A. Pharmaceutical Compositions [00101] In other embodiments, the present disclosure provides pharmaceutical compositions. The pharmaceutical compositions of the instant disclosure include at least one polymer according to the instant disclosure for use to treat, prevent, or ameliorate a microbial infection in a subject in need thereof. The polymer can be, for example as described in Section I. [00102] In some embodiments, pharmaceutical compositions can include at least one polymer disclosed herein and at least one pharmaceutically acceptable carrier. In certain embodiments, pharmaceutical compositions can include pharmaceutically acceptable carriers, excipients, and/or stabilizers are nontoxic to recipients at dosages and/or concentrations used to practice the methods disclosed herein. [00103] In some embodiments, the pharmaceutically acceptable excipient can include, but is not limited to a diluent, a binder, a filler, a buffering agent, a pH modifying agent, a disintegrant, a dispersant, a preservative, a lubricant, or a coloring agent. The concentrations and types of excipients utilized to form pharmaceutical compositions disclosed herein and contemplated herein can be selected according to known principles of pharmaceutical science and knowledge in the art. [00104] In some embodiments, the excipient can be a diluent. The diluent can be compressible (i.e., plastically deformable) or abrasively brittle. Non-limiting examples of suitable compressible diluents can include, but are not limited to, microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, dextran, and trehalose or the like. Non-limiting examples of suitable abrasively brittle diluents include dibasic calcium phosphate (anhydrous or dihydrate), calcium phosphate tribasic, calcium carbonate, and magnesium carbonate. [00105] In another embodiment, the excipient can be a binder. Suitable binders include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. [00106] In another embodiment, the excipient can be a filler. Suitable fillers include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone. By way of non- limiting example, the filler can be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol. [00107] In yet other embodiments, the excipient can be a buffering agent. Representative examples of suitable buffering agents include, but are not limited to, phosphates, carbonates, citrates, tris buffers, polysaccharide buffers, and buffered saline salts (e.g., Tris buffered saline, or phosphate buffered saline). In various embodiments, the excipient can be a pH modifier. By way of non-limiting example, the pH modifying agent can be sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, or phosphoric acid. In a further embodiment, the excipient can be a disintegrant. The disintegrant can be non-effervescent or effervescent. Suitable examples of non- effervescent disintegrants include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro- crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid and sodium bicarbonate in combination with tartaric acid. [00108] In another embodiment, the excipient can be a dispersant or dispersing enhancing agent. Suitable dispersants can include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isomorphous silicate, and microcrystalline cellulose. [00109] In certain embodiments, the excipient can be a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as BHA, BHT, vitamin A, vitamin C, vitamin E, or retinyl palmitate, citric acid, sodium citrate; chelators such as EDTA or EGTA; and antimicrobials, such as parabens, chlorobutanol, or phenol. [00110] In other embodiments, the excipient can be a lubricant. Non-limiting examples of suitable lubricants include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate, or stearic acid. [00111] In still a further embodiment, the excipient can be a coloring agent. Suitable color additives include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). [00112] Other pharmaceutically acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEENTM, PLURONICSTM or polyethylene glycol (PEG). B. Compositions and Applications [00113] In some embodiments, the present disclosure provides anti-microbial compositions. In some embodiments, the present disclosure provides anti-microbial and hemostatic compositions. In some embodiments, the present disclosure provides for constructs having at least one of anti- microbial, hemostatic, and wound healing compositions. In some embodiments, the present disclosure provides multimodal compositions including any one or more of anti-microbial compositions, hemostatic compositions, wound healing compositions, analgesic compositions, or compositions of any combinations thereof. [00114] In certain embodiments, anti-microbial polymers disclosed herein provide a diverse range of forms and applications to combat microbial growth and to eliminate existing contaminations. In accordance with these embodiments, these compositions can manifest as sprays, enabling convenient and efficient disinfection of various surfaces and objects. In some embodiments, sprays disclosed herein can be applied to a wound and can cure into a layer or uniform layer that can protect the wound. Sprayable compositions can be easily applied relative to surgical incision drapes that require labor intensive placement to avoid bubble and wrinkles. In other embodiments, these polymers can also take the form of foams, providing