Implantable electrospun structures for the delivery of active agents

Abstract

The instant disclosure is directed to implantable electrospun structures for the delivery of active agents. An electrospun structure may comprise a first sheet and a second sheet. The first sheet and the second sheet may each comprise two supporting layers and an inner layer positioned between the two supporting layers, wherein a perimeter of one supporting layer is affixed to a perimeter of the other supporting layer, encasing the inner layer. The supporting layers may comprise a co-electrospun polymer fiber composition, and each inner layer may comprise an active agent blend-electrospun with a polymer fiber composition. All but one edge of the first sheet may be affixed to all but one edge of the second sheet, forming the electrospun structure, which may be a pouch. A method of using the pouch may comprise implanting it in a surgical site and, optionally, placing a medical device in the pouch.

Description

Attorney Docket No. 437823.000102 PATENTIMPLANTABLE ELECTROSPUN STRUCTURES FOR THE DELIVERY OF ACTIVE AGENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 696,648, filed September 19, 2024, which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure is directed to implantable electrospun structures for the delivery of active agents. More particularly, the present disclosure is related to implantable, multilayer biocompatible electrospun fiber structures, such as pouches and pockets, for the delivery of active agents, such as antibiotics.BACKGROUND

[0003] Electrospun fiber structures may be useful for the delivery of active agents, including pharmaceuticals. Such structures may be particularly useful when surgically implanted, either alone or along with other implantable medical devices. Electrospun fiber structures may be manufactured to finely control the delivery of one or more agents. In particular, there exists a need for an implantable biocompatible electrospun fiber structure that delivers one or more active agents immediately upon implantation while avoiding the long-term leaching of suboptimal concentrations of the active agent(s), and augments healing and / or prevents infection of the surgical site, while also allowing for incorporation into the surrounding tissues.SUMMARY

[0004] The instant disclosure is directed to implantable electrospun structures for the delivery of active agents, such as antibiotics. In an embodiment, an electrospun structure may comprise a first sheet and a second sheet. In an embodiment, the first sheet comprises a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is affixed to a perimeter of the second supporting layer, thereby encasing the first inner layer. In an embodiment, the second sheet comprises a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is affixed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer. In some embodiments, the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each comprise a first electrospun polymer fiber composition. In certain embodiments, the first inner layer and theAttorney Docket No. 437823.000102 PATENT second inner layer each comprise a second electrospun fiber composition comprising an active agent. In an embodiment, at least one edge of the first sheet is affixed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0005] In some embodiments, the first sheet and the second sheet each have four edges, and three edges of the first sheet are affixed to three edges of the second sheet, such that one edge of the first sheet and one edge of the second sheet are not affixed to one another.

[0006] In certain embodiments, the first electrospun polymer fiber composition comprises a first polymer and a second polymer. In some embodiments, the first polymer and the second polymer are co-electrospun. In an embodiment, the first polymer comprises polyglycolic acid (PGA) and the second polymer comprises polylactide-co-caprolactone (PLCL). In certain embodiments, the first polymer comprises polyglycolic acid (PGA) and is present in about 60 wt%, and the second polymer comprises polylactide-co-caprolactone (PLCL) and is present in about 40 wt%.

[0007] In some embodiments, the second electrospun polymer fiber composition comprises a third polymer, a fourth polymer, and the active agent. In certain embodiments, the third polymer, the fourth polymer, and the active agent are blend-electrospun. In an embodiment, the third polymer comprises a first polylactide co-glycolide (PLGA), and the fourth polymer comprises a second polylactide co-glycolide (PLGA). In some embodiments, the first polylactide co-glycolide (PLGA) and the second polylactide co-glycolide (PLGA) each comprise DL-lactide and glycolide in a ratio of about 1 : 1. In an embodiment, the first polylactide co-glycolide (PLGA) comprises DL-lactide and glycolide in a ratio of about 1 : 1 and has a first intrinsic viscosity of about 0.2 dL / g, and the second polylactide co-glycolide (PLGA) comprises DL-lactide and glycolide in a ratio of about 1:1 and has a second intrinsic viscosity of about 0.4 dL / g. In some embodiments, the third polymer and the fourth polymer are each present in about 45 wt%. In other embodiments, the third polymer and the fourth polymer are each present in about 47 wt%.

[0008] In an embodiment, the active agent is an antibiotic. In some embodiments, the active agent is selected from the group consisting of rifampin, minocycline, and combinations thereof. In an embodiment, the active agent is present in about 8 wt%. In another embodiment, the active agent is present in about 4 wt%. In an embodiment, the active agent comprises rifampin and minocycline, wherein the rifampin is present within the second electrospun fiber composition in about 4 wt%, and wherein the minocycline is present within the second electrospun fiber composition in about 4 wt%. In another embodiment, the active agent comprises rifampin and minocycline, wherein the rifampin is present within the second electrospun fiber composition in about 2 wt%, and wherein the minocycline is present within the second electrospun fiber composition in about 2 wt%.Attorney Docket No. 437823.000102 PATENT

[0009] In certain embodiments, the second electrospun polymer fiber composition further comprises a stabilizing agent. In some embodiments, the stabilizing agent is selected from the group consisting of magnesium, salts thereof, derivatives thereof, and combinations thereof. In an embodiment, the stabilizing agent is present in about 2 wt%. In another embodiment, the stabilizing agent is present in about 1 wt%.

[0010] In certain embodiments, the electrospun structure is a pouch. In an embodiment, a method of using the pouch comprises implanting the pouch in a surgical site of a subject. In some embodiments, the method further comprises placing a medical device in the pouch.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a schematic diagram of components used to heat-seal an embodiment of an electrospun structure as described herein.

[0012] FIG. 2A is a graphical representation of the results of strength testing of a first set of supporting layers having various compositions, as described herein.

[0013] FIG. 2B is a graphical representation of the results of strength testing of a second set of supporting layers having various compositions, as described herein.

[0014] FIG. 2C is a graphical representation of the results of strength testing of a third set of supporting layers having various compositions, as described herein.

[0015] FIG. 3 A is a scanning electron microscope (SEM) image at lOOOx magnification of an embodiment of an inner layer of an electrospun structure as described herein.

[0016] FIG. 3B shows an SEM image at 2000x magnification of an embodiment of an inner layer as described herein, such as the one shown in FIG. 3A.

[0017] FIG. 4 is a graphical representation of the results of a 7-day in vivo infection model using embodiments of electrospun structures, as described herein, with (“Experimental”) and without (“Control”) an active agent included in the inner layer, as described herein.DETAILED DESCRIPTION

[0018] This disclosure is not limited to the particular systems, devices, media, and methods described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the disclosure.

[0019] The following terms shall have, for the purposes of this application, the respective meanings set forth below. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Nothing inAttorney Docket No. 437823.000102 PATENT this disclosure is to be construed as an admission that the embodiments described in this disclosure are not entitled to antedate such disclosure by virtue of prior invention.

[0020] As used herein, the singular forms “a,” “an,” and “the” include plural references, unless the context clearly dictates otherwise. Thus, for example, reference to a “fiber” is a reference to one or more fibers and equivalents thereof known to those skilled in the art, and so forth.

[0021] As used herein, the term “consists of’ or “consisting of’ means that the device, medium, or method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim.

[0022] In embodiments or claims where the term “comprising” is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of’ or “consisting essentially of.”

[0023] As used herein, the term “biocompatible” refers to materials exhibiting non-harmful compatibility with living tissue. Biocompatibility is a broad term that describes a number of materials, including bioinert materials, bioactive materials, bioabsorbable materials, biostable materials, biotolerant materials, or any combination thereof.

[0024] As used herein, the term “bioresorbable” refers to materials that are biodegradable or are naturally absorbed by a body over time.

[0025] As used herein, the term “about” means plus or minus 10% of the numerical value of the number with which it is being used. For example, about 50 mm means in the range of 45 mm to 55 mm.

[0026] As used herein, the term “subject” includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals.

[0027] “Administering,” when used in conjunction with a therapeutic, means to administer a therapeutic directly into or onto a target tissue or site, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. A composition may be administered by injection, topical administration, oral administration, buccal administration, sublingual administration, transdermal administration, surgical implantation, or another known technique.

[0028] As used herein, the term “therapeutic” means an agent used to treat, combat, inhibit, ameliorate, prevent or improve an unwanted condition or disease of a patient. In part, embodiments herein are directed to the treatment of conditions such as infections, inflammation, poor healing, and the like.

[0029] A “therapeutically effective amount” or “effective amount” of an active agent is a predetermined amount calculated to achieve the desired effect, i.e., to ease, inhibit, block, or reverse a disorder or condition. The activity contemplated by the present methods includes bothAttorney Docket No. 437823.000102 PATENT medical therapeutic and / or prophylactic treatment, as appropriate. The specific dose of a compound administered according to this invention to obtain therapeutic and / or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated.

[0030] The terms “treat,” “treated,” or “treating,” as used herein, refer to both therapeutic treatment and prophylactic or preventative measures taken to inhibit, prevent, or slow down (lessen) an undesired physiological condition, disorder, or disease, or to improve, inhibit, or otherwise obtain beneficial or desired clinical results. Treatment includes eliciting a clinically significant response without excessive levels of side effects.Electrospinning

[0031] Electrospinning is a method which may be used to process a polymer solution into a structure, such as a fiber. Generally speaking, a conventional electrospinning setup includes applying a high voltage to a spinneret (e.g., a needle or a wire) through which a polymer solution or melt is driven (e.g., at a rate of 0.1-50 mL / hr). Various types of polymer solution configurations, which can include a polymer dissolved in a solvent, are described below. As the polymer solution flows through the spinneret, it is electrostatically driven to form a Taylor cone. A jet of the polymer solution ejects from the Taylor cone towards a receiving surface that is positioned a distance from the spinneret. This receiving surface may or may not be charged with a high voltage. As the jet travels through the air to the receiving surface, it destabilizes, which causes the polymer within the jet to elongate and thin while the solvent simultaneously evaporates. This leads to the formation of solid polymer nanofibers which deposit on the receiving surface. In embodiments where the diameter of the resulting fiber is on the nanometer scale, the fiber may be referred to as a nanofiber. Fibers may be formed into a variety of shapes by using a range of receiving surfaces, such as mandrels, molds, or collectors.

[0032] Electrospinning methods may involve spinning a structure (e.g., a fiber) from a polymer solution by applying a high DC or AC voltage potential between a polymer injection system and a receiving surface. In some embodiments, a charge may be applied to one or more components of an electrospinning system. In some embodiments, a charge may be applied to the receiving surface, the polymer injection system, the polymer solution, or combinations or portions thereof. Without wishing to be bound by theory, as the polymer solution is ejected from the polymer injection system, it is thought to be destabilized due to its exposure to a charge. The destabilized solution may then be attracted to a charged receiving surface. As the destabilized solution moves from the polymer injection system to the receiving surface, its solvents may evaporate, and theAttorney Docket No. 437823.000102 PATENT polymer may stretch, leaving a long, thin fiber that is deposited onto the receiving surface. The polymer solution may form a Taylor cone as it is ejected from the polymer injection system and exposed to a charge. Further, polymers can be electrospun in a variety of different structures, including fibers, fibrous scaffolds, strips, patches, sheets, or shapes corresponding to anatomical structures. Still further, the structures can be electrospun using one or multiple polymers.

[0033] In some embodiments, multiple polymer types can be electrospun with each other to form structures in a process referred to as “co-electrospinning.” In co-electrospinning, two or more polymer solutions (containing the same or different polymer types) are ejected from different outlets and simultaneously electrospun with each other to form the resultant structure. Coelectrospinning creates different fibers formed from the different polymer solutions that are intertwined with each other. The co-electrospun polymers can be spun from the same or different polymer solutions. The co-electrospun polymer types can have the same or different degradation rates.

[0034] In some embodiments, multiple polymer types can be electrospun with each other to form structures in processes referred to as “coaxial electrospinning” or “multiaxial electrospinning.” In coaxial or multiaxial electrospinning, two or more polymer solutions (containing the same or different polymer types) are ejected from the same outlet and electrospun with each other to form the resultant structure. Coaxial or multiaxial electrospinning creates a single fiber composed of the different polymer types that has a core-shell structure. The coaxially or multi-axially electrospun polymer types can have the same or different degradation rates.

