Polyhedral oligomeric silsequioxane polymer for ENT wound dressing & hemorrhage agent

Abstract

In one aspect, the present disclosure describes wound dressings that may be used in the treatment of wounds. In particular traumatic and surgical wounds within the ear, nose, throat, or mouth regions. These wound dressings may further comprise a second therapeutic agent or be used in ENT (Ears Nose Throat) surgery. This wound dressing may be used to establish a hemostatic seal.

Description

[0001] POLYHEDRAL OLIGOMERIC SILSEQUIOXANE POLYMER FOR ENT WOUND DRESSING & HEMORRHAGE AGENT

[0002] This application claims the benefit of priority to United States Provisional Application No. 63 / 586,848, filed on September 29, 2023, the entire contents of which are hereby incorporated by reference.

[0003] BACKGROUND

[0004] 1. Field

[0005] This disclosure relates to the fields of medince, ear, nose and throat wounds, and wound dressings. In particular, this disclosure relates to hemostatic wound dressings.

[0006] 2. Related Art

[0007] Following Ears Nose & Throat (ENT) surgery, wound dressings are a critical portion of the healing process. The most common complications of ENT surgery include scar tissue formation, adhesions, pain, bleeding (hemorrhage), and infection. Wound dressings in ENT surgery are designed to reduce these complications and provide a platform for tissue healing. In addition to wound healing, achieving, and maintaining hemostasis during surgery is of utmost importance. Bleeding complications for ENT surgeries can range from mild to severe (life threatening) depending on the anatomic location, type of surgery, and patient comorbidities. Many of these anatomic regions are difficult to achieve hemostasis due to the cavernous shapes, limited surgical visibility, and high vascularity. Therefore, wound dressings that can satisfy these conditions are highly sought after.

[0008] Two of the most common ENT surgeries in the US include functional endoscopic surgery (FESS) and tonsillectomy. Both of these surgeries can be complicated by poor wound healing, infection, bleeding, and postoperative pain. Hemorrhage during or after tonsillectomy (post tonsillar hemorrhage) can be a dangerous and potentially life-threatening complication. Beyond these surgeries, other surgical applications include the skull sinuses, nasal cavity, adenoids, ear canals, middle ear, teeth, periodontal structures (gingiva, tooth sockets, etc.), tympanic membranes, trachea, vocal cords, and regions of nasal polyp removal. Currently, there are very few hemostatic options to treat these serious bleeding events.

[0009] In addition to post-surgical bleeding, spontaneous and traumatic bleeding from the ENT regions of the body can also be particularly challenging to treat. Epistaxis is a very common condition (affecting 60 million Americans each year) that often requires medical and / or surgical intervention. The majority of patients seeking medical care will undergo a procedure which can include chemical / electrical cautery, vasoconstrictor drug delivery, nasal packing, or surgery. However, these interventions can lead to complications such as aspiration, airway obstruction, tissue damage, infection, and have high rates of rebleeding. Traditional nasal packings generally are required to be left in place for several days (usually 48-72 hours) and need medical follow up for removal. Therefore, a composition that can be adapted to the space but that is naturally cleared is desirable.

[0010] ENT surgical wound dressings and epistaxis therapies fall into several categories including non-absorbable sponges, gauze, absorbable sponges, flowable gels, and balloonbased devices. The most desirable attributes of these devices include providing a wound dressing, augment tissue healing, anti-inflammatory effects, achieving hemostasis, providing “stenting” of the mucous drainage pathways (example: middle meatus), and preventing infection. ENT wound dressings and epistaxis devices are often combined with antibiotics, corticosteroids, vasoconstrictors / nasal decongestants, collagen, and pro-coagulants (example: tranexamic acid). Some of these devices are soaked in nasal decongestants (oxymetazoline, naphazoline, phenylephrine, synephrine, tetryzoline, tramazoline, and xylometazoline), anesthetics (lidocaine, bupivacaine, ropivacaine, cocaine, procaine, benzocaine, 2- chloroprocaine, mepivacaine, tetracaine, etidocaine, levobupivacaine, bupivacaine), and procoagulants (tranexamic acid, thombin) prior to insertion to augment their hemostatic attributes. In addition, due to the risk of infection (sinusitis and toxic shock syndrome) with nasal packing, topical and oral antibiotics are often administered. Topical antimicrobial gels (example: triple antibiotics ointment) are commonly applied to these devices to prevent infection after insertion. Intraoperatively and postoperatively corticosteroids (nasally inhaled) are often given to reduce tissue inflammation and edema. The wound healing attributes can also be amplified by mixing it with collagen or other therapeutic agents within the polymer. Therefore, development of a wound dressing that can accommodate addtiaionl therapeutic agents is desirable.

[0011] SUMMARY

[0012] As provided herein, the present disclosure relates to compositions for use as wound dressings, particularly in ENT application.

[0013] In some aspects, the present disclosure provides wound dressing comprising:

[0014] (A) a silanol carrier, wherein the silanol carrier is a polyhedral oligomeric silsequioxane; and

[0015] (B) a therapeutic agent; wherein the therapeutic agent is an antimicrobial agent, tranexamic acid, thrombin, a corticosteroid, an anesthetic, a vasoconstricting agent, or a nasal decongestant agent; wherein the therapeutic agent has been mixed with the silanol carrier.