a versatile means of targeting specific areas or achieving controlled coverage. For solid forms, such as soaps, anti- microbial polymers can be incorporated to offer enhanced hygiene benefits during handwashing or body cleansing routines. Additionally, these compositions can be found in gels, creams, and ointments, providing localized anti-microbial properties for skincare or wound care applications. Overall, the versatility of anti-microbial polymer compositions allows for their integration into numerous products, enabling effective microbial control across a wide range of settings. When in a liquid form, the polymers of the instant disclosure can include, but is not limited to, suspensions in organic solvents. In some embodiments, the solvent is a protic solvent. Suitable examples of protic solvents include, but are not limited to, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof. III. Methods of Preparing [00115] Another aspect of the instant disclosure encompasses a method of preparing multimodal polymers of the instant disclosure. The multimodal polymers can be as described in Section (I) herein above. Methods of the instant disclosure [00116] In certain embodiments, the present disclosure provides methods of preparing the polymers in the construct. In some embodiments, the method of preparing the polymer includes a first reaction mixture of a first organocatalyst, a first solvent, a primary amine, and a terminal di- epoxide. The method further includes performing a first heat treatment to the first reaction mixture for a period of time sufficient to allow the formation of the polymer of formula (I) [00117] In some embodiments, the primary amine can be a polymer of formula (VII) or (IX) and the terminal di-epoxide can be a polymer of formula (X),
Figure imgf000029_0001
wherein R1, R2, R5, a, and n are as described previously; and p is an integer between 1 to 20. [00118] In some embodiments, the terminal di-epoxide can include a structure selected from the group including, but not limited to:
Figure imgf000030_0001
Figure imgf000030_0002
[00119] In some embodiments, the terminal di-epoxide can be neopentyl glycol diglycidyl ether, alkyl diglycidyl ethers, propylene glycol diglycidyl ether, glycerol diglycidyl ether, bisphenol A diglycidyl ether, and/or polyethylene glycol diglycidyl ether. [00120] In some embodiments, the first organocatalyst is triphenyl phosphine (TPP). [00121] In some embodiments, where the first organocatalyst is 4-dimethylaminopyridine (DMAP); optionally where the first organocatalyst is triphenyl phosphine (TPP ). [00122] In some embodiments, the first solvent is a polar solvent. [00123] In some embodiments, the first heat treatment includes heating the first reaction mixture to a first temperature. [00124] In certain embodiments, the present disclosure provides methods of preparing polymers in the construct. The method of preparing the polymer can include forming a second reaction mixture using the polymer of formula (I), an alkyl halide, a second solvent, and a bicarbonate salt. The method further includes performing a second heat treatment to the second reaction mixture allowing formation of a quaternized polymer of formula (II). In some embodiments, a quaternized polymer can have antibacterial properties. [00125] In some embodiments, the second solvent is a polar solvent. [00126] In some embodiments, during the second heat treatment the second reaction mixture is heated to a second temperature. [00127] In certain embodiments, the present disclosure provides methods of preparing polymers in the construct. In certain embodiments, the method of preparing the polymer includes forming a third reaction mixture using the quaternized polymer, a diglycidyl ether, and a third organocatalyst. The method can include performing a third heat treatment to the third reaction mixture to form the crosslinked polymer of formula (III). [00128] In some embodiments, the third organocatalyst is a Lewis acid. [00129] In some embodiments, during the third heat treatment the third reaction mixture is heated to a third temperature. [00130] In certain embodiments, the method can include forming a fourth reaction mixture using the polymer and a sultone forming the anionic quaternized polymer of formula (IV). In accordance with these embodiments, the anionic quaternized polymer can have antibacterial and wound healing properties. [00131] In certain embodiments, the method can include forming a fifth reaction mixture using the quaternized polymer and a coupling agent, performing a fourth heat treatment to the fifth reaction mixture to form a coupled-quaternized polymer, forming a sixth reaction mixture using the coupled-quaternized polymer and a peptide, and performing a fifth heat treatment to the sixth reaction mixture to form the peptide coupled-quaternized polymer of formulae (V) or (VI). In some embodiments, the peptide coupled-quaternized polymer can have both antibacterial and hemostatic properties. IV. Methods of Use [00132] In certain embodiments, the present disclosure provides methods of providing an antimicrobial agent to a subject, medical device, or surface such as a table or military items or other surfaces for quick and rapid elimination of bacterial contamination and prevention of future contamination, these methods can include applying to the subject, medical device, or surface a composition of at least one construct of formula (I). In some embodiments, the pharmaceutical composition can include an aqueous formulation, gelatinous formulation, a sprayable formulation, a wipeable formulation, a formulation on a pad or other wound dressing or a paste formulation, or any applicable formulation. A. Substrate [00133] In certain embodiments, the present disclosure encompasses methods of preparing a substrate with antimicrobial activity, hemostatic activity, or both using a polymer of the instant disclosure. In some embodiments, the polymers can be as described in Section (I) herein above. In certain embodiments, the method includes coating or spraying the substrate with the construct of formulae (I) to (VI). [00134] Coating a substrate with an antimicrobial polymer can include applying a specially formulated polymer solution onto the substrate to provide antimicrobial properties. This process is particularly useful in medical facilities, kitchens, industrial food facilities, and other settings where controlling the growth and spread of harmful microorganisms is crucial. [00135] In some embodiments, the method can include spraying a liquid form of the polymer onto a substrate to provide an antimicrobial coating to the substrate. Accordingly, in some embodiments, methods of the instant disclosure can include preparing the polymers of the instant disclosure in a sprayable liquid suspension, allowing for easy application and effective dispersion of the active antimicrobial agents. [00136] In other embodiments, the composition and nature of the polymer can vary depending on the specific requirements and desired performance characteristics. In some embodiments, the liquid form of the polymer can include a suspension of the polymer in a buffer or solution (e.g., alcohol, for example for quick drying). In other embodiments, a gel form of the polymer can be formulated to be syringable and able to be injected via a syringe. In other embodiments, the polymer(s) can be a viscous fluid or a spreadable fluid. In other embodiments, the polymer can be formulated as a firm gel that can be placed or cut and used as needed. Methods of Use [00137] In certain embodiments and further to the previous paragraphs, the present disclosure provides methods for treating, preventing, reducing onset of, or ameliorating a health condition in a subject having, is suspected of developing, or is at risk of developing the health condition resulting from an external microbial infection such as a wound (e.g., chronically infected wound). In accordance with these embodiments, methods can include applying to an affected area a therapeutically effective amount of a polymer according to the instant disclosure alone or as combination therapies in treating, reducing onset or ameliorating the health condition in the subject in need thereof. In accordance with these embodiment, the polymer can be in the form of a therapeutic composition including at least one polymer according to the instant disclosure. Certain embodiments of the method and health conditions are described below. Disclosed polymers and therapeutic compositions and formulations are described herein, for example, in Sections I and II. Kits [00138] In some embodiments, the present disclosure provides kits for harboring or storing any of the constructs and/or compositions and for practicing any of the methods disclosed herein. In some embodiments, kits can include one or more polymers disclosed herein and/or one or more anyone pharmaceutically-acceptable formulations disclosed herein and at least one container. In some embodiments, kits disclosed herein can be used for antimicrobial and hemostatic effect. [00139] In certain embodiments, kits are provided herein for use in providing an antimicrobial agent to a subject, medical device, or surface, the method including applying to the subject, medical device, or surface a composition of at least one construct of formula (I). In some embodiments, the pharmaceutical composition can include aqueous formulation, gelatinous formulation, a formulation on a pad or other wound dressing or a paste formulation. [00140] In certain embodiments, the kit can include at least one polymer or composition containing at least one polymer disclosed herein, and at least one container. In some embodiments, the kit can include instructions for use in accordance with any of the methods described herein. In other embodiments, instructions can include a description for applying to a surface or administering at least one polymer and/or pharmaceutical composition disclosed herein to a subject. In accordance with embodiments herein, kits can include instructions that provide information as to dosage, dosing schedule, and route of administration for the intended treatment. [00141] In some embodiments, kits disclosed herein can include at least one container. In accordance with embodiments herein, containers can be any container capable of storing at least one polymer or at least one composition containing at least one polymer disclosed herein such as spray bottles, tubes, vials, bottles, syringe, such as unit doses, bulk packages (e.g., multi-dose packages) or sub-unit doses. Instructions supplied in the kits of the invention can be written instructions on a label or package insert (e.g., a paper sheet included in the kit), but machine- readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable. The label or package insert indicates that the