[0035] In certain embodiments, multiple polymer types can be mixed or blended into a single polymer solution, and that polymer solution can then be electrospun in a process known as “blendelectrospinning” or “blend-spinning.” In blend-electrospinning, the resulting fiber contains a blend of the multiple polymer types used to create it. The blend-electrospun polymer types can have the same or different degradation rates.

[0036] In some embodiments, the co-electrospinning, coaxial or multiaxial electrospinning, and blend-electrospinning techniques described above could also be used in combination with each other. For example, coaxial polymers or fibers could be co-electrospun with each other. Accordingly, the various techniques described above can be used to create electrospun structures having various degradation rates for the constituent polymers.Polymer Injection System

[0037] A polymer injection system may include any system configured to eject some amount of a polymer solution into an atmosphere to permit the flow of the polymer solution from the injection system to the receiving surface. In some embodiments, the polymer injection systemAttorney Docket No. 437823.000102 PATENT may deliver a continuous or linear stream with a controlled volumetric flow rate of a polymer solution to be formed into a structure (e.g., a fiber). In some embodiments, the polymer injection system may deliver a variable stream of a polymer solution to be formed into a fiber. In some embodiments, the polymer injection system may be configured to deliver intermittent streams of a polymer solution to be formed into multiple fibers.

[0038] The polymer injection system could include a variety of different components and / or mechanisms for ejecting the polymer solution, including needle-based injection systems (e.g., a syringe) or needleless injection systems (e.g., a rotating surface, a wire-based injection system, or any type of free-surface with an applied electrical charge). In some embodiments, the polymer injection system may include a syringe under manual or automated control. In some embodiments, the polymer injection system may include multiple syringes and multiple needles or needle-like components under individual or combined manual or automated control. In some embodiments, a multi-syringe polymer injection system may include multiple syringes and multiple needles or needle-like components, with each syringe containing the same polymer solution. In some embodiments, a multi-syringe polymer injection system may include multiple syringes and multiple needles or needle-like components, with one or more syringes containing one or more different polymer solutions.

[0039] The needless injection systems could include a variety of different configurations, all of which are within the scope of the present disclosure. In some embodiments, the polymer injection system could include a rotating drum or any type of surface that dips into the polymer solution and ejects the solution as the drum or surface rotates. In some embodiments, the polymer injection system could include a wire-based electrospinning system (e.g., the NS 8S1600U electrospinning production line available from ELMARCO®).

[0040] In some embodiments, the polymer injection system could include a slit injector system. A slit injector essentially functions as a hybrid between needle-based and needless electrospinning designs. A slit injector includes an extended slit that is positioned opposite the receiving surface. In operation, the electrospun polymer solution is ejected longitudinally along the slit and received by the receiving surface. Slit injector systems could be used to form conventional electrospun fibers, as well as core-shell fibers and other fiber configurations.

[0041] In some embodiments, the polymer solution may be ejected from the polymer injection system at a flow rate per needle of less than or equal to about 5 mL / h. Some non-limiting examples of flow rates per needle may include about 0.1 mL / h, about 0.5 mL / h, about 1 mL / h, about 1.5 mL / h, about 2 mL / h, about 2.5 mL / h, about 3 mL / h, about 3.5 mL / h, about 4 mL / h, about 4.5 mL / h, about 5 mL / h, about 6 mL / h, about 7 mL / h, about 8 mL / h, about 9 mL / h, about 10 mL / h, about 11 mL / h, about 12 mL / h, about 13 mL / h, about 14 mL / h, about 15 mL / h, about 16 mL / h,Attorney Docket No. 437823.000102 PATENT about 17 mL / h, about 18 mL / h, about 19 mL / h, about 20 mL / h, about 21 mL / h, about 22 mL / h, about 23 mL / h, about 24 mL / h, about 25 mL / h, about 26 mL / h, about 27 mL / h, about 28 mL / h, about 29 mL / h, about 30 mL / h, about 31 mL / h, about 32 mL / h, about 33 mL / h, about 34 mL / h, about 35 mL / h, about 36 mL / h, about 37 mL / h, about 38 mL / h, about 39 mL / h, about 40 mL / h, about 41 mL / h, about 42 mL / h, about 43 mL / h, about 44 mL / h, about 45 mL / h, about 46 mL / h, about 47 mL / h, about 48 mL / h, about 49 mL / h, about 50 mL / h, or any ranges between any two of these values, including endpoints.

[0042] As the polymer solution travels from the polymer injection system toward the receiving surface, the diameter of the resulting fibers may be in the range of about 50 nm to about 50 pm. In some embodiments, an electrospun fiber may have a diameter of, for example, about 50 nm, about 100 nm, about 150 nm, about 200 nm, about 250 nm, about 300 nm, about 350 nm, about 400 nm, about 450 nm, about 500 nm, about 550 nm, about 600 nm, about 650 nm, about 700 nm, about 750 nm, about 800 nm, about 850 nm, about 900 nm, about 950 nm, about 1 pm, about 2 pm, about 3 pm, about 4 pm, about 5 pm, about 10 pm, about 15 pm, about 20 pm, about 25 pm, about 30 pm, about 35 pm, about 40 pm, about 45 pm, about 50 pm, or any range between any two of these values, including endpoints.

[0043] In certain embodiments, the resulting electrospun fiber may be formed into a shape such as, for example, a fragment, a cluster, a strand, a thread, a rope, a braid, a sheet, a coil, a tube, a cylinder, a textile, a pouch, a mold of an organ, or a shape of a suture.Electrospinning Polymer Solution

[0044] In some embodiments, the polymer injection system may be filled with a solution from which structures, such as fibers, can be electrospun. Various components of the solution are described below.

[0045] In some embodiments, the polymer can include natural, synthetic, or semi-synthetic polymers such as, without limitation, poly(ethylene oxide) (PEO), polypropylene oxide) (PPO), polyvinyl pyrrolidone, Dextran, saccharide, cellulose, chitosan, gelatin, collagen, polyvinyl alcohol, Eudragit, polyethylene terephthalate (PET), polyester, polymethylmethacrylate, polyacrylonitrile, silicone, polyurethane, polycarbonate, polyether ketone ketone, polyether ether ketone, polyether imide, polyamide, polystyrene, polyether sulfone, polysulfone, polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polycaprolactone (PCL), polylactic acid (PLA), polylactide co-caprolactone (PLCL), polylactide co-glycolide (PLGA), polyglycolic acid (PGA), polyglycerol sebacic, polydiol citrate, polyhydroxy butyrate, polyether amide, polydioxanone, poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and / or combinations thereof.Attorney Docket No. 437823.000102 PATENT

[0046] In some embodiments, a polymer may be present in an amount of about 1 wt% to about 55 wt% based on the weight of the polymer solution. In some non-limiting examples, the polymer may be present in the amount of, for example, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 26 wt%, about 27 wt%, about 28 wt%, about 29 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 51 wt%, about 52 wt%, about 53 wt%, about 54 wt%, about 55 wt%, or ranges between any two of these values, including endpoints.

[0047] In some embodiments, the polymer solution may comprise a solvent. The solvents can include organic or inorganic solvents. In some embodiments, the solvent may comprise, for example, acetone, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, N,N- dimethylformamide, acetonitrile, hexanes, ether, dioxane, ethyl acetate, pyridine, toluene, xylene, tetrahydrofuran, trifluoroacetic acid, hexafluoroisopropanol, acetic acid, dimethylacetamide, chloroform, dichloromethane (DCM), dimethylformamide, water, alcohols, ionic compounds, and / or combinations thereof. Non-limiting examples of alcohols include methanol, ethanol, isopropanol, butanol, and the like. The concentration range of polymer or polymers in solvent or solvents may be, without limitation, from about 1 wt% to about 55 wt%. Some non-limiting examples of polymer concentration in solution may include about 1 wt%, 3 wt%, 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or ranges between any two of these values, including endpoints.

[0048] In some embodiments, the polymer solution may further comprise one or more active agents. An active agent may comprise an oil, a liquid, a powder, a crystal, a droplet, or any other form known in the art. In embodiments wherein an active agent is incorporated into the polymer solution, the active agent is dispersed or otherwise incorporated throughout the resulting electrospun fiber(s). These embodiments differ from delivery vehicles (whether electrospun or not) that employ a core / shell structure, dipping, spraying, or otherwise treating the outside surface of an electrospun structure with an active agent, such that the active agent is present only on the outside of the structure (e.g., in the shell) or only contained within the structure (e.g., within the core). Comparatively, an advantage of these embodiments is dispersal of the active agent withinAttorney Docket No. 437823.000102 PATENT and throughout the electrospun polymer fiber safeguards the active agent against unintentional or unanticipated removal from the electrospun structure fiber.

[0049] In certain embodiments, the active agent may comprise one or more: steroids, antiinflammatories, non-steroidal anti-inflammatories, analgesics, statins, antibiotics, antimicrobials, antivirals, antifungals, anticoagulants, antithrombotic agents, immunosuppressants, immunomodulators, antiproliferatives, sedatives, vitamins, hormones, growth factors, vasodilators, vasoconstrictors, antihistamines, opioids, derivatives thereof, and / or combinations thereof.

[0050] In some embodiments, the active agent is selected from the group consisting of vancomycin, tobramycin, gentamicin, rifampin, rifabutin, rifapentine, rifalazil, rifaximin, lymecycline, methacycline, minocycline, rolitetracycline, tetracycline, doxycycline, eravacycline, sarecycline, omadacycline, a derivative thereof, and / or a combination thereof. In an embodiment, the active agent comprises rifampin and minocycline.

[0051] In certain embodiments, the polymer solution may further comprise one or more stabilizing agents. A stabilizing agent may comprise an oil, a liquid, a powder, a crystal, a droplet, or any other form known in the art. In embodiments wherein an stabilizing agent is incorporated into the polymer solution, the stabilizing agent is dispersed or otherwise incorporated throughout the resulting electrospun fiber(s). In certain embodiments, the stabilizing agent may comprise, for example, magnesium (such as magnesium stearate, magnesium acetate, magnesium chloride, magnesium chloride hexahydrate, magnesium oxide, and / or salts thereof, hydrates thereof, or derivatives thereof), calcium carbonate, polysorbate 80, ethylene glycol, 1,8-cineole, trichloroacetic acid 0.5%, glycerine, lactose monohydrate, cyclodextrin, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, potassium sulfite, ascorbic acid, thiourea, vitamin E, derivatives thereof, and / or combinations thereof. In an embodiment, the stabilizing agent comprises magnesium. In certain embodiments, the stabilizing agent is selected from the group consisting of magnesium, salts thereof, and combinations thereof. In another embodiment, the stabilizing agent consists essentially of magnesium chloride hexahydrate. In still another embodiment, the stabilizing agent comprises one or more of magnesium, vitamin E, and combinations thereof.Applying Charges to Electrospinning Components

[0052] In an electrospinning system, a charge may be applied to one or more components, or portions of components, such as, for example, a receiving surface, a polymer injection system, a polymer solution, or portions thereof. In some embodiments, a positive charge may be applied to the polymer injection system, or portions thereof. In some embodiments, a negative charge mayAttorney Docket No. 437823.000102 PATENT be applied to the polymer injection system, or portions thereof. In some embodiments, the polymer injection system, or portions thereof, may be grounded. In some embodiments, a positive charge may be applied to the polymer solution, or portions thereof. In some embodiments, a negative charge may be applied to the polymer solution, or portions thereof. In some embodiments, the polymer solution, or portions thereof, may be grounded. In some embodiments, a positive charge may be applied to the receiving surface, or portions thereof. In some embodiments, a negative charge may be applied to the receiving surface, or portions thereof. In some embodiments, the receiving surface, or portions thereof, may be grounded. In some embodiments, one or more components or portions thereof may receive the same charge. In some embodiments, one or more components, or portions thereof, may receive one or more different charges.

