WO2014137454A1 - Procédés et compositions permettant d'inhiber l'assemblage de cellules microbiennes se liant de façon irréversible à la surface de dispositifs médicaux - Google Patents

Procédés et compositions permettant d'inhiber l'assemblage de cellules microbiennes se liant de façon irréversible à la surface de dispositifs médicaux Download PDF

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Publication number
WO2014137454A1
WO2014137454A1 PCT/US2013/077084 US2013077084W WO2014137454A1 WO 2014137454 A1 WO2014137454 A1 WO 2014137454A1 US 2013077084 W US2013077084 W US 2013077084W WO 2014137454 A1 WO2014137454 A1 WO 2014137454A1
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WIPO (PCT)
Prior art keywords
mesh
poly
polymer
pouch
coating
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PCT/US2013/077084
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English (en)
Inventor
Daniel Jeremy Lerner
William Mcjames
Fatima Buevich
Satish Pulapura
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Tyrx, Inc.
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Publication of WO2014137454A1 publication Critical patent/WO2014137454A1/fr

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    • 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
    • A61L31/148—Materials at least partially resorbable by the body
    • 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
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • Prosthetic implants such as meshes, combination mesh products or other porous prostheses are commonly used to provide a physical barrier between types of tissue or extra strength to a physical defect in soft tissue.
  • such devices are often associated with post-surgical complications including post-implant infection, pain, excessive scar tissue formation and shrinkage of the prosthesis or mesh.
  • Excessive scar tissue formation, limited patient mobility, and chronic pain are often attributed to the size, shape, and mass of the implant and a variety of efforts have been undertaken to reduce the amount of scar tissue formation. For example, lighter meshes using smaller fibers, larger weaves, and/or larger pore sizes as well as meshes woven from both non- resorbable and resorbable materials are in use to address these concerns.
  • Post-operative infection is tied to a number of different elements: lack of host defense mechanisms, the clinical site where the surgery is performed, the length of the surgery, and bacteria present at the time of device implantation. 5
  • the general health of the patient i.e., the host factor
  • the general health of the patient is always important; however, since many patients requiring surgery are compromised in some way--and there is little that can be done to mitigate that factor-- controlling the other two factors becomes important.
  • Controlling the inoculation levels is the third component to the intra- and post-operative surgical infection control triad.
  • One aspect to microbial control is the use antibiotics.
  • one practice advocates the administration of systemic antibiotics within 60 minutes prior to incision, with additional dosing if the surgery exceeds 3 hours. 5
  • Such pre-incision administration has shown some positive effects on the incidence of infection associated with the placement of pacemakers.
  • 7 Surgeons also routinely wash the surgical site with an antimicrobial agent such as an Iodophor or antibiotic or a combination of agents . None of these procedures have been standardized nor have they been found to be efficacious.
  • An adjunctive approach to managing the potential for implant contamination has been the introduction of antimicrobial agents on implantable medical devices . 8,9
  • CFUs colony forming units
  • bacteria such as Staphylococcus can produce bacteremia within a short time after implantation (i.e., within 90 days) with a device or lay dormant for months before producing an active infection so eradication of the bacterial inoculum at the time of implantation is key and may help to reduce late-stage as well as early-stage device- related infections.
  • the combination of rifampin and minocycline has demonstrated antimicrobial effectiveness as a coating for catheters and other implanted devices, including use of those drugs in a non-resorbable coating such as silicone and polyurethane . 13 ' 19-21
  • the combination of rifampin and minocycline has also been shown to reduce the incidence of clinical infection when used as a prophylactic coating on penile implants.
  • U.S. Ser. No. 11/672,929 describes a bioresorbable polymer coating on a surgical mesh as a carrier for the antimicrobial agents rifampin and minocycline.
  • Such meshes can be fashioned into a pouch of various sizes and shapes to match the implanted pacemakers, pulse generators, defibrillators and other implantable medical devices.
  • the addition of the antimicrobial agents permits the pouch to deliver antimicrobial agents at the implant site and thus to provide a barrier to microbial colonization of a CRM during surgical implantation as an adjunct to surgical and systemic infection control .
  • CRM infection increased the risk of in- hospital death more than 2-fold.
  • Staphylococcus aureus S. aureus
  • coagulase-negative Staphylococci such as S. epidermidis
  • Staphylococcal species including methicillin-resistant S. aureus (MRSA)
  • MRSA methicillin-resistant S. aureus
  • Cardiac device infections by these microorganisms most often occur within the generator pocket, and are believed to be due mainly to local contamination at the time of device implantation. Studies have shown that approximately 30% of the patients with pocket infections also had bacteremia. In most cases, whether the patient presents with bacteremia or not, infection of the intravascular portion of the lead is often present, generally caused by progression of the infection from the generator pocket. Due to the ineffectiveness of systemic antibiotics to penetrate through tissue and reach high enough concentrations to eradicate the localized device contamination and pocket infection, as well as the involvement of generator and leads, the prevailing medical opinion is that surgical removal of the generator and leads is the most effective treatment once a pocket infection is diagnosed. This type of surgical treatment is both costly and risky for patients dependent on the device. The estimated cost to treat each infection is $32,000, with total estimated costs of all device-related infections estimated at $640 million per year, excluding the costs of device replacement.
  • Coating antimicrobial agents directly onto implantable medical devices or impregnating such devices with antimicrobial agents can potentially eliminate or reduce the microorganism burden at implant, and has been proposed to provide a device with "long lasting resistance to staphylococcal biofilm colonization" by coating or impregnating rifampin and minocycline, or rifampin and novobiocin, on the surface of an indwelling medical devices (Abstract, U.S. Pat. No. 5, 217, 493 and generally, U.S. Pat. Nos. 5,624,704 and 5,902,283).
  • impregnation of central venous catheters with a combination of rifampin and minocyclin has been associated with a reduction of catheter-associated bacteremia.
  • these impregnated devices have minimal capacity to elute the antimicrobial agents into the surrounding tissue and little if any ability to deliver it in more than miniscule quantities by virtue of the methodology employed to coat or impregnate the drugs.
  • These limitations may make prevention or reduction of biofilm formation less effective, and may increase the development of resistant strains by eluting such low quantities of drug such that all organisms are not eradicated .
  • the present invention demonstrates that a pouch made of biopolymer/polypropylene mesh incorporated with one or more antimicrobial drugs is effective at preventing bacteria from colonizing the device and forming biofilms.
  • the present invention addresses these needs (preventing or inhibiting infections) as well as others, such as pain relief and inhibition or reduction of scar tissue, fibrosis and the like, by providing temporarily stiffened meshes formed into pouches or other receptacles to hold an implantable medical device upon implantation.
  • the present invention relates to pouches, coverings and the like made from implantable surgical meshes comprising one or more biodegradable polymer coatings.
  • the mesh pouches of the invention can be shaped as desired into pouches, bags, coverings, shells, skins, receptacles and the like to fit any implantable medical device.
  • Preferred meshes of the invention are comprised of woven polypropylene coated with one or more biodegradable polymer to impart drug elution or other temporary effects .
  • pouch means any pouch, bag, skin, shell, covering, or other receptacle made from an implantable surgical mesh comprising one or more biodegradable polymer coatings and shaped to encapsulate, encase, surround, cover or hold, in whole or in substantial part, an implantable medical device.
  • the pouches of the invention have openings to permit leads and tubes of the IMD to extend unhindered from the IMD though the opening of the pouch.
  • the pouches may also have porosity to accommodate monopolar devices that require the IMD to be electrically grounded to the surrounding tissue.
  • the coated surgical meshes can be formed to encapsulate a pacemaker, a defibrillator, a generator, an implantable access system, a neurostimulator, or any other implantable device for the purpose of securing them in position, providing pain relief, inhibiting scarring or fibrosis and/or inhibiting bacterial growth.
  • Such coated meshes are formed into an appropriate shape either before or after coating with the biodegradable polymers .
  • the pouches of the invention may act as medical prostheses (providing support to or "stabilizing" the device and the tissue surrounding the area of implant, e.g., to minimize movement of the device in the body of the patient), and are thus also referred to as medical prostheses .
  • the pouches of the invention comprise a mesh and one or more coating which temporarily stiffens the mesh to at least 1.1 times its original stiffness.
  • the coatings on such meshes do not alter the integrity of the mesh and thus allow the mesh to remain porous.
  • the coatings do not substantially alter the porosity of the mesh.
  • the pouches of the invention comprise a mesh with one or more coatings with at least one of the coatings comprising a stiffening agent (s) that coats the filaments or fibers of the mesh so to temporarily immobilize the contact points of those filaments or fibers.
  • the coatings on such meshes do not alter the integrity or strength of the underlying mesh and allow the mesh to remain porous after coating.
  • the coatings do not substantially alter the porosity of the mesh.
  • the meshes are capable of substantially reverting to their original stiffness under conditions of use.
  • the stiffening agents i.e., as applied in the coatings of the invention, can selectively, partially or fully coat the contact points of the filaments or said fibers of the mesh to create a coating.
  • the contact points generally include the knots of woven meshes.
  • Such coating can be positioned on the mesh in a templated pattern or in an array such as might be deposited with ink jet type technology, including computer controlled deposition techniques . Additionally, the coatings can be applied on one or both sides of the mesh.