composition is used for treating, delaying the onset and/or alleviating onset of a health condition or disease contemplated herein. Instructions can be provided for practicing any of the methods described herein. [00142] In other embodiments, kits disclosed herein can include suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Also contemplated herein are packages for use in combination with a specific device, such as an inhaler, nasal administration device (e.g., an atomizer), patch or an infusion device such as a minipump. A kit can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container can also have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition can be a polymer disclosed herein. [00143] In yet other embodiments, kits can optionally provide additional components such as buffers and interpretive information. Normally, the kit includes a container and a label or package insert(s) on or associated with the container. In some embodiments, the invention provides articles of manufacture including contents of the kits described above. EXAMPLES [00144] The following examples are included to illustrate certain embodiments. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered to function well in the practice of the claimed methods, compositions and apparatus. However, those of skill in the art should, in light of the present disclosure, appreciate that changes can be made in some embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of embodiments of the inventions. Example 1 Synthesis of Polymer 1 (pONDEA) [00145] In one exemplary method, poly(octyl neopentyl diglycidyl ether amine) or pONDEA (Polymer 1) was synthesized. FIG.1 illustrates the chemical reaction equation for synthesis of Polymer 1. [00146] 2,2’-(((2,2-dimethylpropane-1,3-diyl)bis(oxy))bis(methylene))bis(oxirane) (0.81mL, 3.87 mmol) and octan-1-amine (0.70 mL, 4.26 mmol) were dissolved in dry dimethylformamide (DMF) (0.5 mL) in an inert nitrogen atmosphere. A catalytic amount (0.1 mg of a 2 wt% solution) of triphenylphosphine or 4-dimethylaminopyridine (DMAP) was added to the mixture. The resulting mixture was stirred at 120 °C for 48 hrs forming pONDEA (Polymer 1 ). The reaction was stopped by cooling to room temperature. The resulting polymer was purified by a series of hexane washes remove unreacted reagents. The resulting polymer was obtained by roto- evaporating the residual hexane and DMF. Example 2 Synthesis of Polymer 2 (Hexyl-pONDEA) – Quaternization of polymer backbone [00147] In one exemplary method, Hexyl-pONDEA (Polymer 2) was synthesized. FIG. 2 illustrates the chemical reaction equation for synthesis of Polymer 2. [00148] pONDEA (Polymer 1)(6670 mg or mL), 1-bromohexane (0.5 mL, 2.57 mmol), and sodium carbonate (100 mg) were dissolved in dry dimethylformamide (DMF) (0.5 mL). The resulting mixture was stirred at 120 °C for 24 hrs forming H-pONDEA (Polymer 2)in an inert nitrogen atmosphere. The reaction was stopped by cooling to room temperature. The resulting polymer was purified by washing in hexane three times to remove unreacted reagents. The resulting polymer was obtained by roto-evaporating the residual hexane and DMF. Example 3 Synthesis of Polymer 3 – Cross-linking of quaternized polymer [00149] In one exemplary method, ’Polymer 3 was synthesized. FIG.3 illustrates the chemical reaction equation for synthesis of Polymer 3. [00150] Polymer 2 (144 mg), polyethylene glycol diglycidyl ether (Mn 526, 72 mg), and catalytic amount of boron trifluoride diethyl etherate (55.8 µl) were reacted at -20 °C for 2 minutes forming ’Polymer 3. The reaction was stopped by cooling to room temperature. The resulting polymer was purified by washing in hexane three times to remove unreacted reagents. A resulting polymer was obtained by roto-evaporating the residual hexane and DMF. Example 4 Synthesis of Polymer 4 (poly sultone-pONDEA) – Zwitterionic functionalization [00151] In one exemplary method, Polymer 4 (PS-pONDEA) was synthesized. FIG. 4 illustrates the chemical reaction equation for synthesis of Polymer 4. [00152] Polymer 1 and 1,2-oxathiolane 2,2-dioxide (1.5x to 5x molar excess) were reacted at 70 °C for 24 hrs. The reaction was stopped by cooling to room temperature. A resulting polymer was purified by washing in diethyl ether to remove unreacted reagents. This the resulting polymer was obtained by roto-evaporating the residual diethyl ether. Example 5 Peptide conjugation I [00153] In one exemplary method, (2S,8S)-8-amino-1,2-dicarboxy-17-ethyl-N-hexyl-25- hydroxy-N-(2-hydroxypropyl)-13-imino-21,21-dimethyl-N-nonyl-4,7,15-trioxo-16,19,23-trioxa- 3,6,12,14-tetraazahexacosan-26-aminium (Polymer 5) will be synthesized. FIG.5 illustrates the chemical reaction equation for synthesis of Polymer 5. N-(3-(3-(2-((2H-1 ^4-imidazole-1- carbonyl)oxy)butoxy)-2,2-dimethylpropoxy)-2-hydroxypropyl)-N-hexyl-N-(2- hydroxypropyl)nonan-1-aminium [00154] A solution of N-hexyl-N-(2-hydroxy-3-(3-(2-hydroxybutoxy)-2,2- dimethylpropoxy)propyl)-N-(2-hydroxypropyl)octan-1-aminium and di(2H-1 ^4-imidazol-1- yl)methanone in DMF will be stirred at 60 °C for 3 hrs forming N-(3-(3-(2-((2H-1 ^4-imidazole- 1-carbonyl)oxy)butoxy)-2,2-dimethylpropoxy)-2-hydroxypropyl)-N-hexyl-N-(2- hydroxypropyl)nonan-1-aminium. [00155] (2S,8S)-8-amino-1,2-dicarboxy-17-ethyl-N-hexyl-25-hydroxy-N-(2-hydroxypropyl)- 13-imino-21,21-dimethyl-N-nonyl-4,7,15-trioxo-16,19,23-trioxa-3,6,12,14-tetraazahexacosan- 26-aminium. A