[0016] In some embodiments, the wound dressing forms a hemostatic seal with a wound. In some embodiments, the silanol carrier comprises a polyhedral oligomeric silsequioxane trisilanol. In some embodiments, the silanol carrier is an z-octyl polyhedral oligomeric silsequioxane trisilanol. In some embodiments, the therapeutic agent is an antimicrobial agent such as an antibiotic. In some embodiments, the wound dressing comprises from about 0.0001 %-50% w / w of the therapeutic agent. In some embodiments, the wound dressing is formulated for use in an ear, nose, or throat application. In some embodiments, the ear, nose, or throat application is an ear, nose, or throat surgery. In some embodiments, the ear, nose, or throat surgery is functional endoscopic surgery. In some embodiments, the ear, nose, or throat surgery is a tonsillectomy.

[0017] In still another aspect, the present disclosure provides methods of applying a wound dressing to a wound comprising:

[0018] (A) obtaining a wound dressing described herein; and

[0019] (B) applying the wound dressing to the wound; wherein the wound is located in the nasal cavity, the mouth, the throat, or the ears.

[0020] In some embodiments, the wound dressing comprises tranexamic acid or thrombin. In some embodiments, the wound dressing comprises an antimicrobial agent. In some embodiments, the application of the wound dressing results in a hemostatic seal with the wound. In some embodiments, the methods further comprise removing the wound dressing and reapplying a second wound dressing.

[0021] In yet another aspect, the present disclosure provides methods of improving the healing of a wound comprising applying a wound dressing described herein sufficient to establish create a hemostatic seal over the wound. In some embodiments, the wound heals in a short amount of time relative to a traditional wound dressing. In some embodiments, the wound heals in a short amount of time relative to gauze. In some embodiments, the wound heals in at least 5% shorter time than a traditional wound dressing.

[0022] In still yet another aspect, the present disclosure provides methods of applying a wound dressing comprising:

[0023] (A) obtaining a wound dressing, wherein the wound dressing comprises a polyhedral oligomeric silsesquioxane;

[0024] (B) applying the wound dressing to a wound through a cannulated tip to a wound, wherein the wound is in the nose, mouth, throat, or ear.

[0025] In some embodiments, the polyhedral oligomeric silsesquioxane comprises an alkyl polyhedral oligomeric silsequioxane trisilanol. In some embodiments, the wound dressing comprises an z-octyl polyhedral oligomeric silsequioxane trisilanol.

[0026] In another aspect, the present disclosure provides methods of applying a wound dressing to a wound comprising:

[0027] (A) Obtaining a wound dressing described herein in a container comprising a tip; and

[0028] (B) applying the wound dressing with the tip to the wound.

[0029] In some embodiments, the tip is a cannulated tip.

[0030] In another aspect, the present disclosure provides kits comprising:

[0031] (A) a wound dressing, wherein the wound dressing comprises a polyhedral oligomeric silsequioxane trisilanol;

[0032] (B) a container, wherein the wound dressing is stored within the container; and

[0033] (C) an applicator tip, wherein the container is configured to allow the deposition of the wound dressing through the applicator tip onto a wound.

[0034] In some embodiments, the alkyl polyhedral oligomeric silsequioxane trisilanol is z'-octyl polyhedral oligomeric silsequioxane trisilanol. In some embodiments, the applicator tip is a cannulated tip.

[0035] In still another aspect, the present disclosure provides methods of sealing a dressing, a medical device, or a medication to a desired location comprising:

[0036] (A) applying the dressing, the medical device, or the medication to the desired location;

[0037] (B) applying the wound dressing described herein to the dressing, the medical device, or the medication; and (C) drying the wound dressing to sealing the dressing, the medical device, or the medication to the desired location.

[0038] In some embodiments, the dressing is sealed to the desired location through a hemostatic seal. In some embodiments, a wound at the desired location heals in a short amount of time relative to a traditional wound dressing. In some embodiments, the wound heals in a shorter amount of time relative to gauze. In some embodiments, the wound heals in at least 5% shorter time than a traditional wound dressing. In some embodiments, the dressing is gauze. In some embodiments, the medication is a hemostatic agent, an antimicrobial agent, or an analgesic. In some embodiments, the antimicrobial agent is an antibacterial, an antiparasitic, an antifungal, or an antiviral. In some embodiments, the medical device is a hemostatic device.

[0039] It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein. For example, a compound synthesized by one method may be used in the preparation of a final compound according to a different method.

[0040] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The word “about” means plus or minus 5% of the stated number.

[0041] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0042] BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0044] Figure 1 is a table showing various molecules with siloxane (Si-O-Si*) backbones that are frequently denoted using a shorthand notation by the symbols M, D, T, and Q.

[0045] Figure 2 depicts the structural formula of several closed cage silsesquioxane silanols.

[0046] Figure 3 depicts the structural formula of several open cage silsesquioxane silanols.

[0047] Figure 4 depicts the structural formula of several polymeric silsesquioxane silanols.

[0048] Figure 5 depicts the structural formula of several fragmented silsesquioxane silanols.

[0049] Figure 6 depicts the structural formula of z-octyl-silsesquioxane.

[0050] Figure 7 depicts a pathologic specimen of the animal’s nasal septum at the site of the surgical injury.

[0051] Figure 8 depicts a 20x magnification of the pathologic specimen with arrows showing the site of the original surgical wound.

[0052] Figure 9 depicts the zone of inhibition for either drop or well for different antibiotic combinations with the wound dressing described herein.

[0053] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0054] The present disclosure provides a gel based hemostatic and wound healing agent that is comprised of a pure silanol polymer or silanol as a carrier for suspended additives. The silanol carrier fluid may comprise polyhedral oligomeric silsesquioxanes, silsesquioxanes, silicones, and silicates such as a polyhedral oligomeric silicate composition. The solid hemostatic additive may be selected from the group consisting of antibiotics, steroids, vasoconstrictors, or tranexamic acid. The gel-based ENT wound dressing and epistaxis device of the present disclosure exhibits sufficient flowability to allow for injection and spread into the cavities within the head and neck region. The physical characteristics of the polymer provide a protective wound covering, maintain wound moisture for healthy tissue growth, and provide a platform for thrombus formation with bleeding. The polymer can be used as an adjunct to surgical techniques and devices used to close surgical wounds in ENT surgery.