[0053] The charge applied to any component of the electrospinning system, or portions thereof, may be from about -100 kV to about 100 kV, including endpoints. In some non-limiting examples, the charge applied to any component of the electrospinning system, or portions thereof, may be about -100 kV, about -75 kV, about -50 kV, about -30 kV, about -25 kV, about -15kV, about -10 kV, about -5 kV, about -3 kV, about -1 kV, about -0.01 kV, about 0.01 kV, about 1 kV, about 5 kV, about 10 kV, about 12 kV, about 15 kV, about 20 kV, about 25 kV, about 30 kV, about 50 kV, about 60 kV, about 75 kV, about 100 kV, or any range between any two of these values, including endpoints. In some embodiments, any component of the electrospinning system, or portions thereof, may be grounded.Receiving Surface Movement During Electrospinning

[0054] During electrospinning, in some embodiments, the receiving surface may move with respect to the polymer injection system. In some embodiments, the polymer injection system may move with respect to the receiving surface. The movement of one electrospinning component with respect to another electrospinning component may be, for example, substantially rotational, substantially translational, or any combination thereof. In some embodiments, one or more components of the electrospinning system may move under manual control. In some embodiments, one or more components of the electrospinning system may move under automated control. In some embodiments, the receiving surface may be in contact with or mounted upon a support structure that may be moved using one or more motors or motion control systems. The pattern of the electrospun structure deposited on the receiving surface may depend upon one or more motions of the receiving surface with respect to the polymer injection system. In some embodiments, the receiving surface may be configured to rotate about its long axis. In one nonlimiting example, a receiving surface having a rotation rate about its long axis that is faster than a translation rate along a linear axis may result in a nearly helical deposition of an electrospun fiber,Attorney Docket No. 437823.000102 PATENT forming windings about the receiving surface. In another example, a receiving surface having a translation rate along a linear axis that is faster than a rotation rate about a rotational axis may result in a roughly linear deposition of an electrospun fiber along a linear extent of the receiving surface. In some embodiments, the electrospinning system could include a roller electrospinning system.

[0055] In some embodiments, the receiving surface of the electrospinning system can be moved (e.g., rotated) in a continuous or discontinuous manner. In one embodiment, the receiving surface can include a cylindrical mandrel that is rotated about a central axis. In some embodiments, the receiving surface can include metal fibers (e.g., steel wool or steel mesh), an organic woven fabric, an organic non-woven fabric, a synthetic woven fabric, a synthetic non-woven fabric, paper, a paper-like substrate, impregnated paper, polymer film, or combinations thereof. Receiving surfaces including such substrates can improve the ability to mass produce the conjugated fibers compared to conventional methods.Implantable Electrospun Structures for the Delivery of Active Agents

[0056] As described above, there exists a need for an implantable biocompatible electrospun fiber structure that delivers one or more active agents immediately upon implantation while avoiding the long-term leaching of suboptimal concentrations of the active agent(s), and augments healing and / or prevents infection of the surgical site, while also allowing for incorporation into the surrounding tissues. Without wishing to be bound by theory, the electrospun structures described herein have fiber thicknesses and pore sizes that are configured to mimic healthy extracellular matrix, thus supporting cell-nanofiber interactions and immunomodulatory activity, which provides for the transition of macrophages from pro-inflammatory phenotype Ml to antiinflammatory phenotype M2. This support allows the electrospun structure to promote healthy tissue ingrowth around an implantable medical device it may encase, such as a cardiac implantable electronic device (CIED) or neurostimulatory device. The incorporation of an active agent into the electrospun structure further permits the release of the active agent during the degradation or resorption of the electrospun structure material (s). Furthermore, without wishing to be bound by theory, the layer components of the electrospun structures described herein permit healing and tissue incorporation to occur long term, while a distinct layer component containing an active agent prevents long-term active agent leaching and permits a cessation of active agent release. By promoting healthy tissue ingrowth around the implantable medical device, the electrospun structure may limit the risk of biofilm formation, infection, and / or scar formation.

[0057] In an embodiment, an electrospun structure comprises a first sheet and a second sheet. In some embodiments, the first sheet comprises a first supporting layer and a second supportingAttorney Docket No. 437823.000102 PATENT layer. In certain embodiments, the second sheet comprises a third supporting layer and a fourth supporting layer.

[0058] In certain embodiments, the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer may each comprise one or more electrospun polymer fiber compositions. The respective supporting layers may comprise, for example, the same electrospun polymer fiber composition, distinct and independently selected electrospun polymer fiber compositions, electrospun polymer fiber compositions that share certain polymer components but not others, and so on. In some embodiments, the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each comprise a first electrospun polymer fiber composition.

[0059] In an embodiment, the first electrospun polymer fiber composition may comprise one or more polymers such as, for example, poly(ethylene oxide) (PEO), polyethylene glycol (PEG), polypropylene oxide) (PPO), polyvinyl pyrrolidone, Dextran, saccharide, cellulose, chitosan, gelatin, collagen, polyvinyl alcohol, Eudragit, polyethylene terephthalate (PET), polyester, polymethylmethacrylate, polyacrylonitrile, silicone, polyurethane, polycarbonate, polyether ketone ketone, polyether ether ketone, polyether imide, polyamide, polystyrene, polyether sulfone, polysulfone, polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polycaprolactone (PCL), polylactic acid (PLA), polylactide co-caprolactone (PLCL), polylactide co-glycolide (PLGA), polyglycolic acid (PGA), polyglycerol sebacic, polydiol citrate, polyhydroxy butyrate, polyether amide, polydioxanone, poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and / or combinations thereof.

[0060] In certain embodiments, the first electrospun polymer fiber composition comprises a first polymer and a second polymer. The first polymer and the second polymer may each include, for example, polycaprolactone (PCL), polylactic acid (PLA), polylactide-co-caprolactone (PLCL), polylactide-co-glycolide (PLGA), polyglycolic acid (PGA), derivatives thereof, copolymers thereof, and / or combinations thereof. In some embodiments, the first polymer and the second polymer may be co-electrospun, as described herein. In an embodiment, the first polymer comprises polyglycolic acid (PGA), and the second polymer comprises polylactide-co- caprolactone (PLCL). In some instances, and without wishing to be bound by theory, decreasing the relative amount of PLCL present in a fiber composition may increase the composition’s degradation time in vivo, and may decrease the host’s inflammatory response to an implanted object or device.

[0061] In certain embodiments, the first polymer may be present in a range of about 40 wt% to about 100 wt% based on the weight of the polymer fiber composition (i.e., by dry weight). The first polymer may be present, for example, in an amount of about 40 wt%, about 45 wt%, aboutAttorney Docket No. 437823.000102 PATENT50 wt%, about 55 wt%, about 56 wt%, about 57 wt%, about 58 wt%, about 59 wt%, about 60 wt%, about 61 wt%, about 62 wt%, about 63 wt%, about 64 wt%, about 65 wt%, about 66 wt%, about 67 wt%, about 68 wt%, about 69 wt%, about 70 wt%, about 71 wt%, about 72 wt%, about 73 wt%, about 74 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, about 99 wt%, about 100 wt%, or any range between any two of these values, including endpoints. In some embodiments, the first polymer may be present in a range of about 50 wt% to about 90 wt% based on the weight of the polymer fiber composition (i.e., by dry weight). In an embodiment, the first polymer is present in an amount of about 60 wt%.

[0062] In certain embodiments, the second polymer may be present in a range of about 0 wt% to about 60 wt% based on the weight of the polymer fiber composition (i.e., by dry weight). The second polymer may be present, for example, in an amount of about 0 wt%, about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 55 wt%, about 60 wt%, or any range between any two of these values, including endpoints. In some embodiments, the second polymer may be present in a range of about 10 wt% to about 50 wt% based on the weight of the polymer fiber composition (i.e., by dry weight). In an embodiment, the second polymer is present in an amount of about 40 wt%.

[0063] In some embodiments, the first sheet further comprises a first inner layer. In an embodiment, the first inner layer may be positioned between the first supporting layer and the second supporting layer, and the perimeter of the first supporting layer may be affixed to the perimeter of the second supporting layer, thereby encasing the first inner layer between the first supporting layer and the second supporting layer. In such embodiments, the first inner layer is not necessarily affixed to either the first supporting layer or the second supporting layer; rather, the first and second supporting layers are simply affixed to one another around the first inner layer so as to encase or enclose the first inner layer.

[0064] In certain embodiments, the second sheet further comprises a second inner layer. In an embodiment, the second inner layer may be positioned between the third supporting layer and the fourth supporting layer, and the perimeter of the third supporting layer may be affixed to the perimeter of the fourth supporting layer, thereby encasing the second inner layer between the third supporting layer and the fourth supporting layer. In such embodiments, the second inner layer is not necessarily affixed to either the third supporting layer or the fourth supporting layer; rather, the third and fourth supporting layers are simply affixed to one another around the second inner layer so as to encase or enclose the second inner layer.Attorney Docket No. 437823.000102 PATENT

[0065] In some embodiments, the first inner layer and the second inner layer may each comprise one or more electrospun polymer fiber compositions. The respective inner layers may comprise, for example, the same electrospun polymer fiber composition, distinct and independently selected electrospun polymer fiber compositions, electrospun polymer fiber compositions that share certain polymer components but not others, and so on. In some embodiments, the first inner layer and the second inner layer each comprise a second electrospun polymer fiber composition. In an embodiment, the second electrospun polymer fiber composition includes an active agent.

[0066] In an embodiment, the second electrospun polymer fiber composition may comprise one or more polymers such as, for example, polyethylene oxide) (PEO), polyethylene glycol (PEG), polypropylene oxide) (PPO), polyvinyl pyrrolidone, Dextran, saccharide, cellulose, chitosan, gelatin, collagen, polyvinyl alcohol, Eudragit, polyethylene terephthalate (PET), polyester, polymethylmethacrylate, polyacrylonitrile, silicone, polyurethane, polycarbonate, polyether ketone ketone, polyether ether ketone, polyether imide, polyamide, polystyrene, polyether sulfone, polysulfone, polyvinyl alcohol (PVA), polyvinyl acetate (PVAc), polycaprolactone (PCL), polylactic acid (PLA), polylactide co-caprolactone (PLCL), polylactide co-glycolide (PLGA), polyglycolic acid (PGA), polyglycerol sebacic, polydiol citrate, polyhydroxy butyrate, polyether amide, polydioxanone, poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and / or combinations thereof.

[0067] In certain embodiments, the second electrospun polymer fiber composition comprises a third polymer, a fourth polymer, and the active agent. The third polymer and the fourth polymer may each include, for example, polylactide-co-glycolide (PLGA), polyglycolic acid (PGA), poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and / or combinations thereof. In some embodiments, the third polymer, the fourth polymer, and the active agent may be blend- electrospun, as described herein.

[0068] In an embodiment, the third polymer comprises a first polylactide co-glycolide (PLGA). In certain embodiments, the first polylactide co-glycolide comprises DL-lactide and glycolide in a molar ratio ranging from about 2:1 to about 1:2. The ratio of DL-lactide: glycolide in the first polylactide co-glycolide may be, for example, about 2:1, about 3:2, about 1:1, about 2:3, about 1:2, or any range between any two of these values, including endpoints. In an embodiment, the ratio of DL-lactide:glycolide in the first polylactide co-glycolide is about 1:1 (i.e., about 50% DL- lactide and about 50% glycolide).

[0069] In some embodiments, the first polylactide co-glycolide (PLGA) may have an intrinsic viscosity. For clarity, the intrinsic viscosity of the first polylactide co-glycolide (PLGA) is referred to herein as the first intrinsic viscosity. In certain embodiments, the first intrinsic viscosity may range from about 0.2 dL / g to about 1.0 dL / g. The first intrinsic viscosity of the first polylactideAttorney Docket No. 437823.000102 PATENT co-glycolide (PLGA) may be, for example, about 0.2 dL / g, about 0.4 dL / g, about 0.6 dL / g, about 0.8 dL / g, about 1.0 dL / g, or any range between any two of these values, including endpoints. In an embodiment, the first intrinsic viscosity of the first polylactide co-glycolide (PLGA) is about 0.2 dL / g.

