WO2015187555A1 - Matériaux nanofibreux en tant que médicament, protéine ou véhicules de libération génétique - Google Patents

Matériaux nanofibreux en tant que médicament, protéine ou véhicules de libération génétique Download PDF

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Publication number
WO2015187555A1
WO2015187555A1 PCT/US2015/033532 US2015033532W WO2015187555A1 WO 2015187555 A1 WO2015187555 A1 WO 2015187555A1 US 2015033532 W US2015033532 W US 2015033532W WO 2015187555 A1 WO2015187555 A1 WO 2015187555A1
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WIPO (PCT)
Prior art keywords
textile
recited
admixture
fabricated textile
biologically
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PCT/US2015/033532
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English (en)
Inventor
Matthew D. Phaneuf
Philip J. Brown
Martin J. BIDE
Original Assignee
Biosurfaces, Inc.
Clemson University
Rhode Island Board Of Education
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Priority claimed from US14/293,481 external-priority patent/US10328032B2/en
Application filed by Biosurfaces, Inc., Clemson University, Rhode Island Board Of Education filed Critical Biosurfaces, Inc.
Publication of WO2015187555A1 publication Critical patent/WO2015187555A1/fr

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Classifications

    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D1/00—Treatment of filament-forming or like material
    • D01D1/02—Preparation of spinning solutions
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F1/00—General methods for the manufacture of artificial filaments or the like
    • D01F1/02—Addition of substances to the spinning solution or to the melt
    • D01F1/10—Other agents for modifying properties
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01F—CHEMICAL FEATURES IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS; APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OF CARBON FILAMENTS
    • D01F1/00—General methods for the manufacture of artificial filaments or the like
    • D01F1/02—Addition of substances to the spinning solution or to the melt
    • D01F1/10—Other agents for modifying properties
    • D01F1/103—Agents inhibiting growth of microorganisms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices

Definitions

  • the instant invention provides a variety of non-biodegradable, formed fabric materials, articles, and devices suitable for the in-situ delivery of many different biologically-active agents.
  • the disclosure also offers a wide range of fabricated nanofibrous textiles having varying and diverse individual biologic properties, or combinations thereof; and provides medical products which are resistant to breakage and tearing as well as demonstrate a specifically desired localized effect such as resistance to infection—properties which will aid in reducing both the morbidity and mortality of a person afflicted with an injury or ailment.
  • Electrospinning provides a technique for making nanofibrous material substrates. Electrospinning to produce nanoscale fibers, fabrications and textiles, however, is still a manufacturing technique in need of further development and refinement. Utilization of electrospinning as a technique to synthesize various nanofibrous materials from polymers such as polyurethane, polyvinyl alcohol (or "PVA”), poly (lactic glycolic) acid (or “PLGA”), nylon, and polyethylene oxide has been investigated for several decades (see for example Subbiah et al., "Electrospinning Of Nanofibers", J. Applied Polymer Sci. 96:557-569 (2005).
  • PVA polyvinyl alcohol
  • PLGA poly (lactic glycolic) acid
  • the present invention is a major advance in the development of biomedical materials, devices and constructs. Accordingly, the invention has multiple aspects, some of which may be defined as follows.
  • a first aspect provides a method for forming a fabricated textile suitable for use as a medical article.
  • the method includes the steps of dissolving a non-biodegradable polymer and a pre-chosen biologically-active agent in an organic solvent at an ice-cold temperature. Once dissolved, the admixture is permitted to warm before electrospinning at room temperature to form the fabricated textile.
  • FIG. 1 is an illustration of the chemical structure of Ciprofloxacin
  • FIG. 2 is an illustration of the chemical structure of Diflucan
  • FIG. 3 is an illustration of the chemical structure of Paclitaxel
  • FIG. 4 is a an illustration of the apparatus for performing the
  • FIG. 5 A and FIG. 5B are scanning electron microphotographs of a nPET (electrospun polyethylene terephthalate) textile segment showing the diameter size of the fibers within the nanofibrous material;
  • FIG. 6 is an overhead view of the UV illumination differences between nPET segments, nPET-Cipro segments, and nPET -Diflucan segments;
  • FIG. 7 is a graph showing the release profile of Cipro from nPET-Cipro segments over time
  • FIG. 8 is a graph showing the release profile of Diflucan from nPET-
  • FIG. 9 is a an overhead view of the inhibitions zone against
  • FIG. 10 is a graph showing the antimicrobial activity of nPET-Cipro segments over time
  • FIG. 11 is a graph showing the anti-fungal activity of nPET-Diflucan segments against varying concentrations of Candida albicans.
  • FIG. 12 illustrates an overhead view of a flat sheet of electrospun textile fabric.
  • a bioactive, nanofibrous material construct which is manufactured either in tubular or flat sheet form using an unique electrospinning perfusion methodology.
  • One particular embodiment provides a nanofibrous biocomposite material formed as a discrete textile fabric from a prepared liquid admixture of (i) a biodurable synthetic polymer; (ii) a biologically active agent; and (iii) a liquid organic carrier.
  • the prepared liquid admixture of diverse compositions is employed in a novel electrospinning perfusion process to form an agent-releasing textile comprised of nanofibrous material, which in turn, can serve as the antecedent precursor and tangible workpiece for subsequently making the desired medical article or device suitable for use in-vivo.
  • Prior art medical devices generally includes an underlying non-polymeric support (e.g. scaffold, stent, etc) and coat the support with a biodegradable polymer and then soaks the resulting coated support in a biologically- active agent to embed the agent in the polymer.
  • the medical devices of the present invention are discrete articles that omit the underlying scaffold and the medical devices consist essentially of a non-biodegradable polymer that has the biologically- active agent embedded therein.
  • the materials of the present invention have mechanical properties which are sufficient to permit the manufacturer to omit the scaffolds that were previously required by the prior art.
  • one or more pre-chosen biologically- active agents will have become non-permanently immobilized and releaseably bound to the tangible nanofibrous material of the fabricated textile.
  • These non-permanently immobilized biologically-active agents are well established chemical compounds which retain their recognized biological activity both before and after becoming impermanently (i.e., temporarily or reversibly) bound to the textile fabric; and will become subsequently released in-situ and directly delivered into the ambient environment as discrete mobile entities when the textile fabric takes up any fluid ⁇ i.e., any aqueous or organic based liquid. Accordingly, via the transitory immobilization of one or more biologically active molecules to the nanofibrous biocomposite material, the agent-releasing textile is very suitable for inclusion and use in-vivo as a clinical/therapeutic construct.
  • the present electrospinning perfusion method of making agent-releasing nanofibrous textiles provides several major advantages and desirable benefits to the commercial manufacturer as well as to the physician and surgeon. Among these are the following:
  • the manufacturing methodology comprising the present invention does not utilize any immersion techniques and does not require submerging the fabricated textile in any immersion baths, soaking tanks, or dipping pools for any purpose. Rather, the methodology preferably utilizes the unique technique of electrospinning perfusion as a manufacturing method in order to blend a synthetic substance and a biologically active agent of choice together as a fabricated textile.
  • the electrospinning perfusion method of manufacture yields a fabricated textile having particular characteristics.
  • the fabricated textile is initially fashioned either as an elongated hollow tube having two discrete open tubular ends and fixed inner and outer wall diameters; or as a flat or planar sheet of nanofibrous fabric.
  • the fabricated textile can be folded, or twisted, and otherwise manipulated to meet specific requirements of thickness, gauge, or deniers; and can also be cut, split, tailored, and conformed to meet particular shapes, configurations and patterns.
  • the fabricated textile is a nanofibrous material composite comprised of multiple fibers, has a determinable individual fiber thickness in or near the nanometer size range (typically less than 2 microns), and presents a discernible fiber organization and distribution pattern. These fabricated textiles provide and demonstrate excellent suture retention, burst strength, break strength, tear strength and/or biodurability.
  • the manufacturing method comprising the present invention employs limited heat and compression force to alter the exterior surface of the fabricated textile originally formed via the electrospinning perfusion technique.
  • This exterior surface treatment portion of the manufacturing process is optional, but when employed, will produce a highly desirable crimped exterior surface over the entire linear length of the fabricated textile article.
  • a notable feature of this exterior surface treatment procedure is that the inner diameter size (typically less than 1 mm to not greater than about 30 mm, but can vary from these particular parameters) of the fabricated textile remains constant and uniform, despite the effects of the limited heating and compression treatment of the textile exterior surface.
  • the biologically active agent will retain its characteristic biological activity both before and after being temporarily bound to the nanofibrous material.
  • the attributes and properties associated with the biologically active agent of choice will coexist with and be an integrated feature of the resulting textile article at the time it is utilized.