[0055] In a particular embodiment fo the disclosure, the fluidic polymer agent comprises a solid or liquid additive suspended in a silanol-bearing polyhedral oligomeric silsesquioxane fluid. The solid or liquid additive may be selected from the group consisting of antibiotics, corticosteroids, vasoconstrictors / nasal decongestants, collagen, and pro-coagulants. In an embodiment, the liquid silanol-bearing molecule is a polyhedral oligomeric silsesquioxane trisilanol, and more particularly trisilanol hepta-isoOctyl polyhedral oligomeric silsesquioxanes (isoOctyl=2,2,4-trimethylpentyl), having the molecular composition [(z- OctylSiOi.5)4(z-Octyl(OH)SiOi.o)3]y7.. In other embodiments, the silanol component may comprise a silsesquioxane or a silicate, such as a polyhedral oligomeric silicate composition.

[0056] I. Polyhedral Oligomeric Silsesquioxane Polymers

[0057] This polymer can be administered in several different techniques. Direct injection of the polymer gel onto the site of bleeding / injured tissue is the most common way it is utilized. However, using it to coat an epistaxis tampon / balloon device or placing it on the tip of cotton tipped applicator prior to insertion can also be effective. This intervention also can be loaded into a syringe with an attachable straw tip applicator. The applicator allows access into the challenging cavities within the head and neck region.

[0058] As disclosed in PCT / US20 / 25727 to Lichtenhan (hereinafter “Lichtenhan”), the contents of which are incorporated herein in its entirety, polyhedral oligomeric silsesquioxanes — a family of molecules that consist of a silica-like core surrounded by a shell of organic groups — are additives have been shown to be useful in a variety of biomedical applications such as dental restoratives, biomimetic implants, nerve conduits, intestinal tissue scaffolds, cardiac tissue, trachea scaffolds, and for drug delivery agents. The chemical composition of polyhedral oligomeric silsesquioxanes is a hybrid intermediate between that of silica (Si O? ) and silicone (R SiO). The key purpose of polyhedral oligomeric silsesquioxanes compositions is to create hybrid materials that are easy to process like polymers yet possess the characteristics of high-use temperature and oxidation resistance like ceramics. These nanostructures have the empirical formula 7?„(SiO 1.5)0, where R is a hydrogen atom or an organic functional group such as an alkyl, alkylene, acrylate, hydroxyl, or epoxide unit. Unlike silica or modified clays, each polyhedral oligomeric silsesquioxane molecule contains covalently bonded reactive functionalities suitable for polymerization or grafting polyhedral oligomeric silsesquioxane monomers to polymer chains, as well as nonreactive organic functionalities for solubility and compatibility of the polyhedral oligomeric silsesquioxane segments with the various polymer systems. As an additive, polyhedral oligomeric silsesquioxanes provides enhanced compatibility between biological and man-made materials while improving surface and bulk properties.

[0059] As used herein, the term “silanol” describes a functional group in silicon chemistry having the connectivity Si-OH where the OH is a hydroxyl. This functionality is found at the terminal end of a silicone or silsesquioxane polymer or molecule. In the literature for silicon compounds the terms silicone, siloxane, polysiloxane, silsesquioxane, polysilsesquioxane, polyhedral oligomeric silsesquioxane and silicate are frequently used as synonyms to describe polymers and molecules with a silicon-oxygen-silicon (Si-O-Si) backbone or framework. The environment of different structural silicon atoms is frequently denoted using a shorthand notation by the symbols M, D, T, and Q. As shown in Figure 1, these symbols refer only to the number of silicon-oxygen (Si-O-) groups attached to the silicon atom of interest to form siloxane (Si-O-Si*) linkages. The symbol M represents a silicon atom having one Si-O-Si linkage and three organic R groups and is typically found at the terminal end of a silicone or silsesquioxane polymer or molecule. The D symbol represents a silicon atom with two Si-O- Si linkages and two organic groups and is the unit, which makes up linear silicones or polysiloxanes. The T symbol represents a silicon atom having three Si-O-Si linkages and one organic group and typically provides branch points in a silicone or silsesquioxane polymer or molecule. The Q symbol represents a silicon atom having four Si-O-Si linkages and is unique, as it contains no organic R group bound to the central silicon. Q-type silicon atoms are typically branch points in a silicone or silsesquioxane polymer or molecule. The chemistry of silanols is highly diverse and a nearly infinite variety of M, D, T, and Q compositional and structural combinations are possible. Included among these compositions are wholly closed-cage silsesquioxane silanols (see Figure 2); open cage silanols (see Figure 3); polymeric silanol silsesquioxanes (see Figure 4); and fragmented silanols (see Figure 5). For each silanol molecule the organic group (R) is defined as an organic substituent (H, cyclic or linear aliphatic or aromatic groups that may additionally contain functionalities such as alcohols, ethers, acids, esters, ketones, amines, olefins, halides, sulfides, silicones, as well as fluorinated and nonfunctional aliphatic, olefinic, or aromatic groups). The wound dressing described herein is generally directed to a synthetic gel polymer agent used a hemostatic agent, wound dressing, and wound healing agent in ENT pathology. The polymer can be combined / suspended with other agents such as vasoconstrictors, corticosteroids, TXA, or antibiotics and used as a drug delivery agent. Due to the tissue adhesion, viscoelastic properties, and flowable nature of this polymer to disrupted tissue it is well suited for ENT pathologies and surgical interventions. For the present wound dressings, the present disclosure may use a silanol species such as the T-type polyhedral oligomeric silsesquioxane trisilanol iso-Octyl with the molecular representation [(z-ocylSiOi.5)4(i- octyl(OH)SiOi.o)3]y7 (referred to herein as “iso-octyl polyhedral oligomeric silsesquioxane trisilanol” or “i-octyl polyhedral oligomeric silsesquioxane trisilanol”) for to its high viscosity and high equivalent weight of silanol groups. A related and higher viscosity T-type polyhedral oligomeric silsesquioxane trisilanol is the trisilanol octadecyl polyhedral oligomeric silsesquioxane [(octadecylSiOi.5)4(octadecyl(OH)SiOi.o)3]y7. However, other silanol species may be utilized with the fluidic hemostat agent described herein.