solution of N-(3-(3-(2-((2H-1 ^4-imidazole-1-carbonyl)oxy)butoxy)-2,2- dimethylpropoxy)-2-hydroxypropyl)-N-hexyl-N-(2-hydroxypropyl)nonan-1-aminium and arginylglycylaspartic acid in DMF will be stirred at 60 °C for 3 days forming (2S,8S)-8-amino- 1,2-dicarboxy-17-ethyl-N-hexyl-25-hydroxy-N-(2-hydroxypropyl)-13-imino-21,21-dimethyl-N- nonyl-4,7,15-trioxo-16,19,23-trioxa-3,6,12,14-tetraazahexacosan-26-aminium. Example 6 Peptide conjugation II [00156] In one exemplary method, 1,6-diamino-12-carboxy-16-ethyl-N-hexyl-24-hydroxy-N- (2-hydroxypropyl)-1-imino-20,20-dimethyl-N-nonyl-7,10,14-trioxo-15,18,22-trioxa-2,8,11- triazapentacosan-25-aminium (Polymer 6) was synthesized. FIG. 6 illustrates the chemical reaction equation for synthesis of Polymer 6. (Z)-1,6-diamino-12-carboxy-16-(ethylamino)-1- imino-N,N-dimethyl-7,10,14-trioxo-15-oxa-2,8,11,17-tetraazaicos-16-en-20-aminium. [00157] A solution of arginylglycylaspartic acid and 3-(((ethylimino)methylene)amino)-N,N- dimethylpropan-1-aminium will be stirred at room temperature for 3 hrs resulting in the formation of (Z)-1,6-diamino-12-carboxy-16-(ethylamino)-1-imino-N,N-dimethyl-7,10,14-trioxo-15-oxa- 2,8,11,17-tetraazaicos-16-en-20-aminium. [00158] 2-(2-(2-amino-5-guanidinopentanamido)acetamido)-4-((2,5-dioxopyrrolidin-1- yl)oxy)-4-oxobutanoic acid. A solution of (Z)-1,6-diamino-12-carboxy-16-(ethylamino)-1- imino-N,N-dimethyl-7,10,14-trioxo-15-oxa-2,8,11,17-tetraazaicos-16-en-20-aminium and 1- hydroxypyrrolidine-2,5-dione will be stirred at room temperature for 3 hrs forming 2-(2-(2-amino- 5-guanidinopentanamido)acetamido)-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutanoic acid. [00159] 1,6-diamino-12-carboxy-16-ethyl-N-hexyl-24-hydroxy-N-(2-hydroxypropyl)-1- imino-20,20-dimethyl-N-nonyl-7,10,14-trioxo-15,18,22-trioxa-2,8,11-triazapentacosan-25- aminium. A solution of 2-(2-(2-amino-5-guanidinopentanamido)acetamido)-4-((2,5- dioxopyrrolidin-1-yl)oxy)-4-oxobutanoic acid and N-hexyl-N-(2-hydroxy-3-(3-(2- hydroxybutoxy)-2,2-dimethylpropoxy)propyl)-N-(2-hydroxypropyl)octan-1-aminium will be stirred at room temperature for 3 hrs forming 1,6-diamino-12-carboxy-16-ethyl-N-hexyl-24- hydroxy-N-(2-hydroxypropyl)-1-imino-20,20-dimethyl-N-nonyl-7,10,14-trioxo-15,18,22-trioxa- 2,8,11-triazapentacosan-25-aminium. Example 7 – Characterization of Polymers 1, 2, and 4 by Gel Permeation Chromatography [00160] In one exemplary method, Gel Permeation Chromatography (GPC) utilizes a size exclusion column filled with porous beads to separate molecules of different size. Smaller molecules enter the pores and take longer to elute, while larger molecules bypass these pores and elute more quickly. This technique is used primarily to determine the molecular weight distribution of the resultant polymer. [00161] GPC was used to determine how the polymers changed during course of the reaction. GPC was used to determine the range of polymer sizes (molecular weight) and polydispersity to determine the distribution of molecular weights of the synthesized polymers. [00162] In this example, a 30 mg/ml sample of polymer was prepared using chromatography grade Dimethyl Formamide (DMF) as a solvent. This sample was placed into a sampling vial, which was loaded into a Malvern Viscotek GPCmax sampling rack. A 100 µl aliquot was pulled and run through the GPC column at a flow rate of 1 ml/min. The column separates the resultant sample, and contents are analyzed with laser light scattering to determine the dwell time, and therefore size, of the sample contents. Polymer Mn Mw PD unit mw Mn units Mw units an lar
Figure imgf000038_0001
weight, consists of 45 repeating units. [00164] The GPC data on the functionalized polymers (Polymer 2 and Polymer 4) is descriptive of a polymer chain of the same length but functionalized with additional groups. These results also support that the functionalization reactions were successful, by displaying a higher Mw than the un-modified polymer backbone. Example 8 – Characterization of Polymers 1, 2, and 4 by Nuclear Magnetic Resonance [00165] Nuclear Magnetic Resonance (NMR) spectroscopy is helpful in determining the structure of organic compounds. H-NMR utilizes powerful magnetic fields to determine interaction of spin of hydrogens, which will resonate at different characteristic frequencies depending on their chemical environment. This analysis technique is useful in elucidating the sample molecular structure and determining that the spectra of the polymer sample correspond to the predicted structure of the resultant polymer. [00166] A 1 mg/ml sample of polymer was prepared for each polymer formulation (Polymer 1 (pONDEA), Polymer 2 (h-pONDEA), Polymer 4 (PS-pONDEA) and 50%-50% (Polymer 2 and Polymer 4Hexyl-PS-pONDEA) in deuterated DMSO. The samples were loaded into NMR spectroscopy vials, and analyzed with a Bruker Neo 600 MHz NMR instrument. The resulting spectra of these experiments were analyzed using a literature search and comparison to simulated NMR spectra. Refer to NMR Analysis for additional information. [00167] FIGS.8A-8D show NMR spectra and analysis of the NMR spectra of the synthesized polymers. Analysis of the NMR spectra determined that the reaction resulted in the predicted backbone polymer, in the case of non-functionalized pONDEA. Spectra of the functionalized polymers confirmed the presence of a quaternized ammonia, as well as successful functionalization reactions with propane