  • the method of the present invention is directed in part to the making of an agent-releasing textile, an antecedent article of manufacture, which is then employed as a tangible workpiece to generate a subsequently prepared medical article or device suitable for use in-vivo.
  • An agent-releasing textile is a fabricated textile comprising nanofibrous matter which has at least one biologically active agent immobilized onto and/or within the material substance of the textile; and which, upon wetting, is then able to release the biologically active agent in-situ and deliver it in a functionally operative form into the adjacent local area or immediately surrounding environment.
  • Such a prepared nanofibrous textile must provide and release at least one active chemical composition, compound, or molecule which is active, functional and operative either to influence and/or to initiate or cause a recognizable pharmacological effect or determinable physiological change in the living cells, tissues and organs of the host patient.
  • a fabricated textile is an article of manufacture which is comprised, in whole or in part, of fibers arranged as a fabric. The fibers comprising the fabricated textile may be chosen from a diverse range of organic synthetics, prepared polymer compounds, or naturally- occurring matter.
  • the fabricated textile is often prepared as a cloth or fabric; and may comprise a single fiber film, or a single layer of fibrous matter; or exist as multiple and different deniers of fibers which are present in a range of varying thickness, dimensions, and configurations.
  • agent-releasing nanofibrous textile after the agent-releasing nanofibrous textile has been manufactured and is present as a discrete entity, it can optionally serve as a tangible workpiece in combination with other items and additional components and hardware to yield the desired end product, a clinically or therapeutically useful "medical article or device".
  • agent-releasing textile regardless of its true chemical composition/formulation or the particular mode of construction, the initially formed "agent-releasing textile" and the subsequently generated “medical article or device" are directly and intimately related; and thus share a number of specific qualities and characteristics in common.
  • Each agent-releasing textile is formed as an elongated hollow tube having a determinable overall tubular length and two open ends; has at least one internal lumen of determinable volume which is co-incidental and coextensive with the internal wall surface; and has at least one exterior wall surface which is co-incidental and co-extensive with the outer wall topography.
  • Each agent-releasing textile has a determinable length, girth and depth of non-perforated fibrous material which can be prepared to meet specific shapes, sizes and thicknesses of solid matter;
  • Each agent-releasing textile can be employed either as a configured tubular conduit whose internal lumen is usefully employed for the conveyance of fluids in-situ; or, alternatively, as a solid mass of nanofibrous material which achieves its intended purpose without regard to or actual use of the internal lumen then existing within the textile fabric.
  • the agent-releasing nanofibrous textile [00040] By definitional requirement, the agent-releasing nanofibrous textile
  • nanofibrous composite material forming the textile fabric has been electrospun from a liquid admixture and blending in a liquid organic carrier of at least two different materials: a synthetic substance and a biologically active agent.
  • a liquid organic carrier of at least two different materials: a synthetic substance and a biologically active agent.
  • Table 1 To illustrate the range and variety of compositions deemed suitable for use as a blended mixture, a listing of suitable synthetic substances is presented by Table 1 below. It will be noted that the listing of Table 1 presents some exemplary synthetic substances long deemed suitable for use as synthetic fibers. To complete the description, Table 2 lists some of the typical and more commonly available organic liquids which can be usefully employed alone and/or in blends as the liquid carriers.
  • polyethylene terephthalate polybutylene terephthalate; polytrimethylene terephthalate
  • polyamides including nylons and aramids
  • Olefin Polypropylene, polyethylene, and other polyolefms
  • At least some of the fibers comprising the textile fabric will demonstrate a range of properties and characteristics, as follows.
  • the fibers constituting the agent-releasing textile will have a demonstrable capacity to take up water and/or aqueous liquids and/or organic liquids and/or organic based liquids (with or without direct wetting of the fibrous material).
  • the mode or mechanism of action by which organic and aqueous fluids are taken up by the fibers of the textile (and/or become wetted by the fluid) is technically insignificant and functionally meaningless.
  • fluid (aqueous and/or organic) uptake are the individual alternatives of: absorption; adsorption; cohesion; adhesion; covalent bonding; non-covalent bonding; hydrogen bonding; miscible envelopment; molecule entrapment; solution-uptake between fibers; fiber wetting; as well as others well documented in the scientific literature. Any and/or all of these may contribute to organic and/or aqueous fluid uptake in whole or in part. Which mechanism of action among these is actively in effect in any instance or embodiment is irrelevant.
  • the resulting biologically active textile can be prepared as a fabric having a markedly long functional duration and lifespan for in- vivo use. Accordingly, by choosing one or more durable and highly resilient chemical compositions as the fibers of choice, textiles effective for many years' duration and utility may be routinely made. All of these choices and alternatives are conventionally known and commonly used today by practitioners in this field.
  • PETs polyethylene terephthalates
  • IV intrinsic viscosity
  • these differently formulated polyethylene terephthalate compounds can vary from less than 0.6 dl/g [IV] to greater than 1 dl/g [IV]; yet each of these alternative polyethylene terephthalate formulations can be dissolved in ice-cold 100% hexafluoroisopropanol.
  • the fibers comprising the agent-releasing textile can be prepared in a variety of organizations as a tangible structure.
  • the textile fabric may vary in size or thickness; and may optionally receive one or more interior and/or exterior surface treatments to enhance particular attributes such as increased in-vivo biocompatibility or a greater expected time for functional operation and use in-vivo. All of these organizational variances are deemed to be routine matters which will be optionally chosen and desirably used to meet particular medical needs or individual patient requirements.
  • the fibers comprising the agent-releasing textile can be prepared to meet the particulars of the intended in-vivo medical use circumstances or the contingencies of the envisioned clinical/therapeutic application.
  • the textile fabric can alternatively be prepared either as a relatively thin- walled biocomposite, or alternatively as a thick- walled material; be produced as an elongated object having a diverse range of different outer diameter and inner diameter sizes; and be fashioned as a relatively inflexible or unyielding item or as a very flexible and easily contorted length of matter.
  • a number of different biologically active agents can be beneficially and advantageously utilized in tandem with the nanofibrous textile fabric.
  • the biologically active molecule- whatever its particular composition and formulation as a chemical compound, composition or molecule-must demonstrably provide in order to be suitable for use in the present invention.
  • the chosen agent must be capable of demonstrating its characteristic biological activity before becoming temporarily bound to and immobilized by the material substance of the fabricated textile. This characteristic biological activity must be well recognized and will constitute its ability/capacity to function as an active mediator in-situ.
  • substance of the textile fabric must be capable of demonstrating its characteristic biological activity (its mediating capacity) after becoming immobilized and bound;
  • textile fabric will be released in-situ from the non-biodegradable polymer and be delivered into the surrounding local environment as a freely mobile molecule which retains its characteristic biological activity (its mediating capacity) over an extended period of time after the agent-releasing textile has been utilized in- vivo and allowed to take up water.
  • the characteristic biological properties of the chosen agent serve to aid, promote, and/or protect the naturally occurring pathways and processes of the body which occur in-vivo.
  • the primary function and capabilities of the chosen biologically active molecule will differ and vary in many instances; and thus there are multiple purposes and a range of individual goals for the releasable substance, among which are the following: (1) to serve as an antimicrobial agent ⁇ i.e., as an anti-bacterial or anti-fungal composition having a broad or narrow spectrum of activity; (2) to function as an anti-neoplastic compound effective against specific kinds of tumors; (3) to operate as a selective physiological aid ⁇ i.e., as a mediator which serves to avoid vascular complications such as blood coagulation or acts to prevent the formation of blood clots; and (4) to act as a pharmacological composition ⁇ i.e., as a drug or pharmaceutical which deactivates specific types of cells and/or functions to suppress or inhibit a variety of different humoral and cellular responses associated with or related to inflammation and the inflammatory response in- vivo. Examples of each are presented hereinafter.
  • a preferred method for making the agent-releasing textile of the present invention is via the unique technique of electrospinning perfusion.
  • an electrospinning perfusion assembly is erected which comprises, at a minimum, a rotating mandrel with a target surface which can be set at a pre- selected rotation speed; a needle fronted perfusion instrument with a spinerette, such as a syringe, which can be set to deliver a liquid mixture at a pre-specified flow rate; an electrical coupling for controlling and coordinating the electrical voltage applied across the perfusion needle and which is grounded to the rotating mandrel; and a controllable supply of electrical power.
  • An admixture is prepared comprising a chosen non-biodegradable material and a biologically active agent of choice. These components are blended together into an organic liquid carrier.
  • the organic liquid carrier is cooled to an ice- cold (e.g. about 4°C) temperature. For reasons that are not clear, this cooling step facilities the proper formation of the admixture and speeds the dissolution of the nonbiodegradable material.