[0060] The i-octyl polyhedral oligomeric silsesquioxane trisilanol is a hybrid molecule with an inorganic silsesquioxane at the core, seven hydrophobic, organic isooctyl groups attached at the comers of the cage and three active silanol functionalities. It is a liquid over the temperature range from -40 °C to 250 °C, which enables easy application, adhesion, and proliferation within a wound. The silanol characteristic of / '-octyl polyhedral oligomeric silsesquioxane trisilanol provides for biological compatibility, and it is also believed to contribute to the compatibility of silanol-bearing polyhedral oligomeric silsesquioxane molecules with the known solid hemostatic additives antibiotics, corticosteroids, vasoconstrictors / nasal decongestants, collagen, and pro-coagulants. The ability of / -octyl polyhedral oligomeric silsesquioxane trisilanol to function as a carrier fluid for these known solid / liquid additives beneficially enables these otherwise wound / antimicrobial / pro-coagulant / vaso-constrictor agents to exhibit the beneficial features of liquid hemostatic agents, namely injectability and proliferation. While the silanol groups of silanol-bearing polyhedral oligomeric silsesquioxane molecules, and in particular / -octyl polyhedral oligomeric silsesquioxane trisilanol, can also serve as carriers and platelet activators, they do not lyse erythrocytes. This renders the silanol useful and active in achieving coagulation, thereby further enhancing the overall hemostatic activity of the fluidic hemostat agent mixture described herein. The promise of rigid cage structured silanols — and in particular polyhedral oligomeric silsesquioxanes — for biocompatible materials lies in their rigid shape, tailorable R group, highly dispersive nature, and ability to rationally control surface area, volume, and roughness. This control in turn affords the ability to stimulate a biological response in nanoscopic dimensions. Polyhedral oligomeric silsesquioxane chemicals contain a hollow internal cage core comprised of inorganic silicon-oxygen bonds, rigid silsesquioxane, silicate, and silicone. The exterior of the rigid core contains organic functionalities (R), which ensure compatibility and desired tailorability of the molecule with man-made and biological tissues. The desirable silanol attribute is selectively attached to the silicon-oxygen core. These and other properties and features of nanostructured chemicals are discussed in detail in U.S. Pat. Nos. 5,412,053 and U.S. Pat. No. 5,484,867 to Lichtenhan et al., both are incorporated herein by reference in their entirety. The organic group (R) characteristic provides for biological compatibility, adhesion, and control of adhesion and liquid state properties. The nature of the R group also provides for a capability to interact with tissue and blood components. Organic groups can be hydrophobic and hydrophilic in properties and the use of such characteristics for controlling biological interactions with vesicles or cell membranes and use in wound treatment has been reported. Regarding z-octyl polyhedral oligomeric silsesquioxane trisilanol in particular, the R groups cause the molecule to resemble a surfactant with hydrophilic polarity at one end and hydrophobicity at the other. It does not liberate heat upon hydration and, as a clear liquid, exhibits excellent and nonmigrating wet-out adhesion toward collagen and tissue (endothelial and related tissue cells). The z-octyl groups are attributed to tissue adhesion and this property is common to all z-octyl containing polyhedral oligomeric silsesquioxane molecules.

[0061] The rigid three-dimensional structure characteristic of z-octyl polyhedral oligomeric silsesquioxane trisilanol provides for cell binding, high surface area, volume, and viscosity control. High surface area, which is desirable in liquid hemostats for purposes of maximizing blood component interactions and subsequent coagulation, is achieved through use of small yet rigid three-dimensional components. Furthermore, the absence of crystallinity affords the i- octyl polyhedral oligomeric silsesquioxane trisilanol with a high oxygen permeation rate that enables rapid tissue healing and potential defense against anaerobic bacteria. The z-octyl polyhedral oligomeric silsesquioxane trisilanol is not cytotoxic and can be removed from tissue using dry gauze wipes, alcohol or hydrocarbons. IL Therapeutic Agents

[0062] It is envisioned that the wound dressings described herein may be used together with an additional antimicrobial agent such as anti-viral, anti-fungal, antibiotic, or a compound which mitigates one or more of the side effects experienced by the patient.