[0070] In an embodiment, the fourth polymer comprises a second polylactide co-glycolide (PLGA). In certain embodiments, the second polylactide co-glycolide comprises DL-lactide and glycolide in a molar ratio ranging from about 2:1 to about 1:2. The ratio of DL-lactide:glycolide in the second polylactide co-glycolide may be, for example, about 2:1, about 3 :2, about 1:1, about 2:3, about 1:2, or any range between any two of these values, including endpoints. In an embodiment, the ratio of DL-lactide:glycolide in the second polylactide co-glycolide is about 1:1 (i.e., about 50% DL-lactide and about 50% glycolide).

[0071] In some embodiments, the second polylactide co-glycolide (PLGA) may have an intrinsic viscosity. For clarity, the intrinsic viscosity of the second polylactide co-glycolide (PLGA) is referred to herein as the second intrinsic viscosity. In certain embodiments, the second intrinsic viscosity may range from about 0.2 dL / g to about 1.0 dL / g. The second intrinsic viscosity of the second polylactide co-glycolide (PLGA) may be, for example, about 0.2 dL / g, about 0.4 dL / g, about 0.6 dL / g, about 0.8 dL / g, about 1.0 dL / g, or any range between any two of these values, including endpoints. In an embodiment, the second intrinsic viscosity of the second polylactide co-glycolide (PLGA) is about 0.4 dL / g.

[0072] In an embodiment, the first polylactide co-glycolide comprises DL-lactide and glycolide in a ratio of about 1:1 and has a first intrinsic viscosity of about 0.2 dL / g, and the second polylactide co-glycolide comprises DL-lactide and glycolide in a ratio of about 1:1 and has a second intrinsic viscosity of about 0.4 dL / g. Without wishing to be bound by theory, embodiments in which the third polymer comprises such a first polylactide co-glycolide and the fourth polymer comprises such a second polylactide co-glycolide may balance the structural integrity of the inner layer(s) described herein, while also allowing for the rapid release of the active agent(s) incorporated into the second electrospun fiber composition of the inner layer(s) as described herein.

[0073] In certain embodiments, the third polymer may be present in a range of about 30 wt% to about 70 wt% based on the weight of the second electrospun polymer fiber composition (i.e., based on the combined dry weight of the third polymer, the fourth polymer (if present), the active agent, and a stabilizing agent as described herein (if present)). The third polymer may be present, for example, in an amount of about 30 wt%, about 35 wt%, about 40 wt%, about 40.5 wt%, about 41 wt%, about 41.5 wt%, about 42 wt%, about 42.5 wt%, about 43 wt%, about 43.5 wt%, about 44 wt%, about 44.5 wt%, about 45 wt%, about 45.5 wt%, about 46 wt%, about 46.5 wt%, aboutAttorney Docket No. 437823.000102 PATENT47 wt%, about 47.5 wt%, about 48 wt%, about 48.5 wt%, about 49 wt%, about 49.5 wt%, about50 wt%, about 50.5 wt%, about 51 wt%, about 51.5 wt%, about 52 wt%, about 52.5 wt%, about53 wt%, about 53.5 wt%, about 54 wt%, about 54.5 wt%, about 55 wt%, about 55.5 wt%, about56 wt%, about 56.5 wt%, about 57 wt%, about 57.5 wt%, about 58 wt%, about 58.5 wt%, about59 wt%, about 59.5 wt%, about 60 wt%, 65 wt%, about 70 wt%, or any range between any two of these values, including endpoints. In an embodiment, the third polymer is present in an amount of about 45 wt%. In another embodiment, the third polymer is present in an amount of about 47 wt%. In still another embodiment, the third polymer is present in an amount of about 47.5 wt%.

[0074] In certain embodiments, the fourth polymer may be present in a range of about 30 wt% to about 70 wt% based on the weight of the second electrospun polymer fiber composition (i.e., based on the combined dry weight of the third polymer (if present), the fourth polymer, the active agent, and a stabilizing agent as described herein (if present)). The fourth polymer may be present, for example, in an amount of about 30 wt%, about 35 wt%, about 40 wt%, about 40.5 wt%, about 41 wt%, about 41.5 wt%, about 42 wt%, about 42.5 wt%, about 43 wt%, about 43.5 wt%, about44 wt%, about 44.5 wt%, about 45 wt%, about 45.5 wt%, about 46 wt%, about 46.5 wt%, about47 wt%, about 47.5 wt%, about 48 wt%, about 48.5 wt%, about 49 wt%, about 49.5 wt%, about50 wt%, about 50.5 wt%, about 51 wt%, about 51.5 wt%, about 52 wt%, about 52.5 wt%, about53 wt%, about 53.5 wt%, about 54 wt%, about 54.5 wt%, about 55 wt%, about 55.5 wt%, about56 wt%, about 56.5 wt%, about 57 wt%, about 57.5 wt%, about 58 wt%, about 58.5 wt%, about59 wt%, about 59.5 wt%, about 60 wt%, 65 wt%, about 70 wt%, or any range between any two of these values, including endpoints. In an embodiment, the fourth polymer is present an amount of about 45 wt%. In another embodiment, the fourth polymer is present in an amount of about 47 wt%. In still another embodiment, the fourth polymer is present in an amount of about 47.5 wt%.

[0075] In an embodiment, the second electrospun polymer fiber composition includes an active agent, as described herein. In certain embodiments, the active agent may comprise one or more: steroids, anti-inflammatories, non-steroidal anti-inflammatories, analgesics, statins, antibiotics, antimicrobials, antivirals, antifungals, anticoagulants, antithrombotic agents, immunosuppressants, immunomodulators, antiproliferatives, sedatives, vitamins, hormones, growth factors, anticoagulants, antithrombotic agents, vasodilators, vasoconstrictors, antihistamines, opioids, derivatives thereof, and / or combinations thereof. In some embodiments, the active agent may be, for example, vancomycin, tobramycin, gentamicin, rifampin, rifabutin, rifapentine, rifalazil, rifaximin, lymecycline, methacycline, minocycline, rolitetracycline, tetracycline, doxycycline, eravacycline, sarecycline, omadacycline, a derivative thereof, and / or a combination thereof. In an embodiment, the active agent comprises rifampin and / or minocycline. In some instances, and without wishing to be bound by theory, it may be preferable to release theAttorney Docket No. 437823.000102 PATENT active agent(s), or a majority of the active agent(s), from the electrospun polymer fiber composition(s) of the inner layer(s) within a time period of about 7-10 days to reduce the chance of microorganism resistance to the active agent(s).

[0076] In certain embodiments, the active agent is blend-electrospun with the second electrospun fiber composition, as described herein, such that the active agent is dispersed within or throughout the second electrospun fiber composition. In certain embodiments, the active agent may be present in a range of about 2 wt% to about 12 wt% based on the weight of the composition (i.e., based on the combined dry weight of, any polymer(s) present, any stabilizing agent(s) present, and the active agent). The active agent may be present in an amount of, for example, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, or any range between any two of these values, including endpoints. In an embodiment, the active agent is present in an amount of about 8 wt%. In an embodiment, the active agent comprises about 4 wt% rifampin and about 4 wt% minocycline (i.e., the active agent is present in a total amount of about 8 wt% and comprises about equal amounts of rifampin and minocycline). In another embodiment, the active agent is present in an amount of about 4 wt%. In certain embodiments, the active agent comprises about 2 wt% rifampin and about 2 wt% minocycline (i.e., the active agent is present in a total amount of about 4 wt% and comprises about equal amounts of rifampin and minocycline). In certain embodiments, the active agent may comprise two or more components as described herein, which may be present in a weight ratio ranging from about 2:1 to about 1:2. The ratio of a first active agent to a second active agent (i.e., a ratio of active agents) may be, for example, about 2:1, about 3:2, about 1:1, about 2:3, about 1:2, or any range between any two of these values, including endpoints.

[0077] In some embodiments, the second electrospun polymer fiber composition also includes a stabilizing agent. In certain embodiments, the stabilizing agent may be, for example, magnesium (such as magnesium stearate, magnesium acetate, magnesium chloride, magnesium chloride hexahydrate, magnesium oxide, and / or salts thereof, hydrates thereof, or derivatives thereof), calcium carbonate, polysorbate 80, ethylene glycol, 1,8-cineole, trichloroacetic acid 0.5%, glycerine, lactose monohydrate, cyclodextrin, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, potassium sulfite, ascorbic acid, thiourea, vitamin E, salts thereof, derivatives thereof, and / or combinations thereof. In an embodiment, the stabilizing agent comprises magnesium. In certain embodiments, the stabilizing agent is selected from the group consisting of magnesium, salts thereof, and combinations thereof. In another embodiment, the stabilizing agent consists essentially of magnesium chloride hexahydrate. In still another embodiment, the stabilizing agent comprises one or more of magnesium, vitamin E, and combinations thereof.Attorney Docket No. 437823.000102 PATENT

[0078] In certain embodiments, the stabilizing agent is blend-electrospun with the second electrospun fiber composition, as described herein, such that the stabilizing agent is dispersed within or throughout the second electrospun fiber composition. In certain embodiments, the stabilizing agent may be present in a range of about 1 wt% to about 10 wt% based on the weight of the composition (i.e., based on the combined dry weight of, any polymer(s) present, any active agent(s) present, and the stabilizing agent). The stabilizing agent may be present in an amount of, for example, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 9.5 wt%, about 10 wt%, or any range between any two of these values, including endpoints. In an embodiment, the stabilizing agent is present in an amount of about 2 wt%. In another embodiment, the stabilizing agent is present in an amount of about 1 wt%. In certain embodiments, the stabilizing agent comprises about 2 wt% magnesium, as described herein. In other embodiments, the stabilizing agent comprises about 2 wt% magnesium and about 2 wt% vitamin E (i.e., the stabilizing agent is present in a total amount of about 4 wt% and comprises about equal amounts of magnesium and vitamin E). In still other embodiments, the stabilizing agent comprises about 1 wt% magnesium, as described herein. In another embodiment, the stabilizing agent is present in about 1 wt% to about 2 wt% and is selected from the group consisting of magnesium, salts thereof, and combinations thereof. In yet another embodiment, the stabilizing agent consists essentially of about 1 wt% to about 2 wt% magnesium chloride hexahydrate. Without wishing to be bound by theory, incorporating such a stabilizing agent into the second electrospun fiber composition, as described herein, may aid in stabilizing the active agent(s) within the polymer fiber composition, thereby helping prevent any premature release or degradation of the active agent(s).

[0079] In some embodiments, the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer of the electrospun structure described herein each have a thickness ranging from about 80 pm to about 300 pm. Each supporting layer may have a thickness of, for example, about 80 pm, about 90 pm, about 100 pm, about 110 pm, about 120 pm, about 130 pm, about 140 pm, about 150 pm, about 160 pm, about 170 pm, about 180 pm, about 190 pm, about 200 pm, about 210 pm, about 220 pm, about 230 pm, about 240 pm, about 250 pm, about 260 pm, about 270 pm, about 280 pm, about 290 pm, about 300 pm, or any range between any two of these values, including endpoints.

[0080] In certain embodiments, the first inner layer and the second inner layer of the electrospun structure described herein each have a thickness ranging from about 30 pm to about 300 pm. Each inner layer may have a thickness of, for example, about 30 pm, about 40 pm, about 50 pm, about 60 pm, about 70 pm, about 80 pm, about 90 pm, about 100 pm, about 110 pm, about 120 pm,Attorney Docket No. 437823.000102 PATENT about 130 gm, about 140 gm, about 150 gm, about 160 gm, about 170 gm, about 180 gm, about 190 gm, about 200 gm, about 210 gm, about 220 gm, about 230 gm, about 240 gm, about 250 gm, about 260 gm, about 270 gm, about 280 gm, about 290 gm, about 300 gm, or any range between any two of these values, including endpoints.

[0081] In some embodiments, the perimeter (i.e., border or edge portion) of the first supporting layer may be affixed to the perimeter of the second supporting layer. In certain embodiments, the perimeter of the third supporting layer may be affixed to the perimeter of the fourth supporting layer. In some embodiments, the affixing may be done by heat-sealing (i.e., the components may be heat-sealed to one another).