  • the stiffening agents include hydrogels, either alone or in combination with one or more biodegradable polymers.
  • the stiffening agent is one or more biodegradable polymers, and can be applied in layers.
  • One or more biodegradable polymers can be used per individual coating layer.
  • Preferred biodegradable polymer comprises one or more tyrosine-derived diphenol monomer units as polyarylates , polycarbonates or polyiminocarbonates .
  • the pouches of the invention have at least one of the coatings that further comprise one or more drugs.
  • drugs include, but are not limited to, antimicrobial agents, anesthetics, analgesics, anti-inflammatory agents, anti-scarring agents, anti-fibrotic agents, leukotriene inhibitors as well as other classes of drugs, including biological agents such as proteins, growth inhibitors and the like.
  • the biodegradable polymer coatings are capable of releasing one or more drugs into surrounding bodily tissue and proximal to the device such that the drug reduces or prevents implant- or surgery-related complications .
  • an anesthetic agent in the coating that predictably seeps or elutes into the surrounding bodily tissue, bodily fluid, or systemic fluid, one has a useful way to attenuate pain experienced at the implantation site.
  • replacing the anesthetic agent with an antiinflammatory agent provides a way to reduce the swelling and inflammation associated implantation of the mesh, device and/or pouch.
  • one has a way to provide a rate of drug release sufficient to prevent colonization of the mesh pouch, the CRM or other IMD and/or the surgical implantation site by bacteria for at least the period following surgery necessary for initial healing of the surgical incision.
  • the pouches of the present invention are suitable for the prevention and/or retardation of biofilm formation on an implantable medical device.
  • the present method is directed to implanting, in a subject, a medical device which is enveloped or covered, in whole or in part, in a polymer pouch (including both fully resorbable and partially resorbable or non-resorbable pouches) which elute one or more antimicrobial agents in amounts effective to prevent or retard biofilm formation on the device, preferably for an extended period of time.
  • the non-resorbable pouch is a polymer-coated polypropylene mesh that elutes drug.
  • the polymer pouch is a moldable and resorbable composition consisting essentially of (i) one or more one resorbable polymers and (ii) one or more antimicrobial agents in amounts effective to prevent biofilm formation .
  • the coatings on the pouches of the invention can deliver multiple drugs from one or more independent layers, some of which may contain no drug.
  • the invention thus provides a method of delivering drugs at controlled rates and for set durations of time using biodegradable, resorbable polymers from a coating on a surgical mesh formed as a pouch of the invention.
  • [ 0032 ] is a method of retarding biofilm formation on an implantable medical device which comprises: (a) enveloping or covering said device, in whole or in part, in a polymer pouch comprising a polymer-coated mesh pouch comprising one or more resorbable polymers coated on the mesh and including one or more antimicrobial agents in amounts effective to retard biofilm formation; and (b) implanting said enveloped device in a subject; and wherein an average minimum log reduction in CFU is about 1 to about 4. In some embodiments, the log reduction is about 1 to about 3. In some embodiments, the average log reduction is about 3.
  • the polymer-coated mesh pouch comprises one or more resorbable polymers coated on the mesh.
  • the one or more antimicrobial agents inhibit biofilm formation by one or more of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, S. Capitis, S. lugdunenis or Acinetobacter baummanii.
  • the one or more antimicrobial agents inhibit biofilm formation by one or more of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, S. Capitis, S. lugdunenis or Acinetobacter baummanii.
  • the implantable medical device is a cardiac rhythm management device (CRMD), a neurostimulator, a pulse generator, a drug pump or infusion device, a physiological monitoring device, or a textured or smooth breast implant.
  • the implantable medical device is a CRMD selected from the group consisting of a pacemaker, a defibrillator, an implantable cardioverter defibrillator (ICD), and a cardiac resynchronization therapy defibrillator (CRT device).
  • the coating comprises two or more layers, and at least one layer of the coating comprises at least one antimicrobial agent and at least one biocompatible polymer.
  • the at least one antimicrobial agent comprises rifampin and minocycline.
  • the at least one antimicrobial agent comprises rifampin and minocycline.
  • the amounts of rifampin and minocyline in the coating ranges from about 60-140 g/cm 2 for each of rifampin and minocycline.
  • the coating comprises about 0.5-1.5 mg resorbable polymer/cm 2 .
  • the tyrosine-based polyarylates comprise a DTE-27.5% DT succinate polyarylate .
  • the method of claim 13 wherein the resorbable polymer is DTE-27.5% DT succinate polyarylate.
  • a device comprising a mesh having at least one bioresorbable polymer coating, said device at least partially covering at least a portion of an implanted medical device, wherein said device prevents, mitigates, or lessens a growth of a biofilm on said implanted medical device.
  • the device is porous.
  • the device is formed from knitted, braided, woven or non-woven fibers .
  • the mesh is formed of at least one bioresorbable polymer.
  • the at least one bioresorbable polymer coating comprises a tyrosine-derived polyesteramide.
  • the tyrosine-derived polyesteramide is a member of the P22 family of tyrosine-derived polyesteramides. In some embodiments, a percentage of free acid in the P22 family of tyrosine-derived polyesteramides ranges from about 5% to about 40%. In some embodiments, a percentage of free acid in the P22 family of tyrosine-derived polyesteramide is about 27.5%.
  • the coating comprises a tyrosine-derived polyesteramide and at least one polymer selected from the group consisting of polylactic acid, polyglycolic acid, poly ( L-lactide ) (PLLA), poly ( D, L-lactide ) (PLA) polyglycolic acid [polyglycolide (PGA)], poly(L- lactide-co-D, L-lactide ) (PLLA/PLA) , poly ( L-lactide-co- glycolide) (PLLA/PGA) , poly(D, L-lactide-co-glycolide ) (PLA/PGA) , poly ( glycolide-co-trimethylene carbonate)
  • PGA/PTMC poly (D, L-lactide-co-caprolactone) (PLA/PCL), poly ( glycolide-co-caprolactone ) (PGA/PCL) , poly ( oxa ) esters , polyethylene oxide (PEO) , polydioxanone (PDS), polypropylene fumarate, polyethyl glutamate-co-glutamic acid), poly(tert- butyloxy-carbonylmethyl glutamate), polycaprolactone (PCL), polycaprolactone co-butylacrylate, polyhydroxybutyrate
  • PBT polyhydroxybutyrate
  • poly (phosphazene ) poly (phosphate ester)
  • poly (amino acid) polydepsipeptides
  • polyiminocarbonates poly[(97.5% dimethyl-trimethylene carbonate ) -co- ( 2.5% trimethylene carbonate)]
  • poly ( orthoesters ) tyrosine-derived polycarbonates, tyrosine- derived polyiminocarbonates, tyrosine-derived polyphosphonates , polyethylene oxide, polyalkylene oxides, and hydroxypropylmethylcellulose .
  • the active agent is an antimicrobial agent, an anesthetic, a procoagulant agent, or an anti-inflamatory agent.
  • the antimicrobial agent is selected from the group consisting of antibiotics, antiseptics, and disinfectants.
  • the antibiotic is selected from the group consisting of tetracyclines, penicillins, macrolides, rifampin and combinations thereof.
  • the antibiotic comprises a combination of minocycline and rifampin .
  • FIG. 1 graphically depicts the zone of inhibition (ZOI) for polyarylate-coated meshes containing rifampin and minocycline hydrochloride that have been incubated on Staphylococcus aureus lawns for the indicated times (Example 1) .
  • the symbols represent the following meshes: P22-25 20 passes; ⁇ , P22-25 40 passes; A, P22-25 80 passes; x, P22-27.5 20 passes; *, P22-27.5 40 passes; ⁇ , P22-27.5 80 passes; and I , catheter .
  • FIG. 2 graphically depicts cumulative bupivacaine release from multilayer polyarylate-coated meshes.
  • FIG. 3 graphically depicts cumulative bupivacaine release from multilayer polyarylate-coated meshes having various loadings of bupivacaine.
  • the symbols represent the following meshes: P22-27.5 (11 passes, 1 dip); ⁇ , P22-27.5 (11 passes, 2 dips); and A, P22-27.5 (2 passes, 2 dips).
  • FIG. 4 graphically depicts the time course of dermal anesthesia from 1 x 2 cm surgically implanted, polyarylate meshes containing 7.5 mg/cm 2 bupivacaine. Meshes were implanted in rats by subcostal laparotomy; pin-prick responses were determined and are shown as % pain response inhibition (see Examples for details). The "*" indicates statistically significant response at p ⁇ 0.05 compared to the baseline pin-prick response.
  • FIG. 5 graphically depicts mesh stiffness.
  • the bars, from top to bottom, represent the stiffness for (1) a PPM3 mesh without a polyarylate coating and without sterilization, (2) a ProleneTM (Ethicon) mesh sterilized with ethylene oxide, (3) a polyarylate-coated PPM3 mesh 12 months after coating and sterilized by gamma irradiation with a nitrogen flush, and (4) a polyarylate-coated PPM3 mesh 12 months after coating and sterilized by gamma irradiation.