  • one preferred liquid admixture or blending is obtained by combining 20% w:v polyethylene terephthalate (PET) with 1.5% w:v of an antimicrobial (e.g., Cipro or Diflucan), or with 1.5% w:v of an anti-neoplastic compound (e.g., Paclitaxel, Everolimus, Sirolimus), in a sufficient quantity of ice-cold
  • PET polyethylene terephthalate
  • an antimicrobial e.g., Cipro or Diflucan
  • an anti-neoplastic compound e.g., Paclitaxel, Everolimus, Sirolimus
  • HFIP hexafluoroisopropanol
  • a 10 ml syringe with a stainless steel 18-gauge blunt spinneret (0.5 mm internal diameter) is then filled with the liquid polymer blending and placed onto a Harvard Apparatus syringe pump for subsequent perfusion.
  • Perfusion is the action and the act of causing a liquid or other fluid to pass across the external surfaces of, or to permeate through, the substance of a tangible entity or a configured physical construct.
  • Perfusion of a liquid or fluid thus includes the alternative actions of: a sprinkling, pouring, or diffusing through or overlaying action; a covering, spreading, penetrating or saturating action (termed “suffusion”); a slow injection or other gradual introduction of fluid into a configured space or sized internal volume (termed “infusion”); and a passage across a surface or through a discrete surface or tangible thickness of matter, regardless of the mechanism or manner of transfer employed for such fluid passage.
  • the electrical coupling and syringe pump are activated and the admixture is electrospun onto the target surface.
  • the step of electrospinning is carried out at a temperature which does not harm the biological activity of the biologically-active agent in the admixture.
  • the reaction temperature is, in one embodiment, ambient room temperature (20-25°C), but when necessary or desired can be chosen to be within a temperature reaction range of about 0-50 °C.
  • a chemically resistant syringe with a stainless steel blunt spinneret can serve as a functional instrument for perfusion.
  • any other tool, assembly or instrument capable of performing perfusion at a pre-selected flow rate and low reaction temperature can be usefully employed.
  • the perfusion syringe of the assembly is filled with the prepared liquid mixture described above and placed onto a Harvard Apparatus syringe pump.
  • the perfusion rate is preferably set at 3 ml/hour at 25 °C. If desired, however, the flow rate can be increased and/or decreased to meet specific requirements.
  • the reaction temperature is preferably ambient room temperature (20-25 °C), but when necessary or desired can be chosen to be within a temperature reaction range of about 0-50 °C.
  • the rotatable mandrel was then electrically grounded to the power source, with the positive high potential source connected to the syringe needle. The mandrel rotates or spins at a preselected rate of rotation throughout the act of liquid perfusion.
  • Perfusion of the polymer solution begins upon application of the electric current to the tip of the syringe needle (typically 15 kV), which then moves at a preset constant speed and fixed distance from the mandrel surface for a limited time period (typically about 40-90 minutes in duration).
  • This process of manufacture is therefore termed "electrospinning perfusion"; and yields a fully fabricated, elongated nanofibrous textile conduit whose inner diameter size corresponds to the overall diameter of the mandrel (in this instance, 4 mm).
  • a crimping procedure is employed as an optional, but very desirable, follow-up process. Accordingly, after being formed as a hollow tube by electrosp inning perfusion, the thickness and girth of the originally formed fibrous composite wall and exterior surface preferably is then intentionally altered into a crimped structural form via a limited heat (low temperature) set technique, followed by compression of the fibrous composite wall, in order to provide kink-resistance for the elongated tube.
  • the end portions of the formed hollow tube are cut off and discarded.
  • the remainder of the elongated hollow tube is then stretched 25% of the starting segment size while on the mandrel in order to provide a set strain across the fibers, a manipulation that occurs in normal fiber extrusion.
  • the stretched tubes are then immediately exposed to 100% ethanol for 2 hours time at room temperature (or in 100% ethanol for 30 minutes with sonication) in order to remove the residual solvent, followed by air-drying overnight at room temperature.
  • This crimping technique permits a user to form specific shapes (e.g. bends, etc) in the fabric without using high-temperature melt techniques which would damage the biologically- active agent.
  • DACRON chips were dissolved in ice-cold 100% hexafluoroisopropanol (19% w:v) and mixed on an inversion mixer for 48 hours in order completely solubilize the chips.
  • the self-contained, semi- automated electrospinning apparatus containing a Glassman power supply, a Harvard Apparatus syringe pump, an elevated holding rack, a modified polyethylene chamber, a spray head with power attachment and a reciprocating system was again used.
  • the stirrer was used to provide a holding chamber for the new flat collecting plate employed to generate a sheet format.
  • the design of this surface is based upon the collecting plate employed by Li et. al. [see Li W J, Laurencin C T, Caterson E J, Tuan R S, Ko F K., "Electrospun nanofibrous structure: A novel scaffold for tissue engineering", J Biomed Mater Res 60:613 (2002)].
  • a flat 12 cm .times.10 cm copper plate, containing a 6 cm stainless steel rod extending from the underside of the plate was designed and grounded to the power source.
  • a 10 ml chemical-resistant syringe was filled with the polymer liquid.
  • a stainless steel 18-gauge blunt spinneret (0.5 mm internal diameter) was then cut in half, with the syringe fitting end connected to the polymer- filled syringe.
  • Nalgene PVC tubing was connected to the syringe filled with the polymer solution followed by connection to the other half of the blunt spinneret within the spray head.
  • the line was then purged of air, with the syringe then placed onto the syringe pump.
  • the high potential source was connected to the spray head tip, with the plate set at a jet gap distance of 15 cm from the tip of the needle.
  • the perfusion rate was set at 3 ml/hour at 25 °C.
  • the agent releasable nanofibrous textile formed by the electrospinning method described above has a number of unique structural features which are the direct result and characteristic of its unique mode and manner of manufacture.
  • the agent-releasing textile fabricated via one of the two different electrospinning perfusion techniques will yield a discrete tubular article of fixed inner- wall and outer wall diameters, and a solid wall girth and configuration formed of a nanofibrous composite composition.
  • the material substance of the fabricated wall typically shows that the synthetic substance is present as discrete fibers about 10 " meters in diameter size. The fiber size is clearly demonstrated by the empirical data presented subsequently herein.
  • the interior wall surface and the exterior wall surface of the tubular structure comprising the agent-releasing textile are markedly different owing to the crimping and heat setting treatments following the initial electrospinning perfusion steps of the methodology.
  • the exterior wall surface can possess a crimped and a somewhat irregular appearance.
  • the interior wall surface and the internal lumen of the conduit as a whole presents a smooth, regular, and even appearance which is devoid of perceptible projections, lumps, indentations, and, roughness.
  • the nanofibrous composite material substance of the textile fabric is resilient and can be prepared in advance to provide varying degrees of flexibility, springiness, suppleness, and elasticity. Moreover, the nanofibrous biocomposite wall is durable and strong; is hard to tear, cut, or breakup; and is hard-wearing and serviceable for many years' duration.
  • the nanofibrous material substance of the agent releasable textile is biocompatible with the cells, tissues and organs of a living subject; and can be implanted surgically in- vivo without initiating or inducing a major immune response by the living host recipient. While aseptic surgical technique and proper care against casual infection during and after surgery must be exercised, the agent releasable textile can be usefully employed for a variety of applications in- vivo.
  • the electrospinning perfusion technique whether employed to fabricate tubular structures or flat sheets, has a number of advantages over conventionally known manufacturing processes. These include the following:
  • a first benefit is that no exogenous binders, cross-linking compounds, or functional agents are required by the process either to form the substance of the fabric or to maintain the integrity of the fabricated textile.
  • the synthetic substance prepared in liquid organic solvent can be generated directly into nanofibrous fabric form via the low reaction temperatures (typically ranging between 0-50 °C) permitted and used by the electrospinning perfusion process.
  • the nanofibers of the fabric act to seal the interstices of the composite material; therefore, no sealants as such are required.
  • This manufacturing technique also benefits the manufacturer in that the technology is not a dipping or immersion method of preparation, which can be awkward and difficult to perform; or is a process which typically requires the addition of heat, such as if a conventional melt spinning method of fiber formation were employed.
  • a second benefit is that the electrospinning perfusion technique yields a textile fabric formed as a nanofibrous composite in which the fibers (e.g., PET) exist independently and are visibly evident throughout the material of the textile.
  • the fibers e.g., PET
  • This structural distribution of discrete fibers within the fabric adds strength and flexibility to the textile as a whole.
  • the presence of these fibers collectively provides sites into which diverse biological agents (such as antimicrobials, anti-neoplastic agents, and the like) can be temporarily incorporated and indefinitely, although non-permanently, immobilized until such time as the textile takes up fluid— i.e., any aqueous and/or organic liquid.
  • a third benefit is the capability for direct incorporation of biologically-active agents onto the nanofibrous material, whatever its final shape and structure. This process holds several key advantages over other conventionally known methodologies in that:
  • the active agent is incorporated into the fabricated nanofibrous material without molecular modification, and is non-permanently immobilized within each individual fiber surface as the individual fibers are formed.