[0063] Antimicrobial agents or factors suitable for use in wound dressing according to the present disclosure against an infectious disease include antibiotics such as penicillins, cephalosporins, carbapenems, macrolides, aminoglycosides, quinolones (including fluoroquinolones), sulfonamides and tetracylcines. In particular, one may use combination therapies for treating MRS A. Both CA-MRSA and HA-MRSA are resistant to traditional anti- staphylococcal beta-lactam antibiotics, such as cephalexin. CA-MRSA has a greater spectrum of antimicrobial susceptibility, including to sulfa drugs (like co-trimoxazole / trimethoprim- sulfamethoxazole), tetracyclines (like doxycycline and minocycline) and clindamycin (for osteomyelitis), but the drug of choice for treating CA-MRSA is now believed to be vancomycin, according to a Henry Ford Hospital Study. HA-MRSA is resistant even to these antibiotics and often is susceptible only to vancomycin. Newer drugs, such as linezolid (belonging to the newer oxazolidinones class) and daptomycin, are effective against both CA- MRSA and HA-MRSA. The Infectious Disease Society of America recommends vancomycin, linezolid, or clindamycin (if susceptible) for treating patients with MRSA pneumonia. Ceftaroline, a fifth generation cephalosporin, is the first beta-lactam antibiotic approved in the U.S. to treat MRSA infections (skin and soft tissue or community acquired pneumonia only).

[0064] Quinolone-resistant .S', aureus is another emerging pathogen that may be treated with compounds according to the present disclosure, optionally in combination with vancomycin, teicoplanin and linezolid.

[0065] Vancomycin and teicoplanin are glycopeptide antibiotics used to treat MRSA infections. Teicoplanin is a structural congener of vancomycin that has a similar activity spectrum but a longer half-life. Because the oral absorption of vancomycin and teicoplanin is very low, these agents must be administered intravenously to control systemic infections. Treatment of MRSA infection with vancomycin can be complicated, due to its inconvenient route of administration. Moreover, many clinicians believe that the efficacy of vancomycin against MRSA is inferior to that of anti-staphylococcal beta-lactam antibiotics against methicillin-susceptible Staphylococcus aureus (MSSA). Several newly discovered strains of MRSA show antibiotic resistance even to vancomycin and teicoplanin. These new evolutions of the MRSA bacterium have been dubbed Vancomycin intermediate-resistant Staphylococcus aureus (VISA). Linezolid, quinupristin / dalfopristin, daptomycin, ceftaroline, and tigecycline are used to treat more severe infections that do not respond to glycopeptides such as vancomycin. Current guidelines recommend daptomycin for VISA bloodstream infections and endocarditis. Studies also suggest that allicin, a compound found in garlic, may prove to be effective in the treatment of MRSA.

[0066] Other combinations are contemplated. The following is a general discussion of antibiotics and antivirals that may be used in combination with the wound dressings described herein.

[0067] 1. Antibiotics

[0068] The term “antibiotics” are drugs which may be used to treat a bacterial infection through either inhibiting the growth of bacteria or killing bacteria. Without being bound by theory, it is believed that antibiotics can be classified into two major classes: bactericidal agents that kill bacteria or bacteriostatic agents that slow down or prevent the growth of bacteria.

[0069] The first commercially available antibiotic was released in the 1930’s. Since then, many different antibiotics have been developed and widely prescribed. In 2010, on average, 4 in 5 Americans are prescribed antibiotics annually. Given the prevalence of antibiotics, bacteria have started to develop resistance to specific antibiotics and antibiotic mechanisms. Without being bound by theory, the use of antibiotics in combination with another antibiotic may modulate resistance and enhance the efficacy of one or both agents.

[0070] In some embodiments, antibiotics can fall into a wide range of classes. In some embodiments, wound dressings may be used in conjunction with an antibiotic. In some embodiments, the compounds may be used in conjunction with a narrow spectrum antibiotic which targets a specific bacteria type. In some non-limiting examples of bactericidal antibiotics include penicillin, cephalosporin, polymyxin, rifamycin, lipiarmycin, quinolones, and sulfonamides. In some non-limiting examples of bacteriostatic antibiotics include macrolides, lincosamides, or tetracyclines. In some embodiments, the antibiotic is an aminoglycoside such as kanamycin and streptomycin, an ansamycin such as rifaximin and geldanamycin, a carbacephem such as loracarbef, a carbapenem such as ertapenem, imipenem, a cephalosporin such as cephalexin, cefixime, cefepime, and ceftobiprole, a glycopeptide such as vancomycin or teicoplanin, a lincosamide such as lincomycin and clindamycin, a lipopeptide such as daptomycin, a macrolide such as clarithromycin, spiramycin, azithromycin, and telithromycin, a monobactam such as aztreonam, a nitrofuran such as furazolidone and nitrofurantoin, an oxazolidonones such as linezolid, a penicillin such as amoxicillin, azlocillin, flucloxacillin, and penicillin G, an antibiotic polypeptide such as bacitracin, polymyxin B, and colistin, a quinolone such as ciprofloxacin, levofloxacin, and gatifloxacin, a sulfonamide such as silver sulfadiazine, mefenide, sulfadimethoxine, or sulfasalazine, or a tetracycline such as demeclocycline, doxycycline, minocycline, oxytetracycline, or tetracycline. In some embodiments, the compounds could be combined with a drug which acts against mycobacteria such as cycloserine, capreomycin, ethionamide, rifampicin, rifabutin, rifapentine, and streptomycin. Other antibiotics that are contemplated for combination therapies may include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin, dalfopristin, thiamphenicol, tigecycline, tinidazole, or trimethoprim.

[0071] 2. Antivirals

[0072] The term “antiviral” or “antiviral agents” are drugs which may be used to treat a viral infection. In general, antiviral agents act via two major mechanisms: preventing viral entry into the cell and inhibiting viral synthesis. Without being bound by theory, viral replication can be inhibited by using agents that mimic either the virus-associated proteins and thus block the cellular receptors or using agents that mimic the cellular receptors and thus block the virus- associated proteins. Furthermore, agents which cause an uncoating of the virus can also be used as antiviral agents.