  • ProleneTM Ethicon
  • FIG. 6 graphically depicts the change in mesh stiffness over time during the course of polymer degradation for a polymer-coated polypropylene mesh soaking in PBS.
  • FIG. 7 depicts micrographs of a tyrosine polyarylate-coated mesh.
  • the top left panel shows the woven nature of the mesh and the contact points of the filaments .
  • the bottom left panel demonstrates the coating over the contact points of the mesh filaments.
  • the right panel is a scanning electron micrograph of a coated filament.
  • FIG. 8 provides an optical image of a mesh having a tyrosine polyarylate coating containing rifampin and minocycline. On the left, the optical image; on the right, a schematic thereof indicating the areas of intense orange color by the circled areas filled with diagonal lines .
  • FIG. 9 shows a schematic diagram of a polymer- coated CRM pouch with the CRM inserted in the pouch.
  • FIG. 10 is a picture of a polymer-coated pouch containing a CRM.
  • FIG. 11 is a micrograph showing the implant site of a coated-mesh pouch with device at 14 weeks post-implantation (4x magnification) .
  • FIG. 12 depicts the number of bacteria associated with experimental (AIGIS Rx TM) and control envelopes after 72 hours at room temperature.
  • the control and experimental envelopes were removed from the reactors after 72 hours of incubation at room temperature and processed as described to create bacterial suspensions and the number of bacteria associated with each envelope were determined.
  • the numbers of viable bacteria associated with the control and experimental envelopes are expressed as logio CFU/envelope .
  • FIG. 13 Number of bacteria associated with enclosed and unenclosed titanium coupons from experimental and control reactors . Titanium coupons were removed from the reactors after 72 hours of incubation at room temperature and processed as described to create bacterial suspensions and determine the number of bacteria associated with the titanium coupons.
  • CE control/enveloped coupons
  • EE experimental/enveloped coupons
  • CU control/unenveloped (exposed) coupons
  • EU experimental/unenveloped (exposed) coupons .
  • FIG. 14 depicts the number of bacteria in control and experimental reactor fluids after 24, 48, and 72 hours at room temperature. Fluids from the control and experimental reactors were removed after 24, 48, and 72 hours of incubation at room temperature and the number of viable bacteria in the samples was determined. The numbers of viable bacteria found in the control and experimental reactor fluids are expressed as logio CFU/mL.
  • FIG. 15 depicts the S. aureus biofilm formation on control and experimental envelopes at different magnifications after 72 hours of incubation at room temperature.
  • A Control, 500x:
  • B Control l,500x;
  • C Experimental, 500x;
  • D Experimental, l,500x.
  • FIG. 16 depicts the explantation and sampling procedure.
  • A Aseptic surgical exposure of the implant pocket 7 days after implantation demonstrates a biofilm on the device inoculated with S. epidermidis.
  • B In contrast to (A) , the pocket containing the device within an antimicrobial pouch is free of the biofilm material.
  • C Aseptic swabbing of a device implanted without an antimicrobial pouch demonstrates formation of biofilm material,
  • D Removal of the device from the antimicrobial pouch demonstrates a device surface free of the biofilm material.
  • FIG. 17 depicts the macroscopic and scanning electron microscopic analysis of biofilm formation on implanted pacing cans with or without the antimicrobial pouch with Acinetobacter baummnanii inoculation.
  • A Macroscopic appearance of the pacing devices following dehydration, prior to gold sputter-coating. The pacing can on the left was implanted within an antimicrobial pouch, while the pacing can on the right was implanted without an antimicrobial pouch.
  • B SEM of the surface of the device shown on the left in (A)
  • C SEM of the surface of the device shown on the right in (A) .
  • FIG. 18 depicts the confocal microscopy images of the implanted devices with and without the AIGIS Rx TM.
  • FIG. 19 depicts the gross scanning electron microscopy images of the implanted devices with and without the AIGIS Rx TM.
  • FIG. 20 depicts the scanning electron microscopy images of the implanted devices with and without the AIGIS Rx TM.
  • FIG. 21 graphically depicts the average minimum log reduction in antibacterial activity for a non-resorbable device coated with a mesh comprising two antimicrobials.
  • FIG. 22 graphically depicts the average minimum log reduction in antibacterial activity for a resorbable device coated with a mesh comprising two antimicrobials.
  • Biofilm formation and development on a medical device occurs in distinct stages.
  • a surface e.g., the surface of a medical device or implant
  • This attachment step depends upon a number of factors, including the composition or material comprising the device surface, as well as the surface texture, surface charge, and hydrophobicity of the device surface.
  • microbes typically adhere more readily to polymeric surfaces than metallic surfaces, rough surfaces more readily than smooth surfaces, and hydrophobic surfaces more readily than hydrophilic surfaces.
  • the charge of the device surface can also play a role: microorganisms, including staphylococci, are more likely to bind positively-charge polymer surfaces than negatively-charge surfaces .
  • host proteins are thought to play a vital role in the attachment of microbes to device surfaces.
  • Implanted devices rapidly become coated with a film of host-derived proteins including fibronectin, fibrinogen fibrin, albumin, collagen, lamina vitronectin, elastin, and von Willebrand factor (vWf ) .
  • host-derived proteins including fibronectin, fibrinogen fibrin, albumin, collagen, lamina vitronectin, elastin, and von Willebrand factor (vWf ) .
  • Many of these proteins most notably fibronectin, fibrinogen fibrin and vWf promote and enhance the binding of Gram-positive cocci, Gram-negative bacilli, and Candida albicans.
  • the second stage, irreversible adhesion occurs when organisms bind irreversibly to a surface via microbial cell surface adhesins and become extremely resistant to extreme shear stress.
  • Biofilms can comprise Gram- negative, Gram positive bacteria, and/or yeasts. Commonly isolated Gram-positive organisms include S. aureus, S. epidermis (and other coagulase-negative staphylococci), enterococci, and streptococci.
  • Gram- negative bacilli include Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.
  • Acinetobacter spp . and Candida spp. can also form biofilms.
  • Biofilms formed on medical devices can comprise a single organism or multiple types of organisms, including both bacteria and yeast.
  • the method of the present invention for preventing and/or retarding biofilm formation on implantable medical devices susceptible to the formation of biofilms comprises enveloping or covering the medical device with a pouch as described herein, comprising one or more antimicrobial agents
  • the method of the present invention is particularly suitable for the prevention or retardation of biofilms for medical devices particularly susceptible to the formation of biofilms (e.g., vascular catheters, explanted catheter leads, cardiovascular rhythm management devices, breast implants, etc.) or for surgical procedures in which biofilm formation is of particular concern or in which it is difficult to avoid contamination of the surgical site with biofilm forming microorganisms .
  • medical devices particularly susceptible to the formation of biofilms (e.g., vascular catheters, explanted catheter leads, cardiovascular rhythm management devices, breast implants, etc.) or for surgical procedures in which biofilm formation is of particular concern or in which it is difficult to avoid contamination of the surgical site with biofilm forming microorganisms .
  • the pouches of the invention are formed from the coated implantable surgical meshes and comprise a surgical mesh and one or more biodegradable polymer coating layers with each coating layer optionally, and independently, further containing a drug.
  • the physical, mechanical, chemical, and resorption characteristics of the coating enhance the clinical performance of the mesh and the surgeon's ability to implant the device. These characteristics are accomplished by choosing a suitable coating thickness and the biodegradable polymer.
  • a mesh in accordance with the invention is any web or fabric with a construction of knitted, braided, woven or non-woven filaments or fibers that are interlocked in such a way to create a fabric or a fabric-like material.
  • “mesh” also includes any porous prosthesis suitable for temporarily stiffening.
  • Surgical meshes are well known in the art and any such mesh can be coated as described herein.
  • the meshes used in the present invention are made from biocompatible materials, synthetic or natural, including but not limited to, polypropylene, polyester, polytetrafluoroethylene, polyamides and combinations thereof.
  • One of the advantages of the present invention is that the coatings can be used with any commercially available mesh.
  • a preferred mesh is made from woven polypropylene. Pore sizes of meshes vary. For example the Bard Marlex.RTM mesh has pores of 379 ⁇ 143 micrometers or approx. 0.4 mm, whereas the Johnson and Johnson Vypro®. mesh has pores of 3058 ⁇ 62 micrometers or approx. 3 mm.
  • the stiffening agents of the invention include hydrogels, biodegradable polymers and any other compound capable of imparting temporary stiffness to the mesh in accordance with the invention.
  • Temporary stiffness means that, relative to the corresponding uncoated mesh material, there is an increase in stiffness when one or more coatings are applied in accordance with the invention. Upon use, those coatings then soften or degrade over time in a manner that causes the mesh to revert back to its original stiffness, revert nearly back to its original stiffness or sufficient close to its original stiffness to provide the desired surgical outcome and the expected patient comfort.
  • the prosthesis can be evaluated in vitro or in vivo.
  • a coating can be applied to the mesh and then the mesh left in a physiological solution for a period of time before measuring its stiffness.
  • the time period of stiffness is controlled by the degradation rate (for biodegradable polymers) or absorption ability (for hydrogels).
  • the time period can vary from days, to weeks or even a few months and is most conveniently determined in vitro.