[0082] In certain embodiments, at least one edge of the first sheet is affixed to at least one edge of the second sheet, thereby forming the electrospun structure. In some embodiments, the first sheet and the second sheet each comprise four edges. In certain embodiments, three edges of the first sheet may be affixed to three edges of the second sheet, thereby forming an electrospun structure wherein one edge of the first sheet and one edge of the second sheet are not affixed to one another. The resulting electrospun structure may be a pouch or a pocket. In some embodiments, the affixing may be done by heat-sealing (i.e., the components may be heat-sealed to one another).

[0083] FIG. 1 is a schematic diagram of components used to heat-seal an embodiment of an electrospun structure as described herein. As shown in FIG. 1, a first sheet 110a comprises a first supporting layer 120a, a second supporting layer 120b, and a first inner layer 130a positioned between the first supporting layer 120a and the second supporting layer 120b. Also as shown in FIG. 1, a second sheet 110b comprises a third supporting layer 120c, a fourth supporting layer 120d, and a second inner layer 130b positioned between the third supporting layer 120c and the fourth supporting layer 120d.

[0084] In an embodiment, the first supporting layer 120a, the second supporting layer 120b, the third supporting layer 120c. and the fourth supporting layer 120d each comprise a first electrospun polymer fiber composition. In an embodiment, the first electrospun fiber composition comprises a first polymer and a second polymer, and the first and second polymers are co-electrospun with one another. In some embodiments, the first polymer is polyglycolic acid (PGA), and the second polymer is polylactide-co-caprolactone (PLCL). In an embodiment, the PGA is present in about 90 wt% and the PLCL is present in about 10 wt%; in other embodiments, the PGA is present in about 70 wt% and the PLCL is present in about 30 wt%; in other embodiments, the PGA is present in about 60 wt% and the PLCL is present in about 40 wt%; in still other embodiments, the PGA is present in about 50 wt% and the PLCL is present in about 50 wt%.Attorney Docket No. 437823.000102 PATENT

[0085] In an embodiment, the first inner layer 130a and the second inner layer 130b each comprise a second electrospun fiber composition comprising an active agent. In an embodiment, the second electrospun fiber composition comprises a third polymer, a fourth polymer, the active agent, and, optionally, a stabilizing agent. In some embodiments, the third polymer, the fourth polymer, the active agent, and the stabilizing agent (if present) are blend-spun with one another.

[0086] In some embodiments, the third polymer comprises a first polylactide co-glycolide (PLGA), and the fourth polymer comprises a second polylactide co-glycolide (PLGA). In one embodiment, the first PLGA is present in an amount of about 45 wt%, the second PLGA is present in an amount of about 45 wt%, the active agent is present in an amount of about 8 wt%, and the stabilizing agent is present in an amount of about 2 wt%. In certain embodiments, the active agent comprises rifampin, minocycline, or a combination thereof. In an embodiment, the stabilizing agent is present in an amount of about 2 wt% and comprises magnesium. In certain embodiments, the third polymer, the fourth polymer, the active agent, and the stabilizing agent (if present) are blend-electrospun with one another. In an embodiment, the active agent is present in an amount of about 8 wt%, and comprises a 1:1 ratio of rifampin and minocycline, such that rifampin is present in an amount of about 4 wt% and minocycline is present in an amount of about 4 wt%, based on the total weight of the composition (the polymer(s), the active agent(s), and the stabilizing agent(s) (if present)). In other embodiments, the third polymer comprises a first polylactide co-glycolide (PLGA), and the fourth polymer comprises a second polylactide co- glycolide (PLGA). In one embodiment, the first PLGA is present in an amount of about 47 wt%, the second PLGA is present in an amount of about 47 wt%, the active agent is present in an amount of about 4 wt%, and the stabilizing agent is present in an amount of about 2 wt%. In certain embodiments, the active agent comprises rifampin, minocycline, or a combination thereof. In an embodiment, the active agent is present in an amount of about 4 wt%, and comprises a 1 : 1 ratio of rifampin and minocycline, such that rifampin is present in an amount of about 2 wt% and minocycline is present in an amount of about 2 wt%, based on the total weight of the composition (the polymer(s), the active agent(s), and the stabilizing agent(s) (if present)).

[0087] In the embodiment of heat-sealing shown in FIG. 1, a first heat-sealing path 140a and a second heat-sealing path 140b are used to heat-seal: (i) the perimeter of the first supporting layer 120a to the perimeter of the second supporting layer 120b, thereby encasing the first inner layer 130a and forming the first sheet 110a; (ii) the perimeter of the third supporting layer 120c to the perimeter of the fourth supporting layer 120d, thereby encasing the second inner layer 130b and forming the second sheet 120b; and (iii) the perimeter of the first sheet 110a to the perimeter of the second sheet 110b, thereby forming an embodiment of an electrospun structure as described herein. A heat-resistant insert 150 is placed between a portion of the second supporting layer 120bAttorney Docket No. 437823.000102 PATENT and the third supporting layer 120c to prevent sealing of the entire perimeter, thereby leaving an access opening between those components once the heat-sealing process is complete. In the embodiment of FIG. 1, the first sheet 100a and the second sheet 100b each have four edges, and the illustrated heat-sealing process heat-seals three edges of the first sheet 100a to three edges of the second sheet 100b, leaving the fourth edge of the first sheet 100a and the fourth edge of the second sheet 100b (separated by the heat-resistant insert 150 during the heat-sealing process) not affixed to one another. Therefore, in certain embodiments, the resulting electrospun structure may have the shape of a pocket or pouch.

[0088] In some embodiments, the electrospun structure described herein may have a length of about 1 cm to about 10 cm. The electrospun structure may have a length of, for example, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about9 cm, about 10 cm, or any range between any two of these values, including endpoints.

[0089] In certain embodiments, the electrospun structure may have a width of about 1 cm to about10 cm. The width may be, for example, about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, or any range between any two of these values, including endpoints.

[0090] In some embodiments, the electrospun structure may have a thickness of about 0.5 mm to about 2 mm. The thickness may be, for example, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.85 mm, about 0.9 mm, about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2 mm, or any range between any two of these values, including endpoints.

[0091] In certain embodiments, the first inner layer of the electrospun structure described herein may have a surface area that is at least about 80% of the surface area of the first supporting layer of the electrospun structure. In some embodiments, the second inner layer may have a surface area that is at least about 80% of the surface area of the third supporting structure.

[0092] In an embodiment, a pouch may comprise an electrospun structure as described herein. In certain embodiments, a method of using the pouch may comprise implanting the pouch in or at a surgical site within a patient or subject. In some embodiments, the method may further comprise placing a medical device within the pouch. The medical device may include, for example, a cardiac implantable electronic device (CIED), a neurostimulatory device, a pain pump, an insulin pump, a breast implant, a wearable device, an orthopedic implant, a dental implant, a vascular implant, and / or any combination thereof.

[0093] Without wishing to be bound by theory, in such methods, when the electrospun structure, as described herein, is implanted into a surgical site, the electrospun polymer fibers of the various components may begin degrading through various mechanisms, thereby causing the activeAttorney Docket No. 437823.000102 PATENT agent(s) to be released to the surrounding tissues. Carefully selecting the polymer compositions, amounts, and properties of each component may permit finely controlled release of the active agent(s) over one or more select periods of time.Embodiments

[0094] Embodiment 1: An electrospun structure comprising: a first sheet comprising: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is affixed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet comprising: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is affixed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; and wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each comprise a first electrospun polymer fiber composition; wherein the first inner layer and the second inner layer each comprise a second electrospun fiber composition comprising an active agent; and wherein at least one edge of the first sheet is affixed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0095] Embodiment 2: The electrospun structure of embodiment 1, wherein the first electrospun polymer fiber composition and the second electrospun fiber composition each comprise one or more polymers independently selected from the group consisting of polyethylene oxide), polyvinyl pyrrolidone, Dextran, saccharide, cellulose, chitosan, gelatin, collagen, polyvinyl alcohol, Eudragit, polyethylene terephthalate, polyester, polymethylmethacrylate, polyacrylonitrile, silicone, polyurethane, polycarbonate, polyether ketone ketone, polyether ether ketone, polyether imide, polyamide, polystyrene, polyether sulfone, polysulfone, polycaprolactone, polylactic acid, polylactide-co-caprolactone, polylactide-co-glycolide, polyglycolic acid, polyglycerol sebacic, polydiol citrate, polyhydroxy butyrate, polyether amide, polydioxanone, poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and combinations thereof.

[0096] Embodiment 3: The electrospun structure of embodiment 1, wherein the first electrospun polymer fiber composition comprises a first polymer and a second polymer.

[0097] Embodiment 4: The electrospun structure of embodiment 3, wherein the first polymer and the second polymer are independently selected from the group consisting of polycaprolactone, polylactic acid, polylactide-co-caprolactone, polylactide-co-glycolide, polyglycolic acid, copolymers thereof, and combinations thereof.Attorney Docket No. 437823.000102 PATENT

[0098] Embodiment 5: The electrospun structure of embodiments 3 or 4, wherein the first polymer and the second polymer are co-electrospun.

[0099] Embodiment 6: The electrospun structure of any of embodiments 3-5, wherein the first polymer comprises polyglycolic acid, and wherein the second polymer comprises polylactide-co- caprolactone.

[0100] Embodiment 7: The electrospun structure of any of embodiments 3-6, wherein the first polymer is present in about 50 wt% to about 90 wt%.

[0101] Embodiment 8: The electrospun structure of any of embodiments 3-7, wherein the second polymer is present in about 10 wt% to about 50 wt%.

[0102] Embodiment 9: The electrospun structure of embodiment 1, wherein the second electrospun polymer fiber composition comprises a third polymer, a fourth polymer, and the active agent.

[0103] Embodiment 10: The electrospun structure of embodiment 9, wherein the third polymer and the fourth polymer are independently selected from the group consisting of polylactide-co- glycolide, polyglycolic acid, poloxamer, poloxamer 407, copolymers thereof, and combinations thereof.

[0104] Embodiment 11: The electrospun structure of embodiments 9 or 10, wherein the third polymer, the fourth polymer, and the active agent are blend-electrospun.

[0105] Embodiment 12: The electrospun structure of any of embodiments 9-11, wherein the third polymer comprises polyglycolic acid, and wherein the fourth polymer comprises poloxamer 407.

[0106] Embodiment 13: The electrospun structure of any of embodiments 9-12, wherein the third polymer is present in about 76 wt%.

[0107] Embodiment 14: The electrospun structure of any of embodiments 9-13, wherein the fourth polymer is present in about 8 wt%.

[0108] Embodiment 15: The electrospun structure of any of embodiments 1-14, wherein the active agent is selected from the group consisting of a steroid, an anti-inflammatory, a non-steroidal antiinflammatory, an analgesic, a statin, an antibiotic, an antiviral, an antifungal, an antimicrobial, an immunosuppressant, an immunomodulator, an antiproliferative, a sedative, a vitamin, a hormone, a growth factor, a vasodilator, a vasoconstrictor, an antihistamine, an opioid, a derivatives thereof, and a combination thereof.

[0109] Embodiment 16: The electrospun structure of any of embodiments 1-15, wherein the active agent comprises rifampin, minocycline, or a combination thereof.

[0110] Embodiment 17: The electrospun structure of any of embodiments 1-16, wherein the active agent is dispersed within the fibers of the second electrospun fiber composition.Attorney Docket No. 437823.000102 PATENT

[0111] Embodiment 18: The electrospun structure of any of embodiments 1-17, wherein the active agent is present within the electrospun polymer fibers in a range of about 2 wt% to about 12 wt%.

[0112] Embodiment 19: The electrospun structure of any of embodiments 1-18, wherein the active agent comprises rifampin in an amount of about 4 wt% and minocycline in an amount of about 4 wt%.

[0113] Embodiment 20: The electrospun structure of any of embodiments 1-19, wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each have a thickness of about 80 pm to about 300 pm.

[0114] Embodiment 21: The electrospun structure of any of embodiments 1-20, wherein the first inner layer and the second inner layer each have a thickness of about 30 pm to about 300 pm.

[0115] Embodiment 22: The electrospun structure of any of embodiments 1-21, wherein the perimeter of the first supporting layer is affixed to the perimeter of the second supporting layer by heat-sealing.