  • the amount of active agent can be adjusted within the bulk polymer depending on the specific or intended application. [00085] No cross linking agents are needed, or used, or desired at all, thereby avoiding concerns over drug carrier toxicity, biocompatibility, and mutagenicity. [00086] Low reaction temperatures are used during the fiber/fabric formation procedure, thus maintaining the biologic activity of the active agent. [00087] Active agent elution from the textile fabric is controlled and sustained over time, as shown in the experimental studies and empirical data presented hereinafter.
  • Paclitaxel also known as Taxol, a diterpenoid- structured molecule shown by FIG. 3, is a potent anti-neoplastic agent. Paclitaxel has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation, migration and inflammation. Additionally,
  • Paclitaxel has been shown to inhibit the secretion of extracellular matrix by VSMCs, a major component of neointima formation leading to vessel restenosis. Paclitaxel stabilizes and enhances assembly of polymerized microtubules, an important component of the cytoskeleton involved in cell division, cell motility and cell shape.
  • Other examples of anti-proliferative/anti-neoplastic agents such as Sirolimus, Everolimus, Tacrolimus, 5-
  • FU daunomycin, mitomycin and dexamethasone can also be used.
  • microtubules are involved in signal transduction, intracellular transport and gene activation.
  • Paclitaxel has shown promise as a treatment for various types of cancers as well as for the prevention of restenosis following stent placement.
  • Paclitaxel when Paclitaxel is incorporated into a hydrophobic carrier polymer coated onto a metallic stent, it elutes for only 10-14 days.
  • Other research groups have attempted to incorporate Paclitaxel into biodegradable polymers that would comprise the stent.
  • Paclitaxel activity was significantly reduced due to the melt extrusion process for the fibers.
  • Antibiotics vary in structural type, spectrum of activity, and clinical usefulness. Fluoroquinolones such as Ciprofloxacin (hereinafter “Cipro”) are shown structurally by FIG. 1, and are of particular use and value in this invention. Quinolone antibiotics are chemically stable, and effective at low concentrations against the common clinically encountered organisms, particularly those bacteria responsible for biomaterial infection. These antibiotics also have structural features (solubility, molecular mass, and functional groups) that coincide with those of textile dyes known to have interactions with polyethylene terephthalates.
  • This family of antibiotics has expanded considerably-Ciprofloxacin, Ofloxacin, Norfloxacin, Sparfloxacin, Tomafloxacin, Enofloxacin, Lovafloxacin, Lomefloxacin, Pefloxacin, Fleroxacin, Avefloxin, Levofloxavin Moxifloxacio and DU6859a; and the fluoroquinolone family as a whole has become the drug of choice for many applications.
  • These antibiotics are effective at low concentrations; and hold an ideal antimicrobial spectrum against microorganisms most commonly encountered clinically in wound infection, with significant activity against many relevant pathogens- such as S. aureus, methicillin-resistant S. aureus, S.
  • Fluoroquinolones are heat stable; are of 300-400 r.m.m.; and have many structural features analogous to dyes. Accordingly, this family of antibiotics possesses those characteristics which are highly desired for use with the present invention.
  • a list of some representative antimicrobial/antiseptic agents that can be used solely or in conjunction with the fluoroquinolones is includes ⁇ -lactams, biguanides cephalosporins, chloamphenicol, macrolides aminoglycosides, quaternary ammonium salts, tetracyclines, sulfur-containing antimicrobials, silver-containing compounds, bis- phenols (triclosan), vancomycin, novobiocin and steriods (fusidic acid)
  • Fluconazole known as Diflucan, a triazole- structured antifungal agent introduced in early 1990 and structurally shown by
  • FIG. 2 has emerged as one of the primary treatments for Candida infections.
  • the mode of action of Diflucan is the inhibition of 14.alpha.-lanosterol demethylase in the ergosterol biosynthetic pathway, and results in the accumulation of lanosterol and toxic
  • Diflucan has structural features (solubility, molecular mass, and functional groups) that coincide with those of textile dyes known to have interactions with polyethylene terephthalate fibers.
  • a agent-releasing textile combining polyethylene terephthalate with a slow-releasing antifungal agent such as Diflucan will have a marked impact on topical and implantable biomaterials such as medicated pads (useful for nail bed and skin infections), tampons (using localized release for yeast infection) and catheter cuffs.
  • Other examples of anti-fungal agents typically will include amphotericin B, Nystatin, Terbinafme Voriconazole, Echinocandin B and Itraconazole
  • antimicrobial peptides or
  • AMPs AMPs
  • natural antimicrobial agents which consist of a large number of low molecular weight compounds, have been discovered in plants, insects, fish and mammals, including humans [see for example,
  • linear peptides without cysteine residues or hinge region consist of: (1) linear peptides without cysteine residues or hinge region; (2) linear peptides without cysteine residues and a high proportion of certain amino acids; (3) antimicrobial peptides with one disulfite bonds that form a loop structure; (4)
  • antimicrobial peptides with two or more disulfite bonds (5) antimicrobial peptides that have been derived from other larger proteins via post-translational processing.
  • AMPs have shown broad spectrum antimicrobial activity against both gram-positive (i.e., Staphylococcus aureus and epidermidis) and negative (i.e.,
  • AMPs i.e., Nisin and Daptomycin
  • AMPs have been recently approved by the FDA for commercial and medical markets. This acceptance paves the way for utilizing other AMPs such as pleurocidin. Additionally, federal standard testing procedures, which were used to provide safety and efficacy data for these AMPs, have been established.
  • Other representative types of AMPs include Cationic peptides such that Cecropins, Defensins, Thionins, Amino Acid- Enriched Histone-Derived Beta-Hairpin and other Natural and Functional Proteins. Further examples of anionic peptides include Asparitc Acid-Rich, Aromatic Dipeptides and Oxygen-Binding Proteins.
  • Analgesic agents are widely used in human and veterinary medicine in order to prevent inflammation, thereby reducing pain and other symptoms such as itching and swelling. These agents have structural properties that are comparable to standard textile dyes such as molecular weight, functional groups and benzene-ring based composition. Exemplifying such analgesic agents are Diphenhydramine Hydrochloride,
  • Antiviral agents have been used to combat viral infections ranging from the flu to HIV infection and organ transplant rejection.
  • examples of some antiviral agents include Oseltamivir (Flu), Zanamivir (Flu), Saquinavir (HIV), Ritonavir (HIV), Interferon (HIV/Implant Rejection).
  • a number of other classes of biologically active agents can also be used in the agent releasable textile. All of these choices are biochemical mediators which can be initially immobilized via the electrospinning technique without serious deterioration, and then subsequently released from the nanofibrous textile fabric upon uptake of water.
  • each agent-releasing textile can be employed in the alternative either (1) as a configured tubular conduit whose internal lumen is usefully employed for the conveyance of fluids in-situ; or (2) as a solid mass of flat or planar nanofibrous sheet fabric which achieves its intended purpose without regard to or actual use of any internal lumen within the textile fabric.
  • Some representative examples of the tubular format include vascular articles such as arterial vascular grafts; venous vascular grafts; prostheses for aneurysms; liners and covers for stents (coronary or endovascular) as well as non-vascular devices including catheter cuffs and coating for wires for transdermal devices (pacemaker leads).
  • flat sheet formats include wound dressings such as treatment dressings, films, and/or sheets; gauze pads; absorbent sponges; bandages; and sewing cuffs. Further examples include transdermal release patches such as infection treatment; skin tumor treatments; and finger/toenail treatment. Further examples include personal hygiene products such as tampons; and contraceptive delivery.
  • the kinds of clinical/therapeutic applications for the prepared medical articles and devices are intended to include major traumatic wounds caused by accident, negligence, or battlefield conditions; planned surgical incisions and invasive body surgical procedures performed under aseptic conditions; transcutaneous incisions and vascular openings for catheter insertion and blood vessel catheterization procedures; and other body penetrations and openings made for therapeutic and/or prophylactic purposes.
  • the medical articles provided by the present invention thus are intended and expected to be manufactured as pre-packaged and pre- sterilized textile fabric articles; be an item which can be prepared in advance, be stocked in multiples, and be stored indefinitely in a dry state without meaningful loss of biological function or efficacy; and serve effectively in the treatment of disease, disorders, and pathological conditions under many different clinical circumstances.
  • the medical articles should be manufactured and tailored in advance to meet a wide range of intended use circumstances or contingencies expected to be encountered in a particular situation. For this reason, the constructed textile article can and should alternatively be prepared as a thick cloth and as a thin gauze; as a solid- walled configured tube; and as a delicate film. Equally important, the resulting construct may take physical form either as a stiff, inflexible and unyielding mass or as a very flexible and supple layer; have a varied set of dimensions and girth; appear as both a geometrically symmetrical or asymmetrical configured fabric; and can exist even as a slender cord or string-like length of material.