  • Meshes with that revert to their original stiffness in vitro within a reasonable time (from 1 day to 3-4 months) are considered to be temporarily stiffened.
  • animal models can be used to assess temporary stiffness by implanting the mesh and then removing it from the animal and determining if its stiffness had changed. Such in vivo results can be correlated with the in vitro results by those of skill in the art. Methods to measure stiffness of a mesh or a coated mesh are known in the art .
  • a hydrogel is composed of a network of water- soluble polymer chains. Hydrogels are applied as coatings and dried on the mesh. Upon use, e.g., implantation in the body, the hydrogel absorbs water and become soft (hydrogels can contain over 99% water), thereby increasing the flexibility of the mesh and reverting to the original or near original stiffness of the mesh. Typically, hydrogels possess a degree of flexibility very similar to natural tissue, due to their significant water content. Common ingredients for hydrogels, include e.g. polyvinyl alcohol, sodium polyacrylate, acrylate polymers and copolymers with an abundance of hydrophilic groups .
  • Meshes can have one or more polymer coatings and can optionally include drugs in the coatings.
  • Meshes with a single coating are useful to improve handling of the mesh during surgical implantation and use.
  • Meshes with drugs can be coated with single or multiple layers, depending on the amount of drug to be delivered, the type of drug and desired release rate.
  • Each layer can contain the same or different polymers, the same or different drugs, and the same or different amounts of polymers or drugs.
  • a first coating layer can contain drug, while the second layer coating layer contains either no drug or a lower concentration of drug.
  • the biodegradable coating deposited onto the surface of the mesh gives the mesh superior handling characteristics relative to uncoated meshes and facilitates surgical insertion because it imparts stiffness to the mesh and thereby improves handling thereof. Over time, however, the coating resorbs, or the stiffening agents degrades or softens, to leave a flexible mesh that provides greater patient comfort without loss of strength.
  • the surgical mesh can be coated with the biodegradable polymer using standard techniques such as spray or dip coating to achieve a uniform coating having a thickness that provides at least 1.1 to 4.5 and more preferably 1.25 to 2 times the stiffness of the uncoated mesh.
  • the coating is optimized to provide for a uniform, flexible, non-flaking layer that remains adhered to the mesh throughout the implantation and initial wound healing process.
  • the polymer coating must maintain its integrity for at least 1 week.
  • Optimal coating solutions are obtained by choosing a biodegradable polymer with a solubility between about 0.01 to about 30% in volatile solvents such as methylene chloride or other chlorinated solvents, THF, various alcohols, or combinations thereof.
  • biodegradable polymers with a molecular weight between about 10,000 and about 200,000 Daltons . Such polymers degrade at rates that maintain sufficient mechanical and physical integrity over about 1 week at 37°C. in an aqueous environment.
  • a biodegradable polymer-coated implantable mesh is described in which the biodegradable polymer layer (i.e., the coating) has a chemical composition that provides relatively good polymer-drug miscibility.
  • the polymer layer can contain between 1-80% drug at room temperature as well as between 1-95%, 2-80%, 2-50%, 5-40%, 5- 30%, 5-25% and 10-20% drug or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% drug as well as 5% increments from 10-95%, i.e., 10, 15, 20, 25, etc.
  • the biodegradable polymer coating releases drug for at least 2-3 days. Such release is preferred, for example, when the drug is an analgesic to aide in localized pain management at the surgical site.
  • Such loading and release characteristics can be also be obtained for drug polymer-combinations that do not have good miscibility by using multiple layering techniques .
  • the biodegradable polymer for use with the mesh pouch has a chemical composition complementary to the drug so that the polymer layer can contain between 2- 50% drug at room temperature.
  • the layer can contain as much as 80-90% drug and acts as drug reservoir (or depot layer) and drug release can be controlled by using multiple layers with varying amounts of drug (from none, to a few percent, saturation or above the solubility limit for the drug in the polymer) .
  • the anesthetic and/or analgesic should be delivered to the injured tissue shortly after surgery or tissue injury.
  • a drug or drugs for inclusion in the coatings on the pouches of the invention include, but are not limited to analgesics, anti-inflammatory agents, anesthetics, antimicrobial agents, antifungal agents, NSAIDs, other biologies (including proteins and nucleic acids) and the like.
  • Antimicrobial and antifungal agents can prevent the mesh pouch, the device and/or the surrounding tissue from being colonized by bacteria.
  • One or more drugs can be incorporated into the polymer coatings on the mesh pouches of the invention.
  • a mesh pouch of the invention has a coating comprising an anesthetic such that the anesthetic elutes from the implanted coated mesh to the surrounding tissue of the surgical site for between 1 and 10 days, which typically coincides with the period of acute surgical site pain.
  • delivery of an antimicrobial drug via a mesh pouch of the invention can create an inhibition zone against bacterial growth and colonization surrounding the implant during the healing process (e.g., usually about 30 days or less) and/or prevent undue fibrotic responses.
  • biodegradable polymer coatings avoids the issue of drug solubility, impregnation or adherence in or to the underlying device since a coating having suitable chemical properties can be deposited onto the mesh, optionally in concert with one or more drugs, to provide for the release of relatively high concentrations of those drugs over extended periods of time.
  • a coating having suitable chemical properties can be deposited onto the mesh, optionally in concert with one or more drugs, to provide for the release of relatively high concentrations of those drugs over extended periods of time.
  • a clinically- efficacious amount of anesthetic drug can be loaded onto a mesh pouch to assure sufficient drug elution and to provide surgical site, post-operative pain relief for the patient.
  • the mesh pouch should elute from about 30 mg to about 1000 mg of anesthetic over 1-10 days, including, e.g., about 30, 50, 100, 200, 400, 500, 750 or 1000 mg over that time period.
  • the pouch should elute clinically effective amounts of anesthetic during the acute post-operative period when pain is most noticeable to the patient. This period, defined in several clinical studies, tends to be from 12 hours to 5 days after the operation, with pain greatest around 24 hours and subsiding over a period of several days thereafter. Prior to 12 hours, the patient is usually still under the influence of any local anesthetic injection given during the surgery itself. After the 5-day period, most of the pain related to the surgery itself (i.e., incisional pain and manipulation of fascia, muscle, and nerves) has resolved to a significant extent .
  • Bupivacaine has a known toxicity profile, duration of onset, and duration of action. Drug monographs recommend the daily dose not to exceed 400 mg. Those of skill in the art can determine the amount of anesthetic to include in a polymer coating or a hydrogel coating to achieve the desired amount and duration of pain relief. Moreover, anesthetics that contain amines, such as lidocaine and bupivacaine, are hydrophobic and are difficult to load in sufficient amounts into the most commonly used plastics employed in the medical device industry, such as polypropylene and other non- resorbable thermoplastics.
  • sustained release depot systems for post-operative pain relief reported in the literature is a PLGA microsphere-based sustained release formulation of bupivacaine. This formulation was developed and tested in humans for relief of subcutaneous pain as well as neural blocks. Human trials indicated that subcutaneous pain was relieved via injection of between 90 to 180 mg of bupivacaine which then eluted into the surrounding tissue over a 7-day period, with higher concentrations in the initial 24-hour period followed by a gradual taper of the concentration.
  • Other depot sustained-release technologies have successfully suppressed post-operative pain associated with inguinal hernia repair. For example, external pumps and PLGA microsphere formulations have each purportedly release drug for approximately 72 hours .
  • the polymer does not act as a control mechanism for release of the anesthetic, but rather acts as a binder to hold the non-dissolved, anesthetic particles together and alters the crystallization kinetics of the drug.
  • a second coating layer which may or may not contain further anesthetic, is sprayed on top of the first layer.
  • the anesthetic concentration is at a higher ratio of polymer to anesthetic, e.g., a concentration at which the anesthetic is soluble in the polymer layer .
  • the top layer thus can serve to control the release of the drug in the bottom layer (aka depot layer) via the drug-polymer solubility ratio. Moreover, it is possible to alter the release rate of the drug by changing the thickness of the polymer layer and changing the polymer composition according to its water uptake. A polymer that absorbs a significant amount of water within 24 hours will release the contents of the depot layer rapidly. However, a polymer with limited water uptake or variable water uptake (changes as a function of its stage of degradation) will retard release of the water soluble anesthetic agent.
  • the biodegradable polymer coating releases drug for at least 2-3 days. Such release is preferred, for example, when the drug is an analgesic to aide in localized pain management at the surgical site.
  • the anesthetic and/or analgesic should be delivered to the injured tissue shortly after surgery or tissue injury.
  • the coating comprises an anesthetic such that the anesthetic elutes from the implanted coated mesh to the surrounding tissue of the surgical site for between 1 and 10 days, which typically coincides with the period of acute surgical site pain.
  • delivery of an antimicrobial drug via a mesh of the invention can create an inhibition zone against bacterial growth and colonization surrounding the implant during the healing process (e.g., usually about 7-30 days or less) and/or prevent undue fibrotic responses.
  • biodegradable polymer coatings avoids the issue of drug solubility, impregnation or adherence in or to the underlying device since a coating having suitable chemical properties can be deposited onto the mesh pouch, optionally in concert with one or more drugs, to provide for the release of relatively high concentrations of those drugs over extended periods of time.