[0073] The second mechanism of viral inhibition is preventing or interrupting viral synthesis. Such drugs can target different proteins associated with the replication of viral DNA including reverse transcriptase, integrase, transcription factors, or ribozymes. Additionally, the therapeutic agent interrupts translation by acting as an antisense DNA strain, inhibiting the formation of protein processing or assembly, or acting as virus protease inhibitors. Finally, an anti-viral agent could additionally inhibit the release of the virus after viral production in the cell.

[0074] Additionally, anti-viral agents could modulate the body's own immune system to fight a viral infection. Without being bound by theory, the anti-viral agent which stimulates the immune system may be used with a wide variety of viral infections.

[0075] In some embodiments, the wound dressings described herein may be used with an antiviral agent as described above. In some non-limiting examples, the anti-viral agent is abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balavir, boceprevirertet, cidofovir, combivir, dolutegravir, daruavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, ecoliever, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type I, type II, and type III, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, sofosbuvir, stavudine, telaprevir, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, traporved, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, or zidovudine. In some embodiments, the anti-viral agents are an anti-retroviral, a fusion inhibitor, an integrase inhibitor, an interferon, a nucleoside analogues, a protease inhibitor, a reverse transcriptase inhibitor, a synergistic enhancer, or a natural product such as tea tree oil.

[0076] 3. Anti-fungals

[0077] The wound dressing compositions may contain an antimicrobial agent such as an antifungal agent. Examples of antifungal agents include, but are not limited to, ketoconazole, miconazole, bifonazole, butoconazole, clomidazole, clotrimazole, croconazole, eberconazole, econazole, fenticonazole, flutimazole, isoconazole, ketoconazole, lanoconazole, luliconazole, neticonazole, omoconazole, oxiconazole, setraconazole, sulconazole, tioconazole, fluconazole, itraconazole, terconazole, terbinafine, natrifine, amorolfine, amphotericin B, nystatin, natamaycin, flucytosine, griseofulvin, potassium iodide, butenafine, ciclopirox, ciloquinol (iodochlorhydroxy quin), haloprogin, tolnaftate, aluminum chloride, undecylenic acid, potassium permanganate, selenium sulphide, salicylic acid, zinc pyruthione, bromochlorsalicylanilide, methylrosaniline, tribromometacresol, undecylenic acid, polynoxylin, 2-(4-chlorphenoxy)-ethanol, chlorophensesin, ticlatone, sulbentine, ethyl hydroxybenzoate, dimazole, tolciclate, sulphacetamide, benzoic acid and pharmaceutically acceptable salts thereof.

[0078] III. Kits

[0079] The technology disclosed herein includes kits for delivering the wound dressing to the treatment areas. A “kit” refers to a combination of physical elements. For example, a kit may include, for example, one or more components, such as dispensing apparatus, an instruction sheet, and other elements useful to practice the technology described herein. These physical elements can be arranged in any way suitable for carrying out the disclosure.

[0080] The components of the kits may be packaged either. The container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component may be placed, and preferably, suitably aliquoted (e.g., aliquoted into the wells of a microtiter plate). Where there is more than one component in the kit, the kit also will generally contain a second, third or other additional container into which the additional components may be separately placed. However, various combinations of components may be comprised in a single vial. The kits of the present disclosure also will typically include a means for containing the wound dressing and any other reagent containers or instruments in close confinement for commercial sale. Such containers may include injection or blow molded plastic containers into which the desired vials are retained.

[0081] A kit will also include instructions for employing the kit components as well the use of any other reagent not included in the kit. Instructions may include variations that can be implemented. It is contemplated that such reagents are embodiments of kits of the disclosure. Such kits, however, are not limited to the particular items identified above.

[0082] IV. Definitions

[0083] The use of the word “a” or “an,” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0084] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects or patients. Unless otherwise noted, the term “about” is used to indicate a value of ±10% of the reported value, preferably a value of ±5% of the reported value. It is to be understood that, whenever the term “about” is used, a specific reference to the exact numerical value indicated is also included.”

[0085] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

[0086] The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.

[0087] V. Examples

[0088] The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0089] Example 1: Animal Studies

[0090] An animal study was conducted to demonstrate the effectiveness, safety, and outcomes of the application of i-octyl polyhedral oligomeric silsesquioxane trisilanol following an ENT surgical injury. In this study a well-established porcine epistaxis model was utilized to create injuries in the anterior nasal septum. A cohort of 8 pigs were utilized and each animal underwent 2 full thickness wounds (1 in each nostril). Each animal was its own internal control with one nostrils being randomly assigned to the treatment group (i-octyl polyhedral oligomeric silsesquioxane trisilanol) and the other to the control group. The injuries were made in each nostril using a standard 5-mm nasal biopsy punch with the animal allowed to free bleed. After bleeding was verified, the treatment (i-octyl polyhedral oligomeric silsesquioxane trisilanol) versus control article was applied. The i-octyl polyhedral oligomeric silsesquioxane trisilanol gel was delivered using a syringe with engineered cannulated straw tip of approximately 5.5cm in length. The presence or absence of bleeding after treatment and the time of bleeding cessation were recorded. The animals recovered from anesthesia and were monitored for up to 21-days post-surgery. On post-operative day 7, 14, and 21, the surgical wounds were visually inspected and photographed. Half the animals were euthanized on post operative day 14 and half on day 21. Following the euthanasia surgical injuries were inspected and resected with a 5mm border of normal tissue around the edges. These tissue specimens were fixed in formalin and underwent histopathologic review.