  • the agent releasable textile articles of the present invention can be employed in-vivo in the following ways: topically or subtopically; transcutaneously, percutaneously, or subcutaneously; or internally within the body's interior; vascularly or Immorally; and applied to any kind of body cavity, body tissue or body organ without regard to anatomic site or location.
  • POD Peripheral arterial disease
  • APD Peripheral arterial disease
  • An autologous vessel graft is the first and currently only accepted choice in most arterial grafting procedures for these anatomic areas.
  • this situation becomes problematic when disease progression has occurred throughout the vasculature or when the patient has utilized all of the harvestable veins for other surgical procedures, thereby leaving no viable arterial graft alternative for the patient.
  • composition to address problem a copolymer polyester (combination of polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)) and bioactive agents: Anticoagulant (recombinant hirudin or Argatroban), antiproliferative (paclitaxel, everolimus, sodium butyrate and/or silencing siRNA), growth promoting (vascular endothelial growth factor, fibroblast growth factor) and/or antimicrobials (antibiotics, antimicrobial peptides, naturally-occurring antimicrobial proteins).
  • the shape is a straight tubular construct or tapered internal diameter; can also incorporate crimp or inner wall reinforcement to provide greater flexibility. Dimensions: 0.75mm internal diameter and larger (>40mm); length from 1 cm - 60 cm.
  • ESRD End-Stage Renal Disease
  • Synthetic grafts made of ePTFE are the current standards for synthetic vascular access grafts. These grafts have (depending on the study) comparable or worse primary patency rates than autogenous grafts and, similar to autogenous grafts, take a significant time to heal (at least 2 - 4 weeks) thereby preventing instant hemodialysis access. These prosthetic alternatives are also relatively stiff compared to the native vessels and have issues related to infection. The other issues associated with ePTFE grafts are seroma formation and occlusion due to intimal hyperplasia.
  • polyurethane, silicone and PET fibers have recently entered the market.
  • the graft has the self-sealing property and healing behavior comparable to ePTFE grafts. Additionally, VectraTM does not require a long healing time prior to the first puncture. However, the solid silicone film located within two layers of polyurethane in order to impart impermeability and self- sealing to the graft prevents complete healing of the graft. The high elasticity of the graft also causes kinking of the native vein resulting in stenosis.
  • composition to address problem a copolymer of polyethylene
  • PET terephthalate
  • PU polyurethane
  • Shape Straight tubular construct; incorporates crimp within mandrel to provide greater flexibility. Dimensions: 6-8mm internal diameter and smaller; length from 20 - 80cm.
  • This diluted solution was then electrospun onto Teflon-coated stainless steel mandrels with a spring loaded within the mandrel to create the crimped structure (40cm length; 6.2mm diameter), resulting in a graft with an internal diameter of 6mm and a length of 25cm.
  • the graft was then post-treated to remove any residual solvent by sonication in 100% ethanol for 30 minutes followed by sonication in distilled water for 2 minutes. Grafts were then air-dried overnight at room temperature for 72 hours.
  • VAD ventricular assist device
  • thrombosis/thromboembolic phenomenon and infection The annual healthcare cost for this major disorder is estimated at $10 to $40 billion. Significantly reducing these adverse complications would shift VAD use from "bridge to transplant” to "destination therapy", increasing the potential market from the current $100 million annually to $2.5 billion. Development of this technology may also have application for other implantable devices such as hemodialysis access grafts as well as medium-bore prosthetic arterial grafts and sewing cuffs comprised of polyester, in which thrombosis and infection are associated with their use.
  • composition to address problem a copolymer polyester (combination of polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)) and Bioactive Agents: Anticoagulant (recombinant hirudin , Argatroban or Bivalirudin) and
  • antimicrobials antibiotics, antimicrobial peptides, naturally- occurring antimicrobial proteins.
  • Shape Straight tubular construct; can also incorporate crimp or inner wall reinforcement to provide greater flexibility. Dimensions: 4mm internal diameter and larger; length from 5 cm - 60cm.
  • HFIP hexafluoroisopropanol
  • the mandrel set at a jet gap distance of 15cm from the tip of the needle, was then grounded to the power source.
  • the perfusion rate was set at 3ml per hour at 25°C, with perfusion of the polymer started upon application of the current to the tip of the needle (+15kV). Electrospinning time was increased from 60 minutes to 90 minutes in order to significantly increase wall thickness.
  • Staphylococcus aureus S. aureus
  • epidermidis S. epidermidis
  • Streptococci are shown to be responsible for 25-50% of all valve infections.
  • Perioperative parental antibiotics often fail to permeate the avascular spaces immediately around the biomaterial once pathogens have adhered.
  • the health care cost associated with treating PVE is projected to be greater than $60,000 per patient, with the annual market for cardiac surgery devices projected to range from $700 million to $1.4 billion.
  • valvular disease affects 2.5% of the United States population (this percentage is higher in older age groups). Over 90,000 mechanical and bioprosthetic valves are implanted in the United States each year, with over 280,000 valves implanted worldwide. While the emergence of transcatheter heart valve therapy will reduce selection of these devices for certain procedures, overall valve use is still projected to increase due to an aging population and, to a lesser extent, a more aggressive surgical approach to mitral valve insufficiency. Additionally, higher incidences of obesity and diabetes are expected to increase these numbers drastically. Currently, there are no clinically available infection-resistant prosthetic valves or sewing cuffs/annuloplasty rings. Due to the inertness of prosthetic valves, these annuloplasty rings and sewing cuffs are logical targets to provide localized antimicrobial delivery.
  • Composition to address problem Polymer: Combination of polyethylene terephthalate (PET) and polyurethane (PU), Bioactive Agents: Anticoagulant
  • Shape Ring shaped device, thickness can be varied. Dimensions: 5-35mm internal diameter.
  • the electrospun sewing cuff is a composite nanofibrous construct, involving electrospinning of two polymer solutions.
  • a 10% (w:v) PU polymer solution (Chronoflex C Polycarbonate Polyurethane; 80A Durometer) was prepared in ice-cold 100% HFIP.
  • the coated rods were washed in ethanol for 30 minutes with sonication, followed by a 2 minute sonication in distilled water to remove all traces of residual solvent.
  • the edge of the material was rolled towards the opposite end of the rod, while measuring the thickness of the BioCuff with calipers when approaching the desired thickness of the final product.
  • the material was then cut at the edge of the rolled sewing cuff.
  • the detached cuff was rolled off the remainder of the rod length and the edge fused to complete cuff formation. Cuffs were air-dried at room temperature.
  • EtO ethylene oxide
  • Cipro surface fluorescence
  • CVD cardiovascular disease
  • PCI percutaneous intervention
  • IH occurs primarily at the anastomosis, where the suture joins the vein to the artery.
  • ePTFE polytetrafluoroethylene
  • Dissolvable sutures have also been developed for microvascular anastomoses, but the inherent loss of mechanical strength over time, increased cytotoxicity from degradation factors, and the risk of dislodged suture particles forming an embolism are too great to justify their study in a clinical setting.
  • Alternatives to sutures have also been explored, but further work is needed before they are applicable for routine use.
  • a suture that will: a) locally deliver a naturally occurring SMC- specific antiproliferative agent, b) better match the elasticity of the adjoining vessels, and c) encourage natural long-term healing due to its nanofibrous morphology.
  • Polyester combination of polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)
  • PBT polybutylene terephthalate
  • Bioactive Agents Anticoagulant
  • Shape Yarn-like construct (nanofibrous single strand yarn); Dimensions: Thickness can be varied (0.025mm - 2mm); length can be varied from lm -2m. Can be made in a continuous fashion.
  • This device ensures an even coating onto the surface of the torus, while also creating alignment of polymer nanofibers in the toroidal/lengthwise direction of the electrospun coating.
  • This collecting surface was inserted into a custom- designed, computer- automated electrospinning unit. Sutures were electrospun for 5 minutes using a 3ml/hour flow r ate, +20kV applied voltage and 15 cm gap distance. After electrospinning, the tubular nanofibrous material was removed, manually twisted and elongated to its yield strain (300% of its original length) to create a suture. Each suture was then tightly coiled around a spool and placed into a vacuum oven (99.9% vacuum; 40°C, 24 hours). This process facilitates vaporization of residual HFIP while also increasing tensile strength as a result of cold working, annealing, and radially contracting the fibers.