  • a clinically-efficacious amount of anesthetic drug can be loaded onto a mesh pouch to assure sufficient drug elution and to provide surgical site, postoperative pain relief for the patient.
  • the coatings on the pouches of the invention are formed from biodegradable polymeric layers that optionally contain one or more drugs .
  • Methods of making biodegradable polymers are well known in the art.
  • the biodegradable polymers suitable for use in the invention include but are not limited to:
  • polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly ( L-lactide ) (PLLA) , poly ( D, L-lactide ) (PLA) , polyglycolic acid [polyglycolide (PGA)], poly (L-lactide-co-D, L-lactide) (PLLA/PLA) , poly(L- lactide-co-glycolide ) (PLLA/PGA) , poly ( D, L-lactide-co- glycolide) (PLA/PGA) , poly ( glycolide-co-trimethylene carbonate) (PGA/PTMC), poly (D, L-lactide-co-caprolactone)
  • PLA/PCL poly ( glycolide-co-caprolactone )
  • PGA/PCL poly ( glycolide-co-caprolactone )
  • polyethylene oxide PEO
  • polydioxanone PDS
  • polypropylene fumarate poly (ethyl glutamate-co-glutamic acid), poly ( tert-butyloxy-carbonylmethyl glutamate), polycaprolactone (PCL) , polycaprolactone co-butylacrylate, polyhydroxybutyrate (PHBT) and copolymers of polyhydroxybutyrate, poly (phosphazene ) , polyphosphate ester), poly (amino acid), polydepsipeptides, maleic anhydride copolymers, polyiminocarbonates , poly [(97.5% dimethyl- trimethylene carbonate ) -co- ( 2.5% trimethylene carbonate)], poly ( orthoesters ) , tyrosine-derived polyarylates , tyrosine- derived polycarbonates, tyrosine-derived polyiminocarbonates, tyrosine-derived polyphosphonates ,
  • biodegradable polymers of the invention have diphenol monomer units that are copolymerized with an appropriate chemical moiety to form a polyarylate, a polycarbonate, a polyiminocarbonate , a polyphosphonate or any other polymer .
  • the preferred biodegradable polymers are tyrosine- based polyarylates including those described in U.S. Pat. Nos.
  • biodegradable polymers suitable for use in the methods of the present invention include those described in U.S. application Ser. Nos. 12/499,399; 12/500,852; 12/564,736; 12/598,559; 12/641,996; as well as those described in U.S. Patent Publication No. 2009/0088548.
  • DTE is the diphenol monomer desaminotyrosyl-tyrosine ethyl ester
  • DTBn is the diphenol monomer desaminotyrosyl-tyrosine benzyl ester
  • DT is the corresponding free acid form, namely desaminotyrosyl- tyrosine.
  • BTE is the diphenol monomer 4-hydroxy benzoic acid- tyrosyl ethyl ester
  • BT is the corresponding free acid form, namely 4-hydroxy benzoic acid-tyrosine .
  • P22 is a polyarylate copolymer produced by condensation of DTE with succinate.
  • P22-10, P22-15, P22-20, P22-xx, etc. represents copolymers produced by condensation of (1) a mixture of DTE and DT using the indicated percentage of DT (i.e., 10, 15, 20 and xx % DT, etc.) with (2) succinate .
  • Additional preferred polyarylates are copolymers of desaminotyrosyl-tyrosine (DT) and an desaminotyrosyl-tyrosyl ester (DT ester), wherein the copolymer comprises from about 0.001% DT to about 80% DT and the ester moiety can be a branched or unbranched alkyl, alkylaryl, or alkylene ether group having up to 18 carbon atoms, any group of which can, optionally have a polyalkylene oxide therein.
  • another group of polyarylates are the same as the foregoing but the desaminotyrosyl moiety is replaced by a 4- hydroxybenzoyl moiety.
  • Preferred DT or BT contents include those copolymers with from about 1% to about 30%, from about 5% to about 30% from about 10 to about 30% DT or BT .
  • Preferred diacids include succinate, glutarate and glycolic acid.
  • Additional biodegradable polymers useful for the present invention are the biodegradable, resorbable polyarylates and polycarbonates disclosed in U.S. provisional application Ser . No. 60/733,988, filed Nov. 3, 2005 and in its corresponding PCT Appln. No. PCT/US06/42944, filed Nov. 3, 2006.
  • These polymers include, but are not limited to, BTE glutarate, DTM glutarate, DT propylamide glutarate, DT glycineamide glutarate, BTE succinate, BTM succinate, BTE succinate PEG, BTM succinate PEG, DTM succinate PEG, DTM succinate, DT N-hydroxysuccinimide succinate, DT glucosamine succinate, DT glucosamine glutarate, DT PEG ester succinate, DT PEG amide succinate, DT PEG ester glutarate and DT PEG ester succinate.
  • the most preferred polyarylates are the DTE-DT succinate family of polymers, e.g., the P22-xx family of polymers having from 0-50%, 5-50%, 5-40%, 1-30% or 10-30% DT, including but not limited to, about 1, 2, 5, 10, 15, 20, 25, 27.5, 30, 35, 40%, 45% and 50% DT .
  • polyarylate polymers used in the present invention can have from 0.1-99.9% PEG diacid to promote the degradation process as described in U.S. provisional application Ser . No. 60/733, 988. Blends of polyarylates or other biodegradable polymers with polyarylates are also preferred.
  • Any drug, biological agent or active ingredient compatible with the process of preparing the mesh pouches of the invention can be incorporated into one or more layers of the biodegradable polymeric coatings on the mesh. Doses of such drugs and agents are known in the art. Those of skill in the art can readily determine the amount of a particular drug to include in the coatings on the meshes of the invention.
  • drugs suitable for use with the present invention include anesthetics, antibiotics (antimicrobials), anti-inflammatory agents, fibrosis-inhibiting agents, anti- scarring agents, leukotriene inhibitors /antagonists , cell growth inhibitors and the like.
  • drug is used to include all types of therapeutic agents, whether small molecules or large molecules such as proteins, nucleic acids and the like.
  • the drugs of the invention can be used alone or in combination.
  • any pharmaceutically acceptable form of the drugs of the present invention can be employed in the present invention, e.g., the free base or a pharmaceutically acceptable salt or ester thereof.
  • Pharmaceutically acceptable salts for instance, include sulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate, citrate, phosphate and the like.
  • non-steroidal anti-inflammatories include, but are not limited to, naproxen, ketoprofen, ibuprofen as well as diclofenac; celecoxib; sulindac; diflunisal; piroxicam; indomethacin ; etodolac; meloxicam; r- flurbiprofen ; mefenamic; nabumetone; tolmetin, and sodium salts of each of the foregoing; ketorolac bromethamine; ketorolac bromethamine tromethamine ; choline magnesium trisalicylate ; rofecoxib; valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and its sodium salt; salicylate esters of alpha, beta, gamma-tocopherols and tocotrienols (and all their D, L, and racemic isomers); and the methyl,
  • anesthetics include, but are not limited to, lidocaine, bupivacaine, and mepivacaine .
  • Further examples of analgesics, anesthetics and narcotics include, but are not limited to acetaminophen, clonidine, benzodiazepine, the benzodiazepine antagonist flumazenil, lidocaine, tramadol, carbamazepine, meperidine, zaleplon, trimipramine maleate, buprenorphine, nalbuphine, pentazocain, fentanyl, propoxyphene, hydromorphone , methadone, morphine, levorphanol, and hydrocodone .
  • Local anesthetics have weak antibacterial properties and can play a dual role in the prevention of acute pain and infection.
  • antimicrobials include, but are not limited to, triclosan, chlorhexidine, rifampin, minocycline (or other tetracycline derivatives), vancomycin, daptomycin, gentamycin, cephalosporins and the like.
  • the coatings contain rifampin and another antimicrobial agent, preferably that agent is a tetracycline derivative.
  • the coatings contain a cephalosporin and another antimicrobial agent.
  • Preferred combinations include rifampin and minocycline, rifampin and gentamycin, and rifampin and minocycline.
  • antibiotic and antibacterial can be used interchangeably with the term antimicrobial .
  • Further antimicrobials include aztreonam; cefotetan and its disodium salt; loracarbef; cefoxitin and its sodium salt; cefazolin and its sodium salt; cefaclor; ceftibuten and its sodium salt; ceftizoxime; ceftizoxime sodium salt; cefoperazone and its sodium salt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil; ceftazidime; cefotaxime and its sodium salt; cefadroxil; ceftazidime and its sodium salt; cephalexin; cefamandole nafate; cefepime and its hydrochloride, sulfate, and phosphate salt; cefdinir and its sodium salt; ceftriaxone and its sodium salt; cefixime and its sodium salt; cefpodoxime proxetil; meropenem and its sodium salt; imipenem
  • antifungals include amphotericin B; pyrimethamine; flucytosine; caspofungin acetate; fluconazole; griseofulvin; terbinafin and its hydrochloride, sulfate, or phosphate salt; ketoconazole ; micronazole; clotrimazole; econazole; ciclopirox; naftifine; and itraconazole.