[0116] Embodiment 23: The electrospun structure of any of embodiments 1-22, wherein the perimeter of the third supporting layer is affixed to the perimeter of the fourth supporting layer by heat-sealing.

[0117] Embodiment 24: The electrospun structure of any of embodiments 1-23, wherein the at least one edge of the first sheet is affixed to the at least one edge of the second sheet by heatsealing.

[0118] Embodiment 25: The electrospun structure of any of embodiments 1-24, wherein the first sheet and the second sheet each have four edges, and wherein three edges of the first sheet are affixed to three edges of the second sheet, thereby forming the electrospun structure wherein one edge of the first sheet and one edge of the second sheet are not affixed to one another.

[0119] Embodiment 26: The electrospun structure of any of embodiments 1-25, wherein the first inner layer has a surface area that is at least about 80% of the surface area of the first supporting layer.

[0120] Embodiment 27: The electrospun structure of any of embodiments 1-26, wherein the second inner layer has a surface area that is at least about 80% of the surface area of the third supporting layer.

[0121] Embodiment 28: A pouch comprising the electrospun structure of any of embodiments 1- 27.

[0122] Embodiment 29: A method of using the pouch of embodiment 28, the method comprising implanting the pouch in a surgical site.

[0123] Embodiment 30: The method of embodiment 29, further comprising placing a medical device in the pouch.Attorney Docket No. 437823.000102 PATENT

[0124] Embodiment 31: The method of embodiment 30, wherein the medical device is selected from the group consisting of a cardiac implantable electronic device (CIED), a neurostimulatory device, a pain pump, an insulin pump, a breast implant, a wearable device, an orthopedic implant, and combinations thereof.

[0125] Embodiment 32: An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer consisting essentially of about 70 wt% polyglycolic acid electrospun fibers co-electrospun with about 30 wt% polylactide-co-caprolactone electrospun fibers, a second supporting layer consisting essentially of about 70 wt% polyglycolic acid electrospun fibers co-electrospun with about 30 wt% polylactide-co-caprolactone electrospun fibers, and a first inner layer consisting essentially of blend-electrospun polymer fibers consisting essentially of about 76 wt% polyglycolic acid, about 8 wt% poloxamer 407, about 8 wt% of an active agent selected from the group consisting of rifampin, minocycline, and combinations thereof, and about 8 wt% of a stabilizing agent consisting essentially of magnesium acetate, wherein the first inner layer is positioned between the first supporting layer and the second supporting layer, and wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer consisting essentially of about 70 wt% polyglycolic acid electrospun fibers co-electrospun with about 30 wt% polylactide-co-caprolactone electrospun fibers, a fourth supporting layer consisting essentially of about 70 wt% polyglycolic acid electrospun fibers co-electrospun with about 30 wt% polylactide-co-caprolactone electrospun fibers, and a second inner layer consisting essentially of blend-electrospun polymer fibers consisting essentially of about 76 wt% polyglycolic acid, about 8 wt% poloxamer 407, about 8 wt% of the active agent, and about 8 wt% of the stabilizing agent, wherein the second inner layer is positioned between the third supporting layer and the fourth supporting layer, and wherein a perimeter of the third supporting layer is heat-sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; and wherein at least one edge of the first sheet is heat- sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0126] Embodiment 33: An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer consisting essentially of about 70 wt% polyglycolic acid electrospun fibers co-electrospun with about 30 wt% polylactide-co-caprolactone electrospun fibers, a second supporting layer consisting essentially of polyglycolic acid electrospun fibers, and a first inner layer consisting essentially of blend-electrospun polymer fibers consisting essentially of about 76 wt% polyglycolic acid, about 8 wt% poloxamer 407, about 8 wt% of an active agent selected from the group consisting of rifampin, minocycline, and combinations thereof, and about 8 wt% of a stabilizing agent consisting essentially of magnesium acetate, wherein the first innerAttorney Docket No. 437823.000102 PATENT layer is positioned between the first supporting layer and the second supporting layer, and wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer consisting essentially of polyglycolic acid electrospun fibers, a fourth supporting layer consisting essentially of about 70 wt% polyglycolic acid electrospun fibers co-electrospun with about 30 wt% polylactide-co-caprolactone electrospun fibers, and a second inner layer consisting essentially of blend-electrospun polymer fibers consisting essentially of about 76 wt% polyglycolic acid, about 8 wt% poloxamer 407, about 8 wt% of the active agent, and about 8 wt% of the stabilizing agent, wherein the second inner layer is positioned between the third supporting layer and the fourth supporting layer, and wherein a perimeter of the third supporting layer is heat- sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; and wherein at least one edge of the first sheet is heat-sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0127] Embodiment 34: An electrospun structure comprising: a first sheet comprising: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is affixed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet comprising: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is affixed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each comprise a first electrospun polymer fiber composition; wherein the first inner layer and the second inner layer each comprise a second electrospun fiber composition comprising an active agent; and wherein at least one edge of the first sheet is affixed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0128] Embodiment 35: The electrospun structure of embodiment 34, wherein the first electrospun polymer fiber composition and the second electrospun fiber composition each comprise one or more polymers independently selected from the group consisting of poly(ethylene oxide), polyethylene glycol, polypropylene oxide), polyvinyl pyrrolidone, Dextran, saccharide, cellulose, chitosan, gelatin, collagen, polyvinyl alcohol, Eudragit, polyethylene terephthalate, polyester, polymethylmethacrylate, polyacrylonitrile, silicone, polyurethane, polycarbonate, polyether ketone ketone, polyether ether ketone, polyether imide, polyamide, polystyrene, polyether sulfone, polysulfone, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, polylactic acid, polylactide co-caprolactone, polylactide co-glycolide, polyglycolic acid, polyglycerolAttorney Docket No. 437823.000102 PATENT sebacic, polydiol citrate, polyhydroxy butyrate, polyether amide, polydioxanone, poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and combinations thereof.

[0129] Embodiment 36: The electrospun structure of embodiment 34 or 35, wherein the first electrospun polymer fiber composition comprises a first polymer and a second polymer.

[0130] Embodiment 37: The electrospun structure of embodiment 36, wherein the first polymer and the second polymer are independently selected from the group consisting of polycaprolactone, polylactic acid, polylactide-co-caprolactone, polylactide-co-glycolide, polyglycolic acid, copolymers thereof, and combinations thereof.

[0131] Embodiment 38: The electrospun structure of embodiment 36 or 37, wherein the first polymer and the second polymer are co-electrospun.

[0132] Embodiment 39: The electrospun structure of any of embodiments 36-38, wherein the first polymer comprises polyglycolic acid, and wherein the second polymer comprises polylactide-co- caprolactone.

[0133] Embodiment 40: The electrospun structure of any of embodiments 36-39, wherein the first polymer is present in about 50 wt% to about 90 wt%.

[0134] Embodiment 41: The electrospun structure of any of embodiments 36-39, wherein the first polymer is present in about 60 wt%.

[0135] Embodiment 42: The electrospun structure of any of embodiments 36-41, wherein the second polymer is present in about 10 wt% to about 50 wt%.

[0136] Embodiment 43: The electrospun structure of any of embodiments 36-41, wherein the second polymer is present in about 40 wt%.

[0137] Embodiment 44: The electrospun structure of any of embodiments 34-43, wherein the second electrospun polymer fiber composition comprises a third polymer, a fourth polymer, and the active agent.

[0138] Embodiment 45: The electrospun structure of embodiment 44, wherein the third polymer and the fourth polymer are independently selected from the group consisting of polylactide-co- glycolide, polyglycolic acid, poloxamer, poloxamer 407, copolymers thereof, and combinations thereof.

[0139] Embodiment 46: The electrospun structure of embodiment 44 or 45, wherein the third polymer, the fourth polymer, and the active agent are blend-electrospun.

[0140] Embodiment 47: The electrospun structure of any of embodiments 44-46, wherein the third polymer comprises a first polylactide co-glycolide, and wherein the fourth polymer comprises a second polylactide co-glycolide.Attorney Docket No. 437823.000102 PATENT

[0141] Embodiment 48: The electrospun structure of embodiment 47, wherein the first polylactide co-glycolide and the second polylactide co-glycolide each comprise DL-lactide and glycolide in a ratio of about 1:1.

[0142] Embodiment 49: The electrospun structure of embodiment 47 or 48, wherein the first polylactide co-glycolide has a first intrinsic viscosity from about 0.2 dL / g to about 1.0 dL / g, and wherein the second polylactide co-glycolide has a second intrinsic viscosity from about 0.2 dL / g to about 1.0 dL / g.

[0143] Embodiment 50: The electrospun structure of embodiment 47, wherein the first polylactide co-glycolide comprises DL-lactide and glycolide in a ratio of about 1 : 1 and has a first intrinsic viscosity of about 0.2 dL / g.

[0144] Embodiment 51: The electrospun structure of any of embodiments 47, 48, or 50, wherein the second polylactide co-glycolide comprises DL-lactide and glycolide in a ratio of about 1 : 1 and has a second intrinsic viscosity of about 0.4 dL / g.

[0145] Embodiment 52: The electrospun structure of any of embodiments 44-51 , wherein the third polymer is present in about 45 wt%.

[0146] Embodiment 53 : The electrospun structure of any of embodiments 44-51 , wherein the third polymer is present in about 47 wt%.

[0147] Embodiment 54: The electrospun structure of any of embodiments 44-52, wherein the fourth polymer is present in about 45 wt%.

[0148] Embodiment 55: The electrospun structure of any of embodiments 44-51 or 53, wherein the fourth polymer is present in about 47 wt%.

[0149] Embodiment 56: The electrospun structure of any of embodiments 34-55, wherein the active agent is selected from the group consisting of a steroid, an anti-inflammatory, a nonsteroidal anti-inflammatory, an analgesic, a statin, an antibiotic, an antiviral, an antifungal, an antimicrobial, an anticoagulant, an antithrombotic agent, an immunosuppressant, an immunomodulator, an antiproliferative, a sedative, a vitamin, a hormone, a growth factor, a vasodilator, a vasoconstrictor, an antihistamine, an opioid, derivatives thereof, and combinations thereof.

[0150] Embodiment 57: The electrospun structure of any of embodiments 34-56, wherein the active agent is selected from the group consisting of rifampin, minocycline, and combinations thereof.

[0151] Embodiment 58: The electrospun structure of any of embodiments 34-57, wherein the active agent is present within the second electrospun fiber composition in about 2 wt% to about 12 wt%.Attorney Docket No. 437823.000102 PATENT

[0152] Embodiment 59: The electrospun structure of any of embodiments 34-58, wherein the active agent comprises rifampin and minocycline, wherein the rifampin is present within the second electrospun fiber composition in about 4 wt%, and wherein the minocycline is present within the second electrospun fiber composition in about 4 wt%.

[0153] Embodiment 60: The electrospun structure of any of embodiments 34-58, wherein the active agent comprises rifampin and minocycline, wherein the rifampin is present within the second electrospun fiber composition in about 2 wt%, and wherein the minocycline is present within the second electrospun fiber composition in about 2 wt%.

[0154] Embodiment 61: The electrospun structure of any of embodiments 34-60, wherein the second electrospun fiber composition further comprises a stabilizing agent selected from the group consisting of magnesium, vitamin E, calcium carbonate, polysorbate 80, ethylene glycol, 1,8- cineole, trichloroacetic acid 0.5%, glycerine, lactose monohydrate, cyclodextrin, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, potassium sulfite, ascorbic acid, thiourea, derivatives thereof, and combinations thereof.

[0155] Embodiment 62: The electrospun structure of embodiment 61, wherein the stabilizing agent comprises magnesium.

[0156] Embodiment 63: The electrospun structure of embodiment 61 or 62, wherein the stabilizing agent is present in about 1 wt% to about 2 wt%.

[0157] Embodiment 64: The electrospun structure of any of embodiments 34-63, wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each have a thickness of about 80 pm to about 300 pm.

[0158] Embodiment 65: The electrospun structure of any of embodiments 34-64, wherein the first inner layer and the second inner layer each have a thickness of about 30 pm to about 300 pm.