[0091] All animals were stable throughout the peri-operative period and survived to the study end date. In addition, all surgical wounds were performed along the inferior / anterior nasal septum without complication and bleeding was observed in 100% of the wounds. Of the animals that received the treatment (i-octyl polyhedral oligomeric silsesquioxane trisilanol) gel the surgical injury was easily accessible using the cannulated straw tip. The applicator tips navigate the nasal anatomy and provide direct delivery of the gel onto the bleeding site. All surgical injuries that received the treatment (i-octyl polyhedral oligomeric silsesquioxane trisilanol) gel had complete hemostasis noted within 1 minute of application. However, the surgical injuries that received the control article (saline) continued bleeding after 10 minutes of observation.

[0092] Visual inspection of the wounds at post-operative days 7, 14, and 21 demonstrated normal tissue healing at the wound sites treated with z-octyl polyhedral oligomeric silsesquioxane trisilanol. Tn addition, there was no evidence of tissue adhesions or surgical site infection. Figure 6 is a post-mortem pathologic specimen of the animal's nasal septum at the site of surgical injury. On day 15 post-surgery the tissue has completely healed and appears normal in appearance. Figure 7 are post-operative day 21 pathologic specimens at 20x magnification and the arrows demarcate the edges of the original surgical wound. The wounds in the treatment (z-octyl polyhedral oligomeric silsesquioxane trisilanol) group had normal tissue healing within the prior wound bed (region between the arrows). In addition, histopathological evaluation of these z-octyl polyhedral oligomeric silsesquioxane trisilanol treated wounds demonstrated enhanced wound healing with improved tissues maturation and epithelization when compared to the control group.

[0093] Example 2: Analysis of Combination of Wound Dressing with Antimicrobials

[0094] In the treatment of surgical wounds, one of the biggest areas of concern is infections. Next, the ability of the wound dressing to contain other therapeutic agents, such as antimicrobials, was tested. A series of in vitro studies were conducted using a combination of different antimicrobirals with the trisilanol wound dressing. Staphylococcus aureus strain SAP231 and Pseudomonas aeruginosa strain Xen41, Gram positive and negative pathogens commonly associated with wound infections were used as challenge pathogens. Several classes of antibiotics; rifampin (RIF), ciprofloxacin (CIP), tobramycin (TOB), polymyxin B (POLB), vancomycin (VAN), neomycin (NEO) and bacitracin (BAC) and CIP, VAN, and RIF in combination were screened for antimicrobial activity. The minimum inhibitory concentration of the strains was assessed using the microbroth dilution method. Antibiotic powders were mixed into the gel by hand with ranging concentrations from 0. 1 to 7.0 mg / mL of gel. Mixing was assessed by low magnification microscopy. To assess antimicrobial activity, two modifications of the Kirby-Bauer susceptibility diffusion test were used. Overnight cultures were diluted to -106 CFU / mL and 100 pL spread out on nutrient agar plates. 100 pF of antibiotic loaded z-octyl polyhedral oligomeric silsesquioxane trisilanol was either dropped a) into a 6 mm diameter well produced by boring with the back end of a sterile pipette tip or b) onto the center of intact the plate surface. This approach allowed the antimicrobial effect of antibiotic loaded z-octyl polyhedral oligomeric silsesquioxane trisilanol from a) diffusion release alone and b) from spreading due to flow and diffusion release combined to be assessed. Unloaded z-octyl polyhedral oligomeric silsesquioxane trisilanol was used as a control. The plates were incubated at 37 °C and 5% CO2. The zones of inhibition (ZOI) were documented by photograph and the area quantified using FIJI ImageJ image analysis software.

[0095] The CIP+VAN+RIF combination showed the greatest antimicrobial activity against both .S'. aureus and P. aeruginosa. The release of antibiotics was found to occur through a combination of physical spreading and diffusion from the z-octyl polyhedral oligomeric silsesquioxane trisilanol. The ratio of 1 : 1 : 1 mg / mL was equally as effective in clearing as 3 :3 :3 and 7:7:7 mg / mL. No persister cells were observed (subsequent colony formation in the periphery of the ZOI) with this combination. Microscopy showed that non-uniform sized particles of each antibiotic were distributed evenly through the gel. For individual antibiotics, RIF (7 mg / mL) had the best performance against S. aureus in terms of spreading and diffusion alone. Vancomycin (100 pg / mL) showed good potency from spreading but had limited release by diffusion alone. The combination of rifampin, ciprofloxacin and tobramycin has the most inhibitive effects against bacteria growth with even lower concentrations than each individual antibiotic. For P. aeruginosa CIP generated the greatest ZOI in both assays with RIF also showing good activity. NEO (5 mg / mL) and POLYB (1.5 mg / mL) demonstrated an intermediate ZOI inhibition effect from spreading but not from diffusion alone. See Figure 8. Further, the emergence of colonies at the periphery of the ZOI suggested that NEO alone was less effective at killing low population persister cells that may be present. The non-loaded control reduced the amount of growth beneath the drop, presumably due to oxygen restriction.

[0096] Antibiotic loaded z-octyl polyhedral oligomeric silsesquioxane trisilanol was demonstrated to exhibit excellent antibacterial activity against S. aureus and P. aeruginosa with a combination of CIP+VAN+RIF and single antibiotic delivery by two delivery mechanisms. See, for example, Figure 9. One was the release of antibiotics from the gel and the other was from a combination of physical spreading due to flow as well as diffusion out of the gel. All antibiotics showed activity when the pathogen was susceptible from flow spreading demonstrating surface contact efficacy but some antibiotics (VAN, NEO and POLYB) did not show release, suggesting that factors such as molecular weight and charge are important in diffusion release. The fact that no heating is required for antibiotic mixing suggests that z-octyl polyhedral oligomeric silsesquioxane trisilanol has high compatibility with many antibiotic and antimicrobial classes. High concentrations and the combination of antibiotics allow broad spectrum activity against a diverse number of pathogens as would be expected to enter the wound in a battlefield situation and has good anti-biofilm activity. The physical spread of i- octyl polyhedral oligomeric silsesquioxane trisilanol within the wound will allow good physical coverage of antibiotics. This study also demonstrated that z-octyl polyhedral oligomeric silsesquioxane trisilanol provides a physical barrier of protection from further environmental pathogens.