  • drugs that can be incorporated into the coatings on the mesh pouches of the invention include, but are not limited to, keflex, acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin, daunomycin, plumbagin, atropine, quinine, digoxin, quinidine, biologically active peptides, cephradine, cephalothin, cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid, chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus, cyclosporins, 5-fluorouracil and the like.
  • anti-inflammatory compound examples include, but are not limited to, anecortive acetate; tetrahydrocortisol, 4, 9 ( 11 ) -pregnadien-17. alpha . , 21-diol-3, 20-dione and its -21- acetate salt; 11-epicortisol ; 17. alpha .
  • leukotriene inhibitors/antagonists include, but are not limited to, leukotriene receptor antagonists such as acitazanolast, iralukast, montelukast, pranlukast, verlukast, zafirlukast, and zileuton.
  • leukotriene receptor antagonists such as acitazanolast, iralukast, montelukast, pranlukast, verlukast, zafirlukast, and zileuton.
  • Another useful drug that can be incorporated into the coatings of the invention is sodium 2-mercaptoethane sulfonate (Mesna) .
  • Mesna has been shown to diminish myofibroblast formation in animal studies of capsular contracture with breast implants [Ajmal et al . (2003) Plast. Reconstr. Surg. 112:1455-1461] and may thus act as an anti- fibrosis agent.
  • one method to coat the mesh with a stiffening agent is to spray a solution of polymer to coat the filaments or fibers of the mesh to temporarily immobilize contact points of the filaments or fibers of said mesh.
  • This method comprises (a) preparing a coating solution comprising a solvent and the stiffening agent; (b) spraying a mesh one or more times to provide an amount of solution on the mesh to produce a coating having a thickness and placement sufficient to temporarily immobilize contact points of the filaments or fibers of the mesh that coats filaments or fibers; and (c) drying the mesh to produce said coating.
  • An example of ratio of coating thickness to polymer coating is shown in the scanning electron micrograph of FIG. 7. When used with a drug (or combination of drugs), the drug is included in the coating solution at the desired concentration .
  • Spraying can be accomplished by known methods.
  • the coating can be applied to the entire mesh or to that portion of the mesh necessary to stiffen it.
  • One technique is to dip the mesh in the coating material; another is to push the mesh through rollers that transfer the coating on the mesh.
  • Spraying the mesh with microdroplets is also effective.
  • Techniques for selectively coating only those areas necessary to stiffen the mesh include deposition the coating through a template or mask that exposes only the desired areas of coverage for the coating, including dispensing the coating with micro needles or similar means. More preferably the coating can be applied using a photoresist-like mask that expose the desired portions, applying the coating over the photomask and the removing the photomask.
  • the coated meshes can be laser cut to produce the desired shaped and sized pouches, coverings and the like.
  • the pouches can be shaped to fit relatively snugly or more loosely around the implantable medical device. Two pieces can be sealed, by heat, by ultrasound or other method known in the art, leaving one side open to permit insertion of the device at the time of the surgical procedure and to allow the leads or other wires to extend out of the pouch stick out/protrude.
  • the mesh pouches of the invention have a space or opening sufficient to allow the leads from the device to pass through the pouch. The number of spaces or opening in the pouch that are provided can match the number and placement of the leads or other tubes extending from the CRM or other IMD, as applicable for the relevant device.
  • the shape and size of the pouch of the invention is similar to that of the CRM or IMD with which it is being used, and the pouch has a sufficient number of openings or spaces to accommodate the leads or tubing of the particular CRM or other IMD.
  • the pouches of the invention are porous from the mesh but can have additional porosity.
  • additional porosity can be imparted by laser cutting additional holes in the coated mesh porous pouches.
  • the pouch need not completely encase or surround the IMD.
  • An IMD is thus substantially encapsulated, encased, surrounded or covered when the pouch can hold the device and at least 20%, 30%, 50%, 60%, 75%, 80%, 85%, 90%, 95% or 98% of the device is within the pouch.
  • Porous pouches and partially encased pouches permit contact with tissue and body fluids and are particularly useful with monopole CRM or other IMD devices. Porosity will contribute to the percentage of the IMD covered by the pouch. That is, an IMD is considered to be 50% covered if it is completely surrounded by a pouch that is constructed of a film with 50% voids or holes.
  • the CRMs and other IMDs used with the pouches of the invention include but are not limited to pacemakers, defibrillators, implantable access systems, neurostimulators , other stimulation devices, ventricular assist devices, infusion pumps or other implantable devices (or implantable components thereof) for delivering medication, hydrating solutions or other fluids, intrathecal delivery systems, pain pumps, or any other implantable system to provide drugs or electrical stimulation to a body part.
  • CRMs Implantable cardiac rhythm management devices
  • IMDs are a form of IMDs and are life-long medical device implants. CRMs ensure the heart continually beats at a steady rate. There are two main types of CRM devices: implantable cardiac rhythm management devices and implantable defibrillators.
  • the ICDs, or implantable cardioverter defibrillator, and pacemakers share common elements. They are permanent implants inserted through relatively minor surgical procedures. Each has 2 basic components: a generator and a lead.
  • the generator is usually placed in a subcutaneous pocket below the skin of the breastbone and the lead is threaded down and into the heart muscle or ventricle.
  • the common elements of placement and design result in shared morbidities, including lead extrusion, lead-tip fibrosis, and infection.
  • infection rates are purportedly quite low, infection is a serious problem as any bacterial contamination of the lead, generator, or surgical site can travel directly to the heart via bacterial spreading along the generator and leads. Endocarditis, or an infection of the heart, has reported mortality rates as high as 33%.
  • An ICD is an electronic device that constantly monitors heart rate and rhythm. When it detects a fast, abnormal heart rhythm, it delivers energy to the heart muscle. This action causes the heart to beat in a normal rhythm again in an attempt to return it to a sinus rhythm.
  • the ICD has two parts: the lead(s) and a pulse generator.
  • the lead(s) monitor the heart rhythm and deliver energy used for pacing and/or defibrillation (see below for definitions).
  • the lead(s) are directly connected to the heart and the generator.
  • the generator houses the battery and a tiny computer. Energy is stored in the battery until it is needed.
  • the computer receives information on cardiac function via the leads and reacts to that information on the basis of its programming .
  • the different types of ICDs include, but are not limited to, single chamber ICDs in which a lead is attached in the right ventricle. If needed, energy is delivered to the ventricle to help it contract normally; dual chamber ICDs in which the leads are attached in the right atrium and the right ventricle. Energy is delivered first to the right atrium and then to the right ventricle to ensure that the heart beats in a normal sequence; and biventricular ICDs in which leads are attached in the right atrium, the right ventricle and the left ventricle. This arrangement helps the heart beat in a more balanced way and is specifically used for patients with heart failure .
  • a pacemaker is a small device that sends electrical impulses to the heart muscle to maintain a suitable heart rate and rhythm.
  • a pacemaker can also be used to treat fainting spells (syncope), congestive heart failure, and hypertrophic cardiomyopathy.
  • Pacemakers are generally implanted under the skin of the chest during a minor surgical procedure.
  • the pacemaker is also comprised of leads and a battery-driven pulse generator.
  • the pulse generator resides under the skin of the chest.
  • the leads are wires that are threaded through the veins into the heart and implanted into the heart muscle. They send impulses from the pulse generator to the heart muscle, as well as sense the heart's electrical activity.
  • Each impulse causes the heart to contract.
  • the pacemaker may have one to three leads, depending on the type of pacemaker needed to treat your heart problem.
  • the different types of pacemakers include, but are not limited to single chamber pacemakers which use one lead in the upper chambers (atria) or lower chambers (ventricles) of the heart; dual chamber pacemakers which use one lead in the atria and one lead in the ventricles of your heart; and biventricular pacemakers which use three leads: one placed in the right atrium, one placed in the right ventricle, and one placed in the left ventricle (via the coronary sinus vein) .
  • the pouches of the invention can thus be designed to fit a wide range of pacemakers and implantable defibrillators from a variety of manufacturers (see Table 1) . Sizes of the CRMs vary and typically size ranges are listed in Table 1.
  • Implantable neurostimulators are similar to pacemakers in that the devices generate electrical impulses. These devices send electrical signals via leads to the spine and brain to treat pain and other neurological disorders.
  • the neurostimulation can be used to treat chronic pain (especially back and spinal pain) ; when the leads are implanted in the brain, the neurostimulation can be used to treat epilepsy and essential tremor including the tremors associated with Parkinson's disease and other neurological disorders.
  • Neurostimulation can be used to treat severe, chronic nausea and vomiting as well as urological disorders. For the former, electrical impulses are sent to the stomach; for the latter, the electrical impulses are sent to the sacral nerves in the lower back.
  • the implant location of the neurostimulator varies by application but, in all cases, is placed under the skin and is susceptible to infection at the time of implantation and post-implantation. Likewise, reintervention and replacement of batteries in the neurostimulators can occur at regular intervals .
  • the pouches of the invention can thus be designed to fit a wide range of neurostimulators from a variety of manufacturers (see Table 2 ) . Sizes of the neurostimulators vary and typically size ranges are listed in Table 2 .