[0159] Embodiment 66: The electrospun structure of any of embodiments 34-65, wherein the perimeter of the first supporting layer is affixed to the perimeter of the second supporting layer by heat-sealing.

[0160] Embodiment 67: The electrospun structure of any of embodiments 34-66, wherein the perimeter of the third supporting layer is affixed to the perimeter of the fourth supporting layer by heat-sealing.

[0161] Embodiment 68: The electrospun structure of any of embodiments 34-67, wherein the at least one edge of the first sheet is affixed to the at least one edge of the second sheet by heatsealing.

[0162] Embodiment 69: The electrospun structure of any of embodiments 34-68, wherein the first sheet and the second sheet each have four edges, and wherein three edges of the first sheet areAttorney Docket No. 437823.000102 PATENT affixed to three edges of the second sheet, thereby forming the electrospun structure wherein one edge of the first sheet and one edge of the second sheet are not affixed to one another.

[0163] Embodiment 70: The electrospun structure of any of embodiments 34-69, wherein the first inner layer has a surface area that is at least about 80% of the surface area of the first supporting layer.

[0164] Embodiment 71: The electrospun structure of any of embodiments 34-70, wherein the second inner layer has a surface area that is at least about 80% of the surface area of the third supporting layer.

[0165] Embodiment 72: A pouch comprising the electrospun structure of any of embodiments 34- 71.

[0166] Embodiment 73: A method of using the pouch of embodiment 72, the method comprising implanting the pouch in a surgical site.

[0167] Embodiment 74: The method of embodiment 73, further comprising placing a medical device in the pouch.

[0168] Embodiment 75: The method of embodiment 74, wherein the medical device is selected from the group consisting of a cardiac implantable electronic device (CIED), a neurostimulatory device, a pain pump, an insulin pump, a breast implant, a wearable device, an orthopedic implant, a dental implant, a vascular implant, and combinations thereof.

[0169] Embodiment 76: An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is heat-sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each consist essentially of about 60 wt% polyglycolic acid electrospun fibers co-electrospun with about 40 wt% polylactide-co-caprolactone electrospun fibers; wherein the first inner layer and the second inner layer each consist essentially of blend-electrospun polymer fibers consisting essentially of: about 45 wt% of a first polylactide co-glycolide having a first intrinsic viscosity of about 0.2 dL / g, about 45 wt% of a second polylactide co-glycolide having a second intrinsic viscosity of about 0.4 dL / g, about 8 wt% of an active agent consisting essentially of rifampin and minocycline, and about 2 wt% of a stabilizing agent selected from the group consisting of magnesium, salts thereof, and combinations thereof; and wherein at least one edge of the firstAttorney Docket No. 437823.000102 PATENT sheet is heat-sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0170] Embodiment 77: An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is heat-sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each consist essentially of about 60 wt% polyglycolic acid electrospun fibers co-electrospun with about 40 wt% polylactide-co-caprolactone electrospun fibers; wherein the first inner layer and the second inner layer each consist essentially of blend-electrospun polymer fibers consisting essentially of: about 47 wt% of a first polylactide co-glycolide having a first intrinsic viscosity of about 0.2 dL / g, about 47 wt% of a second polylactide co-glycolide having a second intrinsic viscosity of about 0.4 dL / g, about 4 wt% of an active agent consisting essentially of rifampin and minocycline, and about 2 wt% of a stabilizing agent selected from the group consisting of magnesium, salts thereof, and combinations thereof; and wherein at least one edge of the first sheet is heat-sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0171] Embodiment 78: An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is heat-sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each consist essentially of about 60 wt% polyglycolic acid electrospun fibers co-electrospun with about 40 wt% polylactide-co-caprolactone electrospun fibers; wherein the first inner layer and the second inner layer each consist essentially of blend-electrospun polymer fibers consisting essentially of: about 47.5 wt% of a first polylactide co-glycolide having a first intrinsic viscosity of about 0.2 dL / g, about 47.5 wt% of a second polylactide co-glycolide having a second intrinsicAttorney Docket No. 437823.000102 PATENT viscosity of about 0.4 dL / g, about 4 wt% of an active agent consisting essentially of rifampin and minocycline, and about 1 wt% of a stabilizing agent selected from the group consisting of magnesium, salts thereof, and combinations thereof; and wherein at least one edge of the first sheet is heat-sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

[0172] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification. Various aspects of the present invention will be illustrated with reference to the following non-limiting examples.EXAMPLESExample 1 : Electrospun structure containing active agents

[0173] Electrospun structures, as described herein, were constructed in several sizes to hold any type of cardiac implantable electronic device (CIED). Within each electrospun structure, the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each comprised a first electrospun polymer fiber composition containing polyglycolic acid (PGA) as the first polymer and polylactide-co-caprolactone (PLCL) as the second polymer. The first polymer was present in an amount of about 60 wt% and the second polymer was present in an amount of about 40 wt%, as described herein. Alternative structures were also constructed, in which the first polymer was present in amounts of 50 wt%, 70 wt%, 90 wt% and 100 wt%; and the second polymer was present in corresponding amounts of 50 wt%, 30 wt%, 10 wt%, and 0 wt%, respectively. The first polymer and the second polymer were co-electrospun, as described herein. The first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer brought structural integrity and sealing to the electrospun structure. The structure with the first polymer (PGA) present in about 60 wt% and the second polymer (PLCL) present in about 40 wt% demonstrated no or only minimal local tissue inflammation and response following long-term (more than 3 months) subcutaneous implantation in vivo. An alternative structure with the first polymer (PGA) present in the amount of 50 wt% and the second polymer (PLCL) present in the amount of 50 wt% elicited a slight local tissue inflammation and response following long-term (more than 3 months) subcutaneous implantation in vivo.

[0174] Sample structures in which the first polymer (PGA) was present in amounts of 60 wt%, 70 wt% and 100 wt%; and the second polymer (PLCL) was present in corresponding amounts of 40 wt%, 30 wt%, and 0 wt%, respectively, were each experimentally pre-conditioned in vitro underAttorney Docket No. 437823.000102 PATENT physiological conditions for 2 days. The strength (N) of each sample was tested at time 0, after 0.25 days of pre-conditioning, and after 2.0 days of pre-conditioning. This experiment was repeated three times (i.e., with three sets of samples). FIG. 2A, FIG. 2B, and FIG. 2C show the strength (N) of each sample at each time point for the first, second, and third experiments, respectively. In each experiment, the sample structure with the first polymer present in 60 wt% and the second polymer present in 40 wt% (represented in FIG. 2A, FIG. 2B, and FIG. 2C as “60:40”) produced the most favorable strength testing.

[0175] The first and second inner layers of the constructed electrospun structures, which were encased between their respective supporting layers but not in direct contact with their heat-sealed edges, each comprised a second electrospun fiber composition containing a first polylactide coglycolide (PLGA) comprising DL-lactide and glycolide in a ratio of about 1:1 and having an intrinsic viscosity of about 0.2 dL / g as the third polymer, a second polylactide co-glycolide (PLGA) comprising DL-lactide and glycolide in a ratio of about 1:1 and having an intrinsic viscosity of about 0.4 dL / g as the fourth polymer, an active agent that was a combination of rifampin and minocycline HC1 in a 1 : 1 ratio, and a stabilizing agent. The third polymer, the fourth polymer, the active agent, and the stabilizing agent were blend-electrospun, as described herein.

[0176] In a first set of electrospun structures that were constructed, the third polymer was present in about 45 wt% based on the total weight of the second electrospun fiber composition, the fourth polymer was present in about 45 wt% based on the total weight of the second electrospun fiber composition, the rifampin and minocycline HC1 were present in a total amount of about 8 wt% based on the total weight of the second electrospun fiber composition (i.e., about 4 wt% rifampin and about 4 wt% minocycline HC1), and the stabilizing agent, which comprised magnesium, was present in a total amount of about 2 wt% based on the total weight of the second electrospun fiber composition. In a second set of electrospun structures that were constructed, the third polymer was present in about 47 wt% based on the total weight of the second electrospun fiber composition, the fourth polymer was present in about 47 wt% based on the total weight of the second electrospun fiber composition, the rifampin and minocycline HC1 were present in a total amount of about 4 wt% based on the total weight of the second electrospun fiber composition (i.e., about 2 wt% rifampin and about 2 wt% minocycline HC1), and a stabilizing agent, as described herein, was present in a total amount of about 2 wt% based on the total weight of the second electrospun fiber composition.

[0177] In each electrospun structure, the total amount of active agent incorporated into each inner layer (i.e., the total dose available) was dependent upon the size of the electrospun structure. Table 1 below shows the dimensions and corresponding active agent amounts of two representative sizes of electrospun structures that were prepared.Attorney Docket No. 437823.000102 PATENTTable 1. Representative electrospun structure dimensions and active agent contents

[0178] FIG. 3 A shows a scanning electron microscope (SEM) image at lOOOx magnification of such an inner layer, comprising a second electrospun fiber composition containing a first PLGA as the third polymer, a second PLGA as the fourth polymer, an active agent that was a combination of rifampin and minocycline HC1 in a 1:1 ratio, and a stabilizing agent that comprised magnesium acetate. FIG. 3B shows an SEM image at 2000x magnification of an embodiment of an inner layer such as the one shown in FIG. 3A.

[0179] Table 2 below shows the stability of two active agents as described herein, minocycline and rifampin, in an electrospinning polymer solution before it is electrospun to create a second electrospun fiber composition comprising a third polymer, a fourth polymer, the active agents, and a stabilizing agent, as described herein. The electrospinning solution was stored at -20°C, before it was electrospun and the stability of the active agents in solution was measured with HPLC-UV. The data shown in Table 2 illustrate the value of adding the stabilizing agent to the electrospinning polymer solution before it is electrospun to create a second electrospun fiber composition as described herein. The resulting second electrospun fiber composition is stable for at least about 14 days.Table 2. Stability of active agents within an electrospinning polymer solution that includes a stabilizing agentExample 2: In vivo efficacy of pouches against Staphylococcus aureus. Staphylococcus epidermidis, Escherichia coli, and MRSA

[0180] Healthy New Zealand White rabbits were subcutaneously implanted with 4 2.5 cm x 2.5 cm pouches comprising electrospun structures as described herein. The pouches each contained aAttorney Docket No. 437823.000102 PATENT1.5 cm x 1.5 cm titanium coupon, which represented a CIED. Pouches were re-sized for animal welfare purposes. At least one pouch was a negative control, (i.e., its inner layers did not include an active agent). After implantation, 1 mL of a microorganism suspension (5 * 107CFU / mL for S. aureus, 1 * IO10CFU / mL for S. epidermidis, 1 * 107CFU / mL for £. coli, or 1 * 108CFU / mL for MRSA) was introduced into each implantation site. Animals were observed daily for signs of illness, and were euthanized 7 days post-surgery. Bacterial enumeration was performed on the pouch, titanium coupon, muscle, and subcutaneous tissue after explantation. Four rabbits received 4 implants each and had a suspension of S. aureus introduced; 3 rabbits received 6 implants each (and one additional rabbit received 4 implants) and had a suspension of S. epidermidis introduced; 4 rabbits received 6 implants each and had a suspension of£. coli introduced; and 1 rabbit received 4 implants and had a suspension of MRSA introduced.

[0181] FIG. 4 shows the results of this 7-day in vivo infection model. For each microorganism introduced, the pouches with inner layers containing active agents (rifampin and minocycline HC1) (“Experimental”) were able to fully clear the infection, while negative controls (“Control”) showed a sustained infection of over 1 * 106CFU. The structural integrity of the pouches was not compromised at this time point.

[0182] In the above detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, similar symbols typically identify similar components, unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be used, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that various features of the present disclosure, as generally described herein, and illustrated in the Figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are explicitly contemplated herein.

[0183] The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various features. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds,Attorney Docket No. 437823.000102 PATENT compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0184] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity.

[0185] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” et cetera). While various compositions, methods, and media are described in terms of “comprising” various components or steps (interpreted as meaning “including, but not limited to”), the compositions, methods, and media can also “consist essentially of’ or “consist of’ the various components and steps, and such terminology should be interpreted as defining essentially closed-member groups. It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present.