  • Hemostatic devices were one of the treatments developed to reduce hemorrhage and save a soldier's lives. These devices are divided based on the application type into four categories 1) powders/granular agents, 2) solid materials, 3) flexible materials and 4) barrier agents or self-expanding gels. Powders are poured into the wounded areas and mostly work by absorbing fluids and low molecular weight products in the blood, thereby increasing the localized concentration of clotting factors and enhancing clot formation. The void remaining in technology for preventing wound hemorrhage on the battlefield is the rationale behind this BAA solicitation.
  • a light weight bioactive wound dressing/pack has been developed that provides the following characteristics: (1) Stop the bleeding quickly (2 minutes or less) and more efficiently at any point on the body (i.e. extremities or non-compressible wounds in the abdomen region) (2) Be easily applied by either a medic or by the wounded soldier themselves (3) Prevent wound infection resulting from a non-sterile environment via localized delivery of an antimicrobial agent (4) Provide direct pain-relief by controlled release of an analgesic agent (5) Be ready-to-use and requiring no special preparation/training (6) Be breathable to help wound healing and (7) Be stable under various climatic conditions for extended periods (-10°C to 40°C).
  • Composition to address problem Polymer: Polyester (combination of polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)), polyurethane or combination of polyester and polyurethane; Bioactive Agents: Coagulant (thrombin), antimicrobials (antibiotics, antimicrobial peptides, naturally- occurring antimicrobial proteins) and/or analgesic; Shape: Flat narrow material (dressing), rounded tampon shaped, or two flat electrospun materials joined together via ultrasonic welding or heat setting and containing super-absorbent polymer in the mid-portion; Dimensions: Variable width, length and thickness. In one embodiment, the width and length are each about 1 cm.
  • a nanofibrous bioactive hemostatic device prototype has been developed using electrospinning technology. Unlike any other hemostatic wound dressing present in the market, advanced wound dressing (A WD) has two components that work in a synergistic fashion to provide a multi-purpose hemostatic device.
  • the first layer immediate to the wound contains an active agent that rapidly promotes blood clotting.
  • the second layer has antibiotic and analgesics to ease pain, aid recovery and prevent harmful life threatening infections.
  • the materials comprising these layers are made of polyester (PET).
  • PET polymer was selected due to its inertness, ease of electrospinning with drugs, ease of surface modification, soft feel, toughness and flexibility of the final electrospun product.
  • the blood-contacting layer is electrospun PET which is further modified to create reactive groups along the surface of the nanofibrous layer. These functional groups are utilized to bind a potent coagulation enzyme onto the surface of the dressing.
  • This pro-coagulant is adsorbed electrostatically onto the surface of surface-modified electrospun PET, stabilizing the coagulant for long-term storage.
  • the coagulant is immediately released locally within the wound upon contact with blood providing rapid clot formation.
  • Electrospinning also allows incorporation of selected drugs (antibiotic and analgesic agents) which help in the healing process. These not only retain their properties but also are released at a sustained rate as shown in benchtop assays. While the selected blood coagulant protein accelerates the wound clot formation, the antibiotic and analgesic agents prevent bacterial infection while easing wound pain, respectively.
  • the A WD can be cut into different geometries to treat wounds of various types and locations just like standard gauze.
  • the coagulant is a proven non-immunogenic natural enzyme that directly activates the coagulation pathway as compared to other indirect coagulation drugs, chemicals or additives.
  • the antimicrobial agent is a broad spectrum and third generation drug that is effective against a wide range of gram positive and gram negative bacteria encountered in the field under various combat scenarios.
  • the analgesic agent is also a potent drug which is presently a part of the medic kit. This will be the first time to our knowledge that all these agents will be delivered directly through a single hemostatic wound dressing.
  • SMCs is central to lesions of atherosclerosis and restenosis.
  • Metallic stent devices with either a bare metal surface (BMS) or drug-eluting surface (DES), have become widely utilized as a first option for patients with diseased blood vessels in which flow has been significantly restricted due to this proliferative event, thereby compromising organ or limb function.
  • Stents are preferred over standard surgical interventions such as vessel bypass due to less invasiveness of the procedure and accelerated patient recovery times.
  • restenosis rates after BMS placement range from less than 10% to as high as 58%, a significant problem based on the 1.1 million stents annually implanted.
  • BMS have also been prone to late-term thrombosis and thromboembolism formation.
  • Anti-platelet therapy is required in order to prevent thrombus formation on the stent until healing occurs.
  • a significant shift in the length of time for systemic anti-platelet therapy from 1 month minimum delivery to a now recommended minimum 1 year period has been implemented in order to drive down ST rates while attempting to allow healing to occur.
  • This treatment is being carried out at a significant risk in hemorrhagic complications to the patient.
  • any deviation in anti-platelet therapy administration significantly increases the risk of ST. Delivery of anti-proliferative agents, while effective at preventing SMC proliferation, also affects endothelial cells, resulting in delayed re-endothelialization and vascular inflammation.
  • Polyester combination of polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)
  • PBT polybutylene terephthalate
  • Bioactive Agents Anticoagulant
  • hirudin or Argatroban antiproliferative (paclitaxel, everolimus, sodium butyrate and/or silencing siRNA) and/or, growth promoting (vascular endothelial growth factor, fibroblast growth factor); Shape: Uniform thin coating of metallic stent;
  • Thickness can be varied (0.05mm - 0.30mm) as well as overall length.
  • hexafluoroisopropanol HFIP
  • This PET solution was then diluted 50% with HFIP, mixed for 1 hour and split in half.
  • 50 of DyLight 550 (DyLight; lOmg/ml) was added and mixed for 1 hour on an inversion mixer.
  • a 2mm internal diameter metallic stent (Medtronic, Inc.) was slid onto a 2mm Teflon-coated stainless steel mandrel. Both polymer solutions (with and without DyLight) were loaded into 5ml syringes and placed onto our computer-automated electrospinning apparatus.
  • the specific stent/mounting mandrel was set at a jet gap distance of 15cm from the tip of the needle and the perfusion rate set at 3ml per hour at 25°C. Perfusion of the polymer with DyLight was started upon application of the current (+15kV) with electrospinning proceeding for 3 minutes.
  • Top Layer Polyester (combination of polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)), polyurethane or combination of polyester and polyurethane.
  • Bottom Layer comprises a biodegradable polymers (polycaprolactone, polyglycolic acid and/or polylactic glycolic acid);
  • Bioactive Agents Growth promoting (vascular endothelial growth factor, fibroblast growth factor) and antimicrobials ((antibiotics, antimicrobial peptides, naturally- occurring antimicrobial proteins);
  • Shape Flat sheet with non-degradable layer on one side and a degradable polymer on the other Dimensions: Overall thickness can be varied (0.1mm - 0.5mm) as well as overall length.
  • Synthesis Procedure Two polymer solutions were prepared in ice-cold 100% HFIP.
  • the first solution prepared contained a mixture of polyurethane (PU) and polyethylene terephthalate (PET) polymers (7% and 3% w:v, respectively) with an antimicrobial agent.
  • the second solution was composed of a mixture of polycaprolactone (PCL) and polyglycolic acid (PGA) polymers (15% and 5% w:v, respectively) with an antimicrobial agent and growth promoting factor. Both solutions were mixed for 48 hours on an inversion mixer.
  • a self-contained computer-automated electrospinning apparatus was utilized for electrospinning.
  • a stainless steel 18-gauge blunt spinneret (0.5mm internal diameter) was connected to the polymer- filled syringe.
  • the collecting surface (mandrel) was set at a jet gap distance of 15cm from the tip of the needle.
  • the perfusion rate was set at 3ml per hour at 25°C. Perfusion of the polymer was then started upon application of the current to the tip of the needle (15-20kV) with electrospinning proceeding.
  • the PU-PET solution which was loaded into a 10ml syringe, was first electrospun onto a rotating 35mm cylindrical mandrel for 90 minutes (nPU-PET).
  • Residual HFIP on the resulting nPU-PET material was removed via sonication of the material in 100% ethanol for 30 minutes following by a sonication in water for 2 minutes. After 48 hours of drying, the PCL-PGA solution was electrospun onto the pre-existing nPU-PET polymer sheet on the mandrel, yielding the composite dermal scaffold (nPCL-PGA layer). This composite material was then vacuum-dried (600mm Hg) at 37°C for 24 hours to remove residual HFIP from the nPCL-PGA layer.
  • External bone fixation is a method of aligning broken bones when more conventional methods (casting, internal fixation) are precluded.
  • pins or wires are inserted into the bone and anchored by a rigid external frame to maintain proper orientation of the fracture. This can be accomplished for temporary stabilization pending definitive care, or can be used over a prolonged period to stabilize the fracture until union occurs.
  • external fixation can be used for many clinical applications including limb lengthening, deformity correction, and bone transport for treating critical sized bone defects. The most common complication of external fixation is pin site infection, with reported infection rates ranging dramatically in the literature from 11 - 52%.