sultone. The data further demonstrates that the backbone polymer can be modified with both propane sultone and hexyl bromide, to customize the charge balance of functional groups. Example 9 – Solubility of synthesized polymers [00168] Polymer 1, poly(octyl neopentyl diglycidyl ether amine) (pONDEA) consists of several hydrophobic elements, with a relatively high density of hydroxyl groups. In its basic form, Polymer 1 is a highly viscous amber liquid. This liquid polymer was readily solubilized in alcohols, such as isopropyl alcohol, for use. Dimethyl formamide was used in the synthesis and further functionalization of the polymer, due to the high boiling point and good solubility with the polymer, monomers, and constituent elements. The base polymer was soluble in diethyl ether, so hexanes were used to wash the polymer of unreacted monomers and catalyst materials. [00169] Once functionalized, with propane sultone to form Polymer 4 (zwitterionic elements), or with an alkyl halide to form Polymer 2 (quaternary cationic groups), the resultant polymer was insoluble in diethyl ether. This insolubility is diethyl ether was because of the ionic nature. Polymer 2 was functionalized with alkyl halides. Polymer 2 forms the cationic quaternary ammonium salt form of the Polymer 1. Polymer 2 was highly hydrophobic and very insoluble in water. Conversely, Polymer 4 was zwitterionic and displays some ability to be hydrated. This form of the polymer was water miscible up to around 30% water by weight, at which point separation of water from the polymer phase was observed. Example 10 – Blood clotting properties [00170] The potential of Polymer 4 (fully zwitterionic-functionalized polymer construct) to clot blood was evaluated using thromboelastography (TEG). Thromboelastography is a viscoelastic analysis technique, wherein coagulation of blood is monitored under the conditions to assess changes to the clotting process. This technique is used clinically to rapidly evaluate the presence of coagulopathy in trauma patients, and simply characterizes the clotting characteristics of the blood samples. It has also been used to characterize the effectiveness of hemostatic agents. [00171] In the initial evaluation, whole blood was assessed via TEG in three conditions; untreated, treated with a kaolin hemostatic, and treated with polymer. The kaolin treatment group was included, as clinically a small amount of kaolin is typically added to blood samples to catalyze the clotting process, in order to return results more rapidly. For this protocol kaolin served well as a comparison as an established hemostatic material. [00172] For the TEG test procedure, 340 μL of citrated whole blood was added to a TEG cup containing 10 μL of calcium carbonate solution. The addition of calcium carbonate was necessary to chelate the sodium citrate in the blood, to allow for coagulation to proceed. For the treatment groups, prior to the addition to calcium carbonate, the blood was mixed with either kaolin or polymer sample. [00173] The sample was placed in a disposable cup, which oscillates through a 4.75 degree arc around a fixed plastic pin. As a clot forms in the blood, the pin is torqued, with the relative levels of deflection related to clot formation and strength. Table 2 shows variables and values associated with thromboelastography readings. Table 2. Variables and values associated with thromboelastography readings. Variable Typical Clinical Range Description R time 9-27 min Reaction time latency to the beginning of clot de h h
Figure imgf000040_0001
Clinically, it is helpful in assessing coagulopathies; if a patient exhibits hyperfibrinolysis, and formed clots break up rapidly, or hypercoagulability, if their blood is coagulating very rapidly, which may be problematic in the formation of emboli. For the purposes of the assessment of a hemostatic adjunct, this test is helpful in simply indicating if the clotting process is enhanced in any way by interaction with this material, and if the resulting clot exhibits any beneficial properties in comparison to the untreated sample response. [00175] As illustrated in Table 3, Polymer 4 (PS-pONDEA) performed well as a hemostatic agent. Of particular note are the reduction in R-time, increased max amplitude, and decreased LY30. This indicate that coagulation initiated rapidly, and that a very strong clot was formed that did not degrade. Functionally, this illustrates promise that this exemplary polymer not only acts as an adjunct to the hemostasis process in whole blood, but can help to form a highly stable, strong clot. Table 3. Variables and values associated with thromboelastography readings. Sample Control Kaolin PS-pONDEA R time (min) 4.5 3.4 0.4 A),
Figure imgf000041_0001