  • Reported infection rates for first implantation are usually quite low (less than 1%); however, they increase dramatically when a reintervention is necessary. Reintervention often requires the removal of the generator portion of the ICD, pacemaker, neurostimulator , drug pump or other IMD and having a resorbable pouch enhances that process.
  • IMDs for use in the invention are drug pumps, especially pain pumps and intrathecal delivery systems. These devices generally consist of an implantable drug pump and a catheter for dispensing the drug.
  • the implantable drug pump is similar in size to the neurostimulators and CRMs.
  • Further implantable medical devices include, but are not limited to, implantable EGM monitors, implantable access systems, or any other implantable system that utilizes battery power to provide drugs or electrical stimulation to a body part.
  • Antimicrobial efficacy of the pouches of the invention can be demonstrated in laboratory (in vitro), for example, using the modified Kirby—Bauer Antibiotic Susceptibility Test (Disk Diffusion Test) (in vitro) to assess bacterial zones of inhibitions or by the Boburden Test Method (in vitro) . In such experiments, a small disk of the pouch is cut and used. Antimicrobial efficacy can also be demonstrated in vivo using animal models of infection. For example, a pouch and device combination are implanted in an animal, the surgical site is deliberately infected with a pathogenic microorganism, such as Staphylococcus aureus or Staphylococcus epidermis, and the animal is monitored for signs of infection and inflammation. At sacrifice, the animal is assessed for inflammation, fibrosis and bacterial colonization of the pouch, device and the surrounding tissues.
  • a pathogenic microorganism such as Staphylococcus aureus or Staphylococcus epidermis
  • the ability to sample the explanted device and pocket by the multiple swabbing technique assures a thorough sampling of all devices areas, and the additional vortex/ sonication process allows additional sampling of adherent bacteria in a quantitative manner that would allow demonstration of log-reduction of the number of bacteria present .
  • the polymers are the polyarylates P22-xx having xx being the % DT indicated in Table 3.
  • Rxx or Mxx indicates the percentage by weight of rifampin (R) or minocycline (M) in the coating, i.e., R10M10 means 10% rifampin and 10% minocycline hydrochloride with 80% of the indicated polymer.
  • Table 3 provides a list of these polyarylates with their % DT content, exact sample sizes, final coating weights and drug coating weights .
  • ZOI Zone of Inhibition
  • FIG. 1 shows the total ZOI on S. aureus for meshes with 10% each of minocycline hydrochloride and rifampin in a DTE-DT succinate polyarylate coating having 25% or 27.5% DT.
  • the catheter is a COOK SPECTRUM venous catheter impregnated with rifampin and minocycline hydrochloride.
  • Table 6 shows that the duration of in vitro drug release increases with the hydrophilicity of the resorbable polymer. Solvent cast films were soaked in PBS and antibiotic release was monitored by HPLC. Table 6
  • FIG. 2 shows the cumulative release of bupivacaine into PBS from the multilayer polyarylate coating as a function of time. Nearly 80% of the bupivacaine had been released after 25 hours of incubation.
  • FIG. 3 is an example of the changes in release characteristics that can be achieved by altering both the amount of drug in the depot layer and the thickness of the outer layer. These coated surgical meshes are much stiffer than their uncoated counterparts.
  • Rats with jugular cannulas for pharmacokinetic studies were surgically implanted with a 1. times.2 cm P22-27.5 polyarylate-coated mesh containing 7.5 mg of bupivacaine/cm 2 .
  • baseline pin-prick responses to nociception were measured at the planned surgical incision site, and baseline blood samples were obtained.
  • a hernia was created by incision into the peritoneal cavity during via subcostal laparotomy, and a Lichtenstein non-tension repair was performed using the bupivacaine-impregnated polyarylate-coated mesh. Blood samples were drawn at 3, 6, 24, 48, 72, 96, and 120 hours after implantation.
  • the rats Prior to drawing blood, the rats were subjected to a pin prick test to assess dermal anesthesia from bupivacaine release.
  • the behavioral results indicate that moderate levels of dermal anesthesia appeared from 3 to 120 hours, with the amount at 6 and 48 hours significantly above baseline (p ⁇ 0.05) .
  • Pharmacokinetic analysis indicates that the plasma bupivacaine levels fit a one-compartment model with first-order absorption from 0 to 24 hours.
  • a polypropylene mesh was spray coated as described in the first paragraph of Example 2. Individual meshes were cut to 1. times.2 cm, individually packaged, and sterilized by gamma irradiation. The mesh was loaded with 7.5 mg/cm 2 of bupivacaine HC1 for a total of 15 mg of bupivacaine loaded per 1 x 2 cm mesh.
  • a 2.5 cm skin incision was made 0.5 cm caudal to and parallel to the last rib.
  • the underlying subcutaneous space (1 cm on both sides of the incision) was loosened to accommodate the mesh.
  • a 2 cm incision was made through the muscle layers along the same plane as the skin incision, penetrating the peritoneal cavity and the peritoneum was closed with 6-0 Prolene sutures in a continuous suture pattern. Rather than suturing the inner and outer oblique muscles using the classic "tension closure, " a Lichtenstein "non-tension” repair was undertaken using the mesh as the repair material.
  • the mesh prepared in Section A was positioned over the incisional hernia, and sutured into the internal and external oblique muscles using 6-0 Prolene sutures.
  • the subcutaneous tissue was then sutured in a continuous pattern with 6 to 8 6-0 Prolene sutures to prevent the rats from accessing the mesh, followed by 6 to 8 skin sutures.
  • Total surgical time was 10 min for anesthetic induction and preparation and 20 min for the surgery.
  • the rats were allowed to recover in their home cages, and monitored post-surgically until they awoke. Blood samples were drawn for determination of plasma bupivacaine levels at 3, 6, 24, 48, 72, 96, and 120 hours after surgery. The rats were assessed for guarding the incision, and the incision was assessed for signs of inflammation, swelling or other signs of infection. No rats exhibited toxicity or seizures, or were in a moribund state from infection or the release of bupivacaine .
  • the nociceptive pin prick test was used to assess dermal anesthesia (Morrow and Casey, 1983; Kramer et al . , 1996; Haynes et al . , 2000; Khodorova and Strichartz, 2000). Holding the rat in one hand, the other hand was used to apply the pin. Nociception was indicated by a skin-flinch or by a nocifensive (i.e., startle or attempt to escape) response from the rat. While the presence of the mesh interfered with the skin flinch response, nocifensive response remained completely intact .
  • An optical image of the coated mesh is shown in the top left panel of FIG. 7 at a magnification that readily shows the woven nature of the mesh and the contact points of the filaments.
  • a close up of a contact point is shown in the bottom left panel of FIG. 7 and demonstrates that the coating immobilizes the contact points of the mesh filaments.
  • the right panel of FIG. 7 is a scanning electron micrograph of a coated filament .
  • FIG. 8 shows an optical image of a mesh from Example 1, i.e., coated with polymer, rifampin and minocycline.
  • this photograph shows the mesh on a blue background with the filaments appearing greenish with some orange and the knots (or filament contact points) appearing mostly solid orange.
  • the orange color is due to the antibiotics and is more visible on the knots due to the greater surface area of the mesh in that region.
  • the color differentiation is difficult to visualize in the black and white version of this photograph so on the right panel the areas of orange are indicated by circled areas filled with diagonal lines.
  • the antimicrobial pacemaker pouch is a dual component (resorbable and non-resorbable ) , sterile prosthesis designed to hold a pacemaker pulse generator or defibrillator to create a stable environment when implanted in the body.
  • the pouch is constructed of a non-resorbable mesh comprised of knitted filaments of polypropylene and a bioresorbable polyarylate coating on the mesh containing the antimicrobial agents rifampin and minocycline.
  • the antimicrobial agents are released for a minimum of 7 days followed by full resorption of the polymer, leaving a light-weight permanent mesh incorporated into the tissue and providing a stable environment for the pacemaker or defibrillator (see FIGS. 9 and 10) .
  • the mesh for the pouch can be prepared in the same manner as antimicrobial polymer-coated surgical meshes described in U.S. provisional application 60/771,827, filed Feb. 8, 2006.
  • the pouch is constructed of two pieces of flat, coated mesh placed one on top of the other and sealed and cut into the shape using an ultrasonic weld. This results in the formation of a pouch 2.5'' x 2.75'' in size, sealed on approximately 3 and one-half sides, and coated with approximately 50 to 75 mg of polymer and 6.1 mg of rifampin and 6.1 mg of minocycline (of 86.11 .mu.g/cm 2 for each drug) .
  • Such pouches can be designed to fit a wide range of pacemakers, implantable defibrillators, neurostimulators and other IMDs (see Table 1 and 2) .
  • CDC Biofilm Reactor System The CDC biofilm reactor (CDC-BR) system was developed by the Centers for Disease Control and Prevention, Atlanta, Ga., to assess biofilm formation and prevention on surfaces and devices .
  • Two CDC-BR model CBR90 bioreactors (Biosurface Technologies Corporation, Bozeman, Mont., USA) were used in this study.
  • the CDC-BR consists of a 1-L bioreactor vessel with eight polypropylene coupon holders that can accommodate three 0.5-inch diameter sample coupons suspended from the reactor lid.