  • Polyester combination of polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)
  • PBT polybutylene terephthalate
  • Bioactive Agents Antimicrobials
  • a polymer solution comprising polyethylene terephthalate (PET) with polybutylene terephthalate (PBT) (17.5% and 2% w:v, respectively) was prepared in ice-cold 100% HFIP and inversion mixed for 48 hours. This solution was then halved, and one half was kept unchanged to act as a control solution, while the other half was given 1.5% w:v of Gentamicin and mixed for another 24 hours.
  • a self-contained, computer automated electrospinning apparatus was utilized to coat the bone pin. This apparatus can electrospin onto cylindrical constructs, such as bone pins. A stainless steel 18-gauge blunt spinneret (0.5mm internal diameter) was connected to the polymer- filled syringe.
  • One smooth and one surface roughened (via sandblasting) 5mm diameter, 316L stainless steel rod (same material as a commercial bone pin) was positioned in a chuck to rotate at 270 RPMs while the spinneret was set to traverse a 4 inches length of the rod at a rate of 2 inches per second. This 4 inch length reflects the unthreaded portion of the actual bone pin (either left smooth, or sandblasted to improve adherence of the material) that would be coated.
  • the rod was set at a jet gap distance of 15 cm from the tip of the needle.
  • the perfusion rate was set at 3ml/hour and +20kV of voltage was applied to the spinneret at 25°C.
  • Electrosp inning of the polymer solution was then conducted for 10 minutes on one 4 inch section of each mandrel, and for 20 minutes on another 4 inch section of each mandrel.
  • a 70°C heat treatment at 99.99% vacuum was applied for 24 hours to seal loose fibers down to the bulk material and to remove all of the residual solvent.
  • CVCs central venous catheters
  • CVCs are necessary to deliver drugs, nutritive fluids, chemotherapy, hemodialysis therapy, or to take blood samples for testing without causing trauma to the patient.
  • CVCs are prone to failure due to three primary mechanisms: infection (3-14%), dislocation (10-19%), and thrombosis (1-2%). Infections are the primary concern with CVCs, since approximately 9-14% of pediatric patients with CVCs contract catheter-related bloodstream infections (CRBIs), the mortality rate for which is over 13%).
  • CRBIs catheter-related bloodstream infections
  • CVCs in pediatric patients have been reported to increase hospital stays by one week, and cost $39,219-$50,362 on average per infection, with an estimated 250,000 CRBIs occurring in the US each year8.
  • the other major concern is dislocation, where the CVC is accidently pulled out from the original site of implantation. T his occurs most frequently in pediatric patient populations because a child's tendency to pull on the protruding catheter tubing.
  • Bacterial infections of CVCs originate on either the catheter's external surface or within the luminal surface. Most infections and CBRIs are caused by the migration of bacteria from the skin down the external surface of the catheter, although these infections can also migrate down to the internal lumen from the hub.
  • Catheter infections in the lumen can be eradicated using a simple procedure called "antibiotic-, or ethanol-locks," in which either a heparinized antibiotic solution or a 70% ethanol solution is injected into the infected catheter lumen and held there for several hours. Yet, there is no comparable way to eradicate an established bacterial infection on the external surface of a catheter. Infection of the external surface requires complete removal of the CVC, possibly preventing the patient from receiving vital therapy or nutritive fluids. Thus, preventing the migration of bacteria from the skin is essential to reducing catheter infections and CRBIs.
  • Polyester combination of polyethylene terephthalate (PET) and polybutylene terephthalate; (PBT)
  • PBT polybutylene terephthalate
  • Bioactive Agents Antimicrobials
  • HFIP hexafluoroisopropanol
  • a segment of polyethylene catheter tubing (14cm length) with an inner diameter of 1.57mm and outer diameter at 2.08mm was used as a base material onto which the PU-PET solutions were electrospun.
  • nanofibrous materials with increased water moving (wicking) properties are provided.
  • Polyester polymers are electrospun as described elsewhere in this specification.
  • the materials are chemically treated (sodium hydroxide or ethylenediamine treated), resulting in surface functional groups.
  • the materials can be used in various constructs for different applications that require water/solution movement.
  • nanofibrous materials are provided to treat finger/toe nail and yeast infections (anti-fungal delivery).
  • Polyester polymers containing antifungal agents are electrospun as described elsewhere in this specification. The resulting materials are cut and adhered to artificial finger nail or can be formed into its own device (nail coating/tampon device).
  • nanofibrous materials with radiopaque properties are provided.
  • Polyester, polyurethane and/or a polyurethane/polyester combination with radiopaque agents may be synthesized as described elsewhere in this specification.
  • the materials are useful for sutures, device location and wound dressing.
  • nanofibrous materials are used as filtration devices.
  • Polyester polymers are electrospun as described elsewhere in this specification.
  • the materials are chemically treated (sodium hydroxide or ethylenediamine treated), resulting in surface functional groups.
  • Specific bioactive moieties can be immobilized to this material and used as a filtration medium to remove targeted agents.
  • a computer -automated electrospinning perfusion apparatus was assembled which included a power supply, a syringe pump, an elevated holding rack, a modified polyethylene chamber, a spray head with power attachment, a reciprocating system, and a stirrer for controlled mandrel rotation. Such an assembly is shown by FIG. 4.
  • a 10 ml chemical-resistant syringe was filled with the liquid polymer; and a stainless steel 18 gauge blunt spinneret (0.5 mm internal diameter) was cut in half, with the syringe fitting half connected to the chemical-resistant syringe.
  • Nalgene PVC tubing ( 1/32 ID.times. 3/32 OD; 66 cm length) was then connected to the syringe, followed by connection to the other half of the blunt spinneret within the spray head.
  • the line was purged of air, with the syringe then placed onto the syringe pump.
  • the high potential source was connected to the spray head tip; and the mandrel was set at a jet gap distance of 15 cm from the tip of the needle.
  • the mandrel was then grounded to the power source; and the perfusion rate was set at 3 ml/hour at 25°C.
  • a polyethylene terephthalate (20% w:v) polymer was prepared in ice-cold 100% hexafluoroisopropanol.
  • the 10 ml syringe with a stainless steel 18-gauge blunt spinneret (0.5 mm internal diameter) was filled with the solution and placed onto the Harvard Apparatus syringe pump.
  • nPET nanofibrous polyethylene terephthalate
  • a total of 4 nPET structures were synthesized for each method using the above-described process.
  • tubular wall rigidity may be desired for the various medical articles and devices to be employed clinically.
  • the chosen parameters employed for nPET material formation in these experimental studies were uniformly and consistently maintained at 40 minutes of electrosp inning time, a polymer concentration of 20%, an applied voltage (15 kV), and a gap distance of 15 cm.
  • DACRON segments 42 ⁇ 9 pounds force
  • electrospun nPET segments 3. ⁇ 0.9 pounds force
  • This difference in breaking load was expected owing to the significantly greater wall thickness of the knitted DACRON material.
  • the other physical properties such as the percent strain at maximum load (60 ⁇ 24 versus 55 ⁇ 8) and percent strain at break (60 versus 62 ⁇ 3), were comparable between the two test materials, indicating that the difference in break strength was directly related to wall thickness.
  • the nPET material is shown to possess significant physical characteristics that would permit its presence and application in various medical devices.
  • polyethylene terephthalate (19%) polymer solutions containing either Cipro, or Diflucan, or Paclitaxel (1.5% w:v) respectively were prepared.in ice-cold 100% hexafluoroisopropanol.
  • These individually prepared polymer solutions of Cipro, or Diflucan, or Paclitaxel were mixed on an inversion mixer for 48 hours in order to completely solubilize both the polyethylene terephthalate polymer and each active agent component in their respective individual solutions.
  • the self-contained, semi- automated electrospinning apparatus (described previously herein) was again employed for fabricating each version of nanofibrous textile material.
  • nPET segments, nPET-Cipro segments, and nPET -Diflucan segments were individually placed into 5 ml of phosphate buffered saline (PBS) followed by continuous agitation using Rugged Rotator inversion mixer (33 r.p.m.) at 37 °C. Wash solutions were sampled at acute (0, 1, 4 and 24 hours) and chronic (2-21 days for Cipro and 2-7 days for Diflucan) time periods, with replacement of the wash solution with a fresh 5 ml PBS after sampling. The absorbance of wash solutions were read at 322 nm (PBS blank) using a Beckman DU640 UV/VIS spectrophotometer.
  • Cipro concentrations ranging from 0-100 micrograms per ml was prepared. This Cipro standard curve was then used to extrapolate the antibiotic concentration within the wash solutions.
  • the release profiles for the nPET-Cipro segments are shown by FIG. 7, and the release profiles for the nPET -Diflucan segments are shown by FIG. 8. Notably, the release profiles for each type of segment are markedly different.