Example 11 – Cytotoxicity of synthesized polymers [00177] In another exemplary method, cytotoxicity testing was used as a way to identify biocompatible properties of a material. Testing in support of regulatory approval is defined by international standard ISO 10993-5:2009, but is sufficiently detailed to recreate the conditions for this testing to perform pre-clinically. The test method defines several options for evaluation, of which the extraction method was used. Briefly, this method consists of extracting a polymer sample with cell growth media, then culturing cells using the extracted media and assessing cell viability and growth compared to an untreated control culture. [00178] Two concentrations, 2 mg/ml and 10 mg/ml Polymer 4 (PS-pONDEA in 3T3 cell growth media) were selected for testing. Polymer 4 was selected as a test material, as this was functionalized to serve as the baseline high-biocompatibility material, due to the presence of sulfonate functional groups. The rationale behind concentration selections was determined by the high end of what was observed in publications (2 mg/ml), and a significant challenge to those conditions (10 mg/ml). Each sample was extracted in the 3T3 cell growth media for 24 hours at 37°C. The resulting media was filtered using a 0.45 µm filter to remove any particulate. For the test, L929 mouse fibroblasts were selected, based on the similarity to cell types in the relevant treatment environment. The plates were seeded at a rate of 10,000 cells/well of a 24 well plate. The cells were incubated in control media, 2mg/ml extract media, or 10mg/ml extract media. Each two days after incubation, up to day 6, an Alamar Blue assay was performed to identify cell viability. This assay utilizes a cell permeable, non-toxic compound to identify living cells. The compound is blue in color, but upon absorption to a living cell, is reduced to a red compound. The assay can be assessed by detection in an absorbance or fluorescence-based plate reader. The cell viability of the test groups can easily be compared to the control groups to determine if any cytotoxic effect is observed. Each group was incubated with 1 ml of 10% Alamar Blue solution for 2 hours at 37 °C, then assessed by microplate reader. [00179] FIGS. 10 A-C illustrate cytoxicity of Polymer 4 (PS-pondea) at two different concentrations using the AlamarBlue Assay. These results depict each day of testing, grouped by test group. This data indicates that growth was observed in each test group, with the control media group having the most growth over the tested period. Grouped by day, the amount of cell viability observed for the test groups can be compared to the untreated control. The test groups illustrated similar viability to each-other, and slightly less cell viability compared to the control for each test day. When normalized to the control group, the percentage of cell viability related to an untreated group of cells can be compared. This data illustrates that the lowest comparative cell viability was observed as 70.37% compared to the control group, observed in the 10 mg/ml group on day 4. The significance of this data is that, per ISO 10993-5, a cytotoxic effect is considered to be present when greater than a 30% reduction in cell viability is observed after exposure to the extract. Given that this threshold was not reached even in the extreme test extract, and that continued cell growth was observed for the test period, it is likely that this material can be considered non-cytotoxic according to this standard. ****************************************** All the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods have been described in terms of embodiments, it is apparent to those of skill in the art that variations can be applied to the compositions and methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope herein. More specifically, certain agents that are both chemically and physiologically related can be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept as defined by the appended claims.

Claims

WHAT IS CLAIMED IS: 1. A construct comprising a polymer comprising Formula (I),
Figure imgf000043_0001
; wherein: R1, R2, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, a heterocycle, an aryl, and a heteroaryl, wherein the heterocycle, the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio; R3 comprises a substituted or unsubstituted alkyl; n is independently an integer from 1 to 5; a is independently 0 or an integer from 1 to 5; r is independently an integer from 1 to 150; and m is independently an integer from 10 to 200.
2. The construct according to claim 1, wherein in R1 and R2 are each independently H, methyl, ethyl, propyl, butyl, pentyl, hydroxyl, or any combination thereof.
3. The construct according to claims 1 or 2, wherein R5 is alkyl, aryl, or any combination thereof.
4. The construct according to any one of the preceding claims, wherein R3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, or any combinations thereof.
5. The construct according to any one of claims 1-4, wherein R6 is hydrogen.
6. The construct according to claim 1, wherein R1 and R2 are methyl, R5 is methyl, R6 is hydrogen, n is 1, and a is 1.
7. The construct according to claim 1, wherein R1, R2, and R6 are hydrogen, n is an integer from 1 to 5, and a is 0.
8. The construct according to claim 1, wherein R1 is methyl, R2 and R6 are hydrogen, n is 1, and a is 0.
9. The construct according to claim 1, wherein R1 is hydroxyl, R2 and R6 are hydrogen, n is 1, and a is 0.
10. The construct according to claim 1, wherein R1 and R2 are methyl, R5 is phenyl, R6 is hydrogen, n is 1, and a is 1.
11. The construct according to claim 1, wherein R1, R2, and R6 are hydrogen, n is 1, a is 0, and r is an integer from 1 to 150.
12. The construct according to claim 1, wherein the polymer comprises Formula (II),
Figure imgf000044_0001
(II); wherein R4 is a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl.
13. The construct according to claim 12, wherein R1 and R2 are methyl, R3 is octyl, R4 is hexyl, R5 is methyl, R6 is hydrogen, n is 1, and a is 1.