[0186] For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (for example, “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations.

[0187] In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of "two recitations," without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, and C” would include but not be limited toAttorney Docket No. 437823.000102 PATENT systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, et cetera). In those instances where a convention analogous to “at least one of A, B, or C, et cetera” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, et cetera). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”

[0188] In addition, where features of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0189] As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, et cetera. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, et cetera. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges that can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 fibers refers to groups having 1, 2, or 3 fibers. Similarly, a group having 1-5 fibers refers to groups having 1, 2, 3, 4, or 5 fibers, and so forth.

[0190] Various of the above-disclosed and other features and functions, or alternatives thereof, may be combined into many other different systems or applications. Various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art, each of which is also intended to be encompassed by the disclosed embodiments.

Claims

Attorney Docket No. 437823.000102 PATENTCLAIMS1. An electrospun structure comprising: a first sheet comprising: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is affixed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet comprising: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is affixed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each comprise a first electrospun polymer fiber composition; wherein the first inner layer and the second inner layer each comprise a second electrospun fiber composition comprising an active agent; and wherein at least one edge of the first sheet is affixed to at least one edge of the second sheet, thereby forming the electrospun structure.

2. The electrospun structure of claim 1, wherein the first electrospun polymer fiber composition and the second electrospun fiber composition each comprise one or more polymers independently selected from the group consisting of poly(ethylene oxide), polyethylene glycol, polypropylene oxide), polyvinyl pyrrolidone, Dextran, saccharide, cellulose, chitosan, gelatin, collagen, polyvinyl alcohol, Eudragit, polyethylene terephthalate, polyester, polymethylmethacrylate, polyacrylonitrile, silicone, polyurethane, polycarbonate, polyether ketone ketone, polyether ether ketone, polyether imide, polyamide, polystyrene, polyether sulfone, polysulfone, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, polylactic acid, polylactide co-caprolactone, polylactide co-glycolide, polyglycolic acid, polyglycerol sebacic, polydiol citrate, polyhydroxy butyrate, polyether amide, polydioxanone, poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and combinations thereof.

3. The electrospun structure of claim 1 or 2, wherein the first electrospun polymer fiber composition comprises a first polymer and a second polymer.Attorney Docket No. 437823.000102 PATENT4. The electrospun structure of claim 3, wherein the first polymer and the second polymer are independently selected from the group consisting of polycaprolactone, polylactic acid, polylactide-co-caprolactone, polylactide-co-glycolide, polyglycolic acid, derivatives thereof, copolymers thereof, and combinations thereof.

5. The electrospun structure of claim 3 or 4, wherein the first polymer and the second polymer are co-electrospun.

6. The electrospun structure of any of claims 3-5, wherein the first polymer comprises polyglycolic acid, and wherein the second polymer comprises polylactide-co-caprolactone.

7. The electrospun structure of any of claims 3-6, wherein the first polymer is present in about 50 wt% to about 90 wt%.

8. The electrospun structure of any of claims 3-6, wherein the first polymer is present in about 60 wt%.

9. The electrospun structure of any of claims 3-8, wherein the second polymer is present in about 10 wt% to about 50 wt%.

10. The electrospun structure of any of claims 3-8, wherein the second polymer is present in about 40 wt%.

11. The electrospun structure of any of claims 1-10, wherein the second electrospun polymer fiber composition comprises a third polymer, a fourth polymer, and the active agent.

12. The electrospun structure of claim 11, wherein the third polymer and the fourth polymer are independently selected from the group consisting of polylactide-co-glycolide, polyglycolic acid, poloxamer, poloxamer 407, derivatives thereof, copolymers thereof, and combinations thereof.

13. The electrospun structure of claim 11 or 12, wherein the third polymer, the fourth polymer, and the active agent are blend-electrospun.

14. The electrospun structure of any of claims 11-13, wherein the third polymer comprises a first polylactide co-glycolide, and wherein the fourth polymer comprises a second polylactide coglycolide.

15. The electrospun structure of claim 14, wherein the first polylactide co-glycolide and the second polylactide co-glycolide each comprise DL-lactide and glycolide in a ratio of about 1:1.Attorney Docket No. 437823.000102 PATENT16. The electrospun structure of claim 14 or 15, wherein the first polylactide co-glycolide has a first intrinsic viscosity from about 0.2 dL / g to about 1.0 dL / g, and wherein the second polylactide co-glycolide has a second intrinsic viscosity from about 0.2 dL / g to about 1.0 dL / g.

17. The electrospun structure of claim 14, wherein the first polylactide co-glycolide comprises DL-lactide and glycolide in a ratio of about 1 : 1 and has a first intrinsic viscosity of about 0.2 dL / g.

18. The electrospun structure of any of claims 14, 15, or 17, wherein the second polylactide co-glycolide comprises DL-lactide and glycolide in a ratio of about 1 : 1 and has a second intrinsic viscosity of about 0.4 dL / g.

19. The electrospun structure of any of claims 11-18, wherein the third polymer is present in about 45 wt%.

20. The electrospun structure of any of claims 11-18, wherein the third polymer is present in about 47 wt%.

21. The electrospun structure of any of claims 11-19, wherein the fourth polymer is present in about 45 wt%.

22. The electrospun structure of any of claims 11-18 or 20, wherein the fourth polymer is present in about 47 wt%.

23. The electrospun structure of any of claims 1-22, wherein the active agent is selected from the group consisting of a steroid, an anti-inflammatory, a non-steroidal anti-inflammatory, an analgesic, a statin, an antibiotic, an antiviral, an antifungal, an antimicrobial, an anticoagulant, an antithrombotic agent, an immunosuppressant, an immunomodulator, an antiproliferative, a sedative, a vitamin, a hormone, a growth factor, a vasodilator, a vasoconstrictor, an antihistamine, an opioid, derivatives thereof, and combinations thereof.

24. The electrospun structure of any of claims 1-23, wherein the active agent is selected from the group consisting of rifampin, minocycline, and combinations thereof.

25. The electrospun structure of any of claims 1-24, wherein the active agent is present within the second electrospun fiber composition in about 2 wt% to about 12 wt%.

26. The electrospun structure of any of claims 1-25, wherein the active agent comprises rifampin and minocycline, wherein the rifampin is present within the second electrospun fiber composition in about 4 wt%, and wherein the minocycline is present within the second electrospun fiber composition in about 4 wt%.Attorney Docket No. 437823.000102 PATENT27. The electrospun structure of any of claims 1-25, wherein the active agent comprises rifampin and minocycline, wherein the rifampin is present within the second electrospun fiber composition in about 2 wt%, and wherein the minocycline is present within the second electrospun fiber composition in about 2 wt%.

28. The electrospun structure of any of claims 1-27, wherein the second electrospun fiber composition further comprises a stabilizing agent selected from the group consisting of magnesium, calcium carbonate, polysorbate 80, ethylene glycol, 1,8-cineole, trichloroacetic acid 0.5%, glycerine, lactose monohydrate, cyclodextrin, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, potassium sulfite, ascorbic acid, thiourea, derivatives thereof, and combinations thereof.

29. The electrospun structure of claim 28, wherein the stabilizing agent comprises magnesium.

30. The electrospun structure of claim 28 or 29, wherein the stabilizing agent is present in about 1 wt% to about 2 wt%.

31. The electrospun structure of any of claims 1-30, wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each have a thickness of about 80 pm to about 300 pm.

32. The electrospun structure of any of claims 1-31, wherein the first inner layer and the second inner layer each have a thickness of about 30 pm to about 300 pm.

33. The electrospun structure of any of claims 1-32, wherein the perimeter of the first supporting layer is affixed to the perimeter of the second supporting layer by heat-sealing.

34. The electrospun structure of any of claims 1-33, wherein the perimeter of the third supporting layer is affixed to the perimeter of the fourth supporting layer by heat-sealing.

35. The electrospun structure of any of claims 1-34, wherein the at least one edge of the first sheet is affixed to the at least one edge of the second sheet by heat-sealing.

36. The electrospun structure of any of claims 1-35, wherein the first sheet and the second sheet each have four edges, and wherein three edges of the first sheet are affixed to three edges of the second sheet, thereby forming the electrospun structure wherein one edge of the first sheet and one edge of the second sheet are not affixed to one another.

37. The electrospun structure of any of claims 1-36, wherein the first inner layer has a surface area that is at least about 80% of the surface area of the first supporting layer.Attorney Docket No. 437823.000102 PATENT38. The electrospun structure of any of claims 1-37, wherein the second inner layer has a surface area that is at least about 80% of the surface area of the third supporting layer.

39. A pouch comprising the electrospun structure of any of claims 1-38.

40. A method of using the pouch of claim 39, the method comprising implanting the pouch in a surgical site.

41. The method of claim 40, further comprising placing a medical device in the pouch.

42. The method of claim 41, wherein the medical device is selected from the group consisting of a cardiac implantable electronic device (CIED), a neurostimulatory device, a pain pump, an insulin pump, a breast implant, a wearable device, an orthopedic implant, a dental implant, a vascular implant, and combinations thereof.

43. An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is heat-sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each consist essentially of about 60 wt% polyglycolic acid electrospun fibers co-electrospun with about 40 wt% polylactide-co- caprolactone electrospun fibers; wherein the first inner layer and the second inner layer each consist essentially of blend-electrospun polymer fibers consisting essentially of: about 45 wt% of a first polylactide co-glycolide having a first intrinsic viscosity of about 0.2 dL / g,Attorney Docket No. 437823.000102 PATENT about 45 wt% of a second polylactide co-glycolide having a second intrinsic viscosity of about 0.4 dL / g, about 8 wt% of an active agent consisting essentially of rifampin and minocycline, and about 2 wt% of a stabilizing agent selected from the group consisting of magnesium, salts thereof, and combinations thereof; and wherein at least one edge of the first sheet is heat-sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

44. An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is heat-sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each consist essentially of about 60 wt% polyglycolic acid electrospun fibers co-electrospun with about 40 wt% polylactide-co- caprolactone electrospun fibers; wherein the first inner layer and the second inner layer each consist essentially of blend-electrospun polymer fibers consisting essentially of: about 47 wt% of a first polylactide co-glycolide having a first intrinsic viscosity of about 0.2 dL / g, about 47 wt% of a second polylactide co-glycolide having a second intrinsic viscosity of about 0.4 dL / g, about 4 wt% of an active agent consisting essentially of rifampin and minocycline, andAttorney Docket No. 437823.000102 PATENT about 2 wt% of a stabilizing agent selected from the group consisting of magnesium, salts thereof, and combinations thereof; and wherein at least one edge of the first sheet is heat-sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

45. An electrospun structure consisting essentially of: a first sheet consisting essentially of: a first supporting layer, a second supporting layer, and a first inner layer positioned between the first supporting layer and the second supporting layer, wherein a perimeter of the first supporting layer is heat-sealed to a perimeter of the second supporting layer, thereby encasing the first inner layer; and a second sheet consisting essentially of: a third supporting layer, a fourth supporting layer, and a second inner layer positioned between the third supporting layer and the fourth supporting layer, wherein a perimeter of the third supporting layer is heat-sealed to a perimeter of the fourth supporting layer, thereby encasing the second inner layer; wherein the first supporting layer, the second supporting layer, the third supporting layer, and the fourth supporting layer each consist essentially of about 60 wt% polyglycolic acid electrospun fibers co-electrospun with about 40 wt% polylactide-co- caprolactone electrospun fibers; wherein the first inner layer and the second inner layer each consist essentially of blend-electrospun polymer fibers consisting essentially of: about 47.5 wt% of a first polylactide co-glycolide having a first intrinsic viscosity of about 0.2 dL / g, about 47.5 wt% of a second polylactide co-glycolide having a second intrinsic viscosity of about 0.4 dL / g, about 4 wt% of an active agent consisting essentially of rifampin and minocycline, and about 1 wt% of a stabilizing agent selected from the group consisting of magnesium, salts thereof, and combinations thereof; and wherein at least one edge of the first sheet is heat-sealed to at least one edge of the second sheet, thereby forming the electrospun structure.

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