  • Cipro release within the first 4 hours was consistent at 5 ⁇ 2 micrograms per ml, and was followed by a sharp increase in rate to 13 ⁇ 4 micrograms per ml at 24 hours. Cipro release then decreased to 6 ⁇ 4 micrograms per ml by 48 hours, but persisted (ranging from 1-2 micrograms per ml ) throughout the time duration of this study (504 hours).
  • Cipro released has significant biological activity, owing to the low MIC 5 o for Cipro (0.26 micrograms per ml ).
  • Diflucan release followed typical first order kinetics in that the greatest release occurred within the first 24 hours (17, 12 and 11 micrograms per ml , respectively). This was followed by a slow sustained release over the remaining time periods over the 168 hour study period, the time duration of this study.
  • nPET segments containing Cipro and Diflucan demonstrated significant release of each active agent throughout the time periods empirically evaluated.
  • a stock solution of S. aureus was thawed at 37 °C for 1 hour. Upon thawing, 1 microlter of this stock was added to 5 ml of Trypticase Soy Broth (TSB) and incubated overnight at 37 °C. From this solution, 10 microliters was streaked onto Trypticase Soy Agar (TSA) plates. nPET segments and nPET-Cipro segments were individually embedded into the S.
  • Cipro Sensi-Discs The zone of inhibition created by the 5 micrograms Cipro Sensi-Discs was consistent at 23 mm.
  • the nPET-Cipro segment antimicrobial activity profile correlated with the Cipro release determined in the spectrophotometric studies—in that the greatest antimicrobial activity occurred within the first 48 hours.
  • Cipro antimicrobial activity presumably caused by lower Cipro concentrations being released over time as determined by the spectrophotometry, decreased slowly over the remaining time periods.
  • a broth macrodilution assay was performed based on the NCCLS M27-A protocol.
  • the stock fungal inoculum concentration was determined via backplating a set volume of the diluted fungus broth onto Trypticase Soy Agar plates. The number of colony forming units (cfu) grown per plate was then counted and extrapolated to determine the starting Candida concentration.
  • the stock fungus solution was then diluted to 10 6 , 10 5 and 10 4 cfu/ml. After incubating the individual test segments in 2 ml of the fungus solutions for 24 hours at 30 °C, the optical density of the broth solutions was measured at 492 nm. These values were compared to Candida solutions without any nPET materials (serving as the positive control) as well as against YM Broth only and Candida solutions with 40 micrograms Diflucan solution (both serving as negative controls).
  • nPET -Diflucan segments had significantly greater antifungal activity at all wash periods as compared to nPET segments which had no antifungal activity (turbidity comparable to Candida control). This is graphically shown by the data of FIG. 11.
  • Diflucan (40 micrograms) in solution demonstrated excellent antifungal activity against this inoculum, with decreasing activity as the inoculum increased. Antifungal activity by the nPET-Diflucan segments was clearly evident at all Candida concentrations evaluated with activity mimicking solution-based Diflucan (data not shown). Thus, this experimental study demonstrated that Diflucan is released from the electrospun nano fibrous material even after extensive washing for 2 days, with Diflucan maintaining it recognized and characteristic antifungal activity after synthesis of the nPET -Diflucan tubular structure.
  • a 10 ml chemical-resistant syringe was filled with the polymer liquid.
  • a stainless steel 18-gauge blunt spinneret (0.5 mm internal diameter) was then cut in half, with the syringe fitting end connected to the polymer- filled syringe.
  • Nalgene PVC tubing was connected to the syringe filled with the polymer solution followed by connection to the other half of the blunt spinneret within the spray head.
  • the line was then purged of air, with the syringe then placed onto the syringe pump.
  • the high potential source was connected to the spray head tip, with the plate set at a jet gap distance of 15 cm from the tip of the needle.
  • the perfusion rate was set at 3 ml/hour at 25 °C.
  • Perfusion of the polymer liquid was started upon application of the current to the tip of the needle (15 kV) with electrosp inning proceeding for 1 hour and 40 minutes, with rotation of the plate 20 ° every 20 minutes. This resulted in a flat, planar sheet of nPET nanofibrous material being formed. The resulting nPET sheet is illustrated by FIG. 12.
  • a flat sheet of electrospun nPET textile fabric (8 cm.times.10 cm) was formed using this alternative method and technology. When viewed in gross, the nPET planar sheet had excellent handling characteristics and possessed physical properties comparable to the nPET tubular structures.
  • the self-contained, semi-automated electrospinning apparatus can be employed to generate two different formats of nanofibrous textile fabrics.
  • One format is a tubular structure having determinable inner wall and outer wall diameter sizes, two open ends, and an internal lumen typically less than about 6 millimeters in diameter.
  • This tubular structure format presents an interior wall surface and an exterior wall surface, and is a conduit biocompatible with and suitable for the conveyance of liquids and gases through its internal lumen.
  • a second format is a flat or planar sheet construction having determinable, length, width, and depth dimensions.
  • the flat sheet fabric can be folded and refolded repeatedly; can be cut and sized to meet specific configurations; is resilient and can be prepared in advance to provide varying degrees of flexibility, springiness, suppleness, and elasticity.
  • agent-releasing textiles can be prepared for use as medical articles and devices using the present invention.
  • the agents are biologically active and well characterized; are incorporated in chosen concentrations as an ingredient in the bulk polymer prior to making the textile fabric; and become indefinitely attached to and non-permanently immobilized upon the fabricated nanofibrous textile material as a concomitant part of the process for manufacturing the textile.
  • the agent- releasing textile After being placed in a water containing environment, the agent- releasing textile will begin to take up water; release its incorporated biologically active agent in-situ over time; and deliver the release active agent at measurable concentrations directly into the adjacent and surrounding milieu.
  • the in-situ released agent is function, operative and potent; and provides/performs its well recognized and characteristic biologically activity whenever and wherever it is delivered.

Abstract

La présente invention concerne une construction en matériau nanofibreux bioactif qui est fabriquée à l'aide d'une méthodologie unique de perfusion par filage électrostatique. Un mode de réalisation fournit un matériau biocomposite nanofibreux formé en tant que tissu textile discret à partir d'un mélange liquide préparé constitué de : (i) un polymère synthétique durable non biodégradable ; (ii) un agent biologiquement actif ; et (iii) un véhicule organique liquide. Ces agents biologiquement actifs sont des composés chimiques qui conservent leur activité biologique reconnue à la fois avant et après avoir adopté une liaison non permanente au matériau textile formé ; et seront libérés ultérieurement in situ du tissu en tant qu'agents discrets librement mobiles lors d'une absorption d'eau de l'environnement ambiant.
PCT/US2015/033532 2014-06-02 2015-06-01 Matériaux nanofibreux en tant que médicament, protéine ou véhicules de libération génétique WO2015187555A1 (fr)

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US10166315B2 (en) 2015-05-04 2019-01-01 Nanofiber Solutions, Inc. Chitosan-enhanced electrospun fiber compositions
CN109811469A (zh) * 2019-02-20 2019-05-28 郑州大学 一种赋予聚合物微纳米纤维卷曲结构的方法
WO2021188814A1 (fr) * 2020-03-18 2021-09-23 Millennium Pharmaceuticals, Inc. Dispositif de chambre cellulaire implantable et ses utilisations

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US20110270411A1 (en) * 2009-09-02 2011-11-03 Nantong University Nerve graft prepared by electrostatic spinning, the preparing method and the special apparatus used therefor
US20120068384A1 (en) * 2005-03-04 2012-03-22 Phaneuf Matthew D Nanofibrous materials as drug, protein, or genetic release vehicles
WO2012097229A2 (fr) * 2011-01-14 2012-07-19 Neograft Technologies, Inc. Appareil servant à la génération de dispositifs pour greffe

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US20120068384A1 (en) * 2005-03-04 2012-03-22 Phaneuf Matthew D Nanofibrous materials as drug, protein, or genetic release vehicles
US20110270411A1 (en) * 2009-09-02 2011-11-03 Nantong University Nerve graft prepared by electrostatic spinning, the preparing method and the special apparatus used therefor
WO2012097229A2 (fr) * 2011-01-14 2012-07-19 Neograft Technologies, Inc. Appareil servant à la génération de dispositifs pour greffe

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Publication number Priority date Publication date Assignee Title
US10166315B2 (en) 2015-05-04 2019-01-01 Nanofiber Solutions, Inc. Chitosan-enhanced electrospun fiber compositions
CN109811469A (zh) * 2019-02-20 2019-05-28 郑州大学 一种赋予聚合物微纳米纤维卷曲结构的方法
WO2021188814A1 (fr) * 2020-03-18 2021-09-23 Millennium Pharmaceuticals, Inc. Dispositif de chambre cellulaire implantable et ses utilisations

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