14. The construct according to claim 12, wherein R1 and R2 are methyl, R3 is octyl, R4 is hexyl, R5 is methyl, R6 is imidazole-1-yl ethan-1-one, n is 1, and a is 1.
15. The construct according to claim 1, wherein the polymer comprises Formula (III),
Figure imgf000045_0001
; wherein the polymer is a crosslinked polymer.
16. The construct according to claim 1, wherein the polymer comprises Formula (IV), ; wherein the
Figure imgf000045_0002
17. The construct according to claim 1, further comprising the polymer of Formula (V),
Figure imgf000046_0001
Formula (VI), wherein the
Figure imgf000046_0002
18. A method of preparing a construct according to any one of claims 1-17, the method comprising: a. forming a first reaction mixture comprising a first organocatalyst, a first solvent, a primary amine, and a terminal di-epoxide; b. performing a first heat treatment to the first reaction mixture for a period sufficient to allow formation of the polymer of claim 1, wherein the primary amine comprises a compound of Formula (VII) or (IX) and the terminal di-epoxide comprises a compound of Formula (X),
Figure imgf000047_0001
; (VII); Formula (IX), ;
Figure imgf000047_0002
(IX), Formula (X), ;
Figure imgf000047_0003
(X); wherein: R1, R2, and R5 are each independently selected from the group consisting of hydrogen, hydroxyl, an alkyl, an aryl, and a heteroaryl, wherein the aryl and the heteroaryl are each independently unsubstituted or are optionally independently substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylsulfo, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio; n is independently an integer from 1 to 5; a is independently 0 or an integer from 1 to 5; r is independently an integer from 1 to 150; and p is an integer between 1 to 15. 19. The method according to claim 18, wherein the terminal di-epoxide comprises neopentyl glycol diglycidyl ether, alkyl diglycidyl ethers, propylene glycol diglycidyl ether, glycerol diglycidyl ether, bisphenol A diglycidyl ether, and/or polyethylene glycol diglycidyl ether. 20. The method according to claim 18 or 19, wherein the first organocatalyst is 4- dimethylaminopyridine (DMAP). 21. The method according to any one of claims 18-20, wherein the first solvent is a polar solvent. 22. The method according to any one of claims 18-21, wherein the first heat treatment comprises heating the first reaction mixture to a first temperature. 23. The method according to claim 18, further comprising: forming a second reaction mixture using the polymer of Formula (I), an alkyl halide, a second solvent, and a bicarbonate salt; performing a second heat treatment to the second reaction mixture allowing formation of a quaternized polymer of claim 12; wherein the second solvent is a polar solvent; and wherein the second heat treatment comprises heating the second reaction mixture to a second temperature. 24. The method according to claim 18, further comprising: forming a third reaction mixture using the quaternized polymer, a diglycidyl ether, and a third organocatalyst; and performing a third heat treatment to the third reaction mixture to form the crosslinked polymer of claim 15; wherein the third organocatalyst is a Lewis acid; and wherein the third heat treatment comprises cooling the third reaction mixture to a third temperature. 25. The method according to claim 18, further comprising forming a fourth reaction mixture using the polymer and a sultone to form the anionic quaternized polymer of claim 16. 26. The method according to claim 18, further comprising: forming a fifth reaction mixture using the quaternized polymer and a coupling agent; performing a fourth heat treatment to the fifth reaction mixture to form a coupled- quaternized polymer; forming a sixth reaction mixture using the coupled-quaternized polymer and a peptide; and performing a fifth heat treatment to the sixth reaction mixture to form the peptide coupled- quaternized polymer of claim 17. 27. A method of preparing a substrate having at least one of antimicrobial activity and hemostatic activity comprising mixing at least one agent with a construct according to any one of claims 1-18; wherein the at least one agent is a formulated polymer solution or a liquid polymer. 28. A method of providing an antimicrobial agent to a subject, medical device, or a surface comprising providing to the subject, medical device, or surface, a composition or pharmaceutical composition comprising at least one construct according to any one of claims 1-18; and at least one excipient. 29. A pharmaceutical composition comprising the construct according to any of claims 1-18; and at least one pharmaceutically acceptable excipient. 30. The pharmaceutical composition according to claim 29, wherein the composition comprises an aqueous formulation, gelatinous formulation, a formulation on a pad, a formulation on gauze, a formulation on a tape or wax, a viscous aqueous fluid, or other wound dressing or a paste formulation. 31. The pharmaceutical composition according to claim 29, wherein the composition comprises a topical formulation. 32. The pharmaceutical composition according to claim 31, wherein the topical formulation comprises a spray, cream, gel, powder, a wax or wound dressing. 33. The pharmaceutical composition according to claim 30, wherein the wound dressing is a pad. 34. A kit comprising the construct according to any one of claims 1-18 or the pharmaceutical composition according to any one of claims 29-33; and at least one container. 35. The kit according to claim 34, wherein the at least one container comprises at least one of a spray bottle, a jar, a tube, a squirt bottle, a canister, and a box.
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