Claims

CLAIMSWhat is claimed is:

1. A wound dressing comprising:(A) a silanol carrier, wherein the silanol carrier is a polyhedral oligomeric silsequioxane; and(B) a therapeutic agent; wherein the therapeutic agent is an antimicrobial agent, tranexamic acid, thrombin, a corticosteroid, an anesthetic, a vasoconstricting agent, or a nasal decongestant agent; wherein the therapeutic agent has been mixed with the silanol carrier.

2. The wound dressing of claim 1 , wherein the wound dressing forms a hemostatic seal with a wound.

3. The wound dressing of either claim 1 or claim 2, wherein the silanol carrier comprises a polyhedral oligomeric silsequioxane trisilanol.

4. The wound dressing according to any one of claims 1-3, wherein the silanol carrier is an z-octyl polyhedral oligomeric silsequioxane trisilanol.

5. The wound dressing according to any one of claims 1-4, wherein the therapeutic agent is an antimicrobial agent.

6. The wound dressing of claim 5, wherein the antimicrobial agent is an antibiotic.

7. The wound dressing according to any one of claims 1-6, wherein the wound dressing comprises from about 0.0001 %-50% w / w of the therapeutic agent.

8. The wound dressing according to any one of claims 1-7, wherein the wound dressing is formulated for use in an ear, nose, or throat application.

9. The wound dressing of claim 8, wherein the ear, nose, or throat application is an ear, nose, or throat surgery.

10. The wound dressing of claim 9, wherein the ear, nose, or throat surgery is functional endoscopic surgery.1 1. The wound dressing of claim 9, wherein the ear, nose, or throat surgery is a tonsillectomy.

12. A method of applying a wound dressing to a wound comprising:(A) obtaining a wound dressing according to any one of claims 1-11; and(B) applying the wound dressing to the wound; wherein the wound is located in the nasal cavity, the mouth, the throat, or the ears.

13. The method of claim 12, wherein the wound dressing comprises tranexamic acid or thrombin.

14. The method of claim 12, wherein the wound dressing comprises an antimicrobial agent.

15. The method according to any one of claims 12-14, wherein the application of the wound dressing results in a hemostatic seal with the wound.

16. The method according to any one 12-15, wherein the method further comprises removing the wound dressing and reapplying a second wound dressing.

17. A method of improving the healing of a wound comprises applying a wound dressing according to any one of claims 1-11 sufficient to establish create a hemostatic seal over the wound.

18. The method of claim 17, wherein the wound heals in a short amount of time relative to a traditional wound dressing.

19. The method of either claim 17 or claim 18, wherein the wound heals in a short amount of time relative to gauze.

20. The method according to any one of claims 17-19, wherein the wound heals in at least 5% shorter time than a traditional wound dressing.

21. A method of applying a wound dressing comprising:(A) obtaining a wound dressing, wherein the wound dressing comprises a polyhedral oligomeric silsesquioxane; and(B) applying the wound dressing to a wound through a cannulated tip to a wound, wherein the wound is in the nose, mouth, throat, or ear.

22. The method of claim 21 , wherein the polyhedral oligomeric silsesquioxane comprises an alkyl polyhedral oligomeric silsequioxane trisilanol.

23. The method of either claim 21 or claim 22, wherein the wound dressing comprises an z-octyl polyhedral oligomeric silsequioxane trisilanol.

24. A method of applying a wound dressing to a wound comprising:(A) Obtaining a wound dressing according to any one of claims 1-11 in a container comprising a tip; and(B) applying the wound dressing with the tip to the wound.

25. The method of claim 24, wherein the tip is a cannulated tip.

26. A kit comprising:(A) a wound dressing, wherein the wound dressing comprises a polyhedral oligomeric silsequioxane trisilanol;(B) a container, wherein the wound dressing is stored within the container; and(C) an applicator tip, wherein the container is configured to allow the deposition of the wound dressing through the applicator tip onto a wound.

27. The kit of claim 26, wherein the alkyl polyhedral oligomeric silsequioxane trisilanol is z-octyl polyhedral oligomeric silsequioxane trisilanol.

28. The kit of either claim 26 or claim 27, wherein the applicator tip is a cannulated tip.

29. A method of sealing a dressing, a medical device, or a medication to a desired location comprising:(A) applying the dressing, the medical device, or the medication to the desired location;(B) applying the wound dressing according to any one of claims 1-11 to the dressing, the medical device, or the medication; and(C) drying the wound dressing to sealing the dressing, the medical device, or the medication to the desired location.

30. The method of claim 29, wherein the dressing is sealed to the desired location through a hemostatic seal.

31. The method of either claim 29 or claim 30, wherein a wound at the desired location heals in a short amount of time relative to a traditional wound dressing.

32. The method according to any one of claims 29-31, wherein the wound heals in a shorter amount of time relative to gauze.

33. The method according to any one of claims 29-32, wherein the wound heals in at least 5% shorter time than a traditional wound dressing.

34. The method according to any one of claims 29-33, wherein the dressing is gauze.

35. The method according to any one of claim 29-34, wherein the medication is a hemostatic agent, an antimicrobial agent, or an analgesic.

36. The method of claim 35, wherein the antimicrobial agent is an antibacterial, an antiparasitic, an antifungal, or an antiviral.

37. The method according to any one of claims 29-36, wherein the medical device is a hemostatic device.

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