  • a liquid growth medium enters through the top of the vessel lid and exits via aside-arm discharge port.
  • a magnetic stir bar incorporating a mixing blade provides fluid mixing and surface shear.
  • the CDC- BR system which forms the basis of a standard method for the growth of Pseudomonas aeruginosa biofilms on polycarbonate surfaces was adapted to test the ability of S. aureus to form biofilms on titanium coupons (mock CRMs) in an antibacterial envelope or non-antibiotic-containing control envelopes .
  • strain 33591 S. aureus ATCC strain 33591 was used in this study. Unless otherwise specified, strain 33591 was grown in tryptic soy broth (TSB; Fisher Scientific Waltham. MA. USA) or on TSB agar plates. Bacteria were grown at room temperature for all biofilm experiments and at 37° C. for plate count experiments .
  • TSB tryptic soy broth
  • TSB agar plates Bacteria were grown at room temperature for all biofilm experiments and at 37° C. for plate count experiments .
  • Antimicrobial pouch The antimicrobial pouch used in these studies was the AIGIS RX TM antimicrobial envelope manufactured by TyRx Pharma, Inc. This antimicrobial pouch consists of a polypropylene mesh with a coating of 10% minocycline hydrochloride and rifampin in a DTE-27.5% DT succinate polyarylate which was manufactured and formed into a pouch as described in Example 6.
  • Biofilm formation experiments Inocula for the bioreactors were prepared by inoculating 800 mL of sterile 10%-strength TSB with overnight cultures of S. aureus strain ATCC 33591 and by growing these cultures at room temperature with continuous stirring for 24 hours. After incubation, 400 mL of the culture was added to a sterile experimental reactor and the remaining 400 mL was added to a second sterile control reactor. Sterile 1% TSB was continuously added to each reactor at a rate of 2.7 mL/min using a peristaltic pump.
  • Reactor fluid samples were removed via the exit ports from both reactors after incubation at room temperature for 24, 48, and 72 hours. After 72 hours of incubation, lid assemblies from both reactors were removed and transferred to beakers containing 400 mL of sterile phosphate buffered saline (PBS) and stirred (washed) for 5 minutes at room temperature. After the wash, the control and experimental coupons and envelopes were removed for microbiological analysis .
  • PBS sterile phosphate buffered saline
  • the number of CFU associated with the titanium coupons was expressed as CFU/cm 2 ) the number of bacteria associated with the control and experimental envelopes as CPU/envelope) and the number of bacteria in the reactor fluids as CFU/mL.
  • Statistical analysis of bacterial counts obtained from the control and treatment reactors was conducted using a 2-tailed, Student's t-test.
  • Bacterial strains were obtained from ATCC (American Type Culture Collection) : Staphylococcus epidermidis (ATCC #35984), Staphylococcus capitis (ATCC #27840), Escherichia coli (ATCC #25922), and Acinetobacter baummanii (ATCC #43608) .
  • ATCC American Type Culture Collection
  • ATCC #35984 Staphylococcus epidermidis
  • ATCC #27840 Staphylococcus capitis
  • Escherichia coli ATCC #25922
  • Acinetobacter baummanii ATCC #43608
  • Each culture was brought to the desired concentration and prepared in individual 1-mL syringes for inoculation.
  • the bacterial inoculum was checked by plating dilutions of the final culture solution as well as plating dilutions from one additional syringe post-surgery.
  • Rabbit Infection Model New Zealand white rabbits, at least 2.5 kg and specific pathogen-free, were weighed and anesthetized using given intramuscular (IM) acepromazine (1 mg/Kg) , ketamine (40 mg/kg) , and xylazine (2.5 mg/Kg) pre- operatively. The fur on the back of the animals was shaved, and the back of each rabbit was washed with a surgical scrub (e.g., Betadine), wiped with dilute alcohol, painted in Betadine, and draped for surgery. A 2.0-2.5 cm lateral incision along the ventral surface on one side of the spine was created through the dermal layer.
  • IM intramuscular
  • ketamine 40 mg/kg
  • xylazine 2.5 mg/Kg
  • a single incision was made parallel to the mid-line of the back, cutting through the fascia and exposing the paravertebral muscle.
  • the fascial membrane and portion of the trapezius muscle was incised with a scalpel creating a nominal implant site. Bleeding was controlled with gauze and pressure. Using blunt dissection, an implant pocket was created along the left lateral wall toward the lateral aspect of the left scapula of the rabbit. The pocket was extended approximately 3-4 cm.
  • a separate, small incision was made just lateral to the first incision, to accept a catheter to be tunneled into the pocket for bacteria delivery .
  • a bacterial injection cannula was created by removing the distal needle from a butterfly catheter.
  • the 1.5 mm tube was placed into the pocket between the pacing device and the infraspinous fossa of the scapula.
  • the tube was temporarily secured with a purse-string suture.
  • a sterile pacing device (with or without a sterile anti-bacterial pouch, as indicated) was then inserted into the pocket, and the pocket was closed by suturing the subcutaneous layer to the underlying muscle layer using a mattress stitch and 3.0 prolene sutures.
  • a syringe containing an individual bacterial dose was used to inject bacteria into the pocket using the cannula followed by 1.0 mL of sterile saline from a separate sterile syringe.
  • the cannula was removed and the purse-string suture was closed to seal the pocket.
  • the same procedure was performed on the contralateral side, using the same cutaneous incision and tunneling with blunt dissection into the contralateral side. Following device implant, the sub-cutaneous tissues were then closed using 3.0 vicryl sutures and interrupted stitches, the bacterial inoculum and saline rinse were injected into the catheter placed into this contralateral pocket, and the cutaneous tissues were closed using surgical staples or sutures . Animals were observed during post-operative recovery until body temperature was normal and animal was alert and responsive. The rabbits were observed daily throughout the seven day study.
  • Antimicrobial pouch The antimicrobial pouch used in these studies was the AIGIS RX TM antimicrobial envelope manufactured by TyRx Pharma, Inc. This antimicrobial pouch consists of a polypropylene mesh with a coating of 10% minocycline hydrochloride and rifampin in a DTE-27.5% DT succinate polyarylate which was manufactured and formed into a pouch as described in Example 6.
  • the device was then placed in a sterile plastic bottle with screw top lid with sterile saline + 0.5% Tween-80 to cover the device. Bacterial recovery from the device proceeded through a series of vortex and sonication steps. The bottle with the device and saline was vigorously vortexed for 15 seconds, followed by sonication for 5 minutes. The device was transferred to a new sterile jar and fresh saline + 0.5% Tween 80. This jar containing the device was vigorously vortexed for 30 seconds, followed by placement in a sonicator bath, and sonication for 5 minutes. Each sonicant solution was transferred to labeled 50 mL sterile tubes, resulting in two sonication samples.
  • Bacterial Strain Identification A single colony recovered from each device was analyzed by Gram stain and APITM test strips (BioMerieux, France) to determine bacterial strain .
  • Analysis of Systemic Antibiotic Level Blood was drawn at study termination, and plasma was collected and frozen for assay of minocycline and rifampin levels. Minocycline (Sigma Aldrich) was stored at approximately 5° C . ; rifampin (Sigma Aldrich) was stored at room temperature; and the internal standard, rifabutin (USP) was stored at approximately -20° C.
  • Plasma samples were extracted in acetonitrile, centrifuged, and supernatant was transferred to a 96-well plate and evaporated to dryness under nitrogen. Each well was reconstituted in acetonitrol-water (15:85) and 5 ⁇ was applied to an LC-MS/MS system (Scitex 4000 Q-trap) . Samples were run on a Synergy Hydro-RP, 50 x 2.0 mm, 4 ⁇ column, with mobile phase 1 in 0.5% formic acid in water, and phase B in 0.5% formic acid in acetonitrile-methanol (1:1) at a flow rate of 0.5 mL/minute. Sample concentrations were determined relative to minocycline and rifampin standards run under identical conditions.
  • SEM Scanning Electron Microscopy
  • E. coli Escherichia coli
  • S. capitis Staphylococcus capitis
  • A. baummannii A.
  • Pilot dosing studies were performed to determine the appropriate dose to yield consistent, non-lethal infection.
  • S. capitis pilot dosing study only minimal bacteria were recovered following a 7 day implant, though the pocket had signs of clinical infection, suggesting that the host's immune system may have fought the bacteria, leaving a sterile exudate.
  • FIG. 17A demonstrates the gross appearance of the dehydrated pacing devices prior to further processing.
  • the pacing can on the left had been implanted within the antimicrobiocrobial pouch, while the device on the right was implanted without an antimicrobial pouch.
  • the biofilm material is evident in the device on the right.
  • phosphate-buffered saline PBS
  • Optical density of each culture was determined by spectrophotometry.
  • the cultures were diluted to the target concentration of 1.0 x 107 CFU/mL (S. aureus and E. coli) and 1.0 x 1010 CFU/mL (S. capitis and S. epidermidis) for inoculation and 1.0 x 10' (S. aureus) and 1.0 x 10' ' (S. epidermidis) for the repeat of Groups 1 and 2 (Table 13), An aliquot from each concentration was diluted appropriately and inoculated onto trypticase soy agar (TSA) plates to confirm CFU/mL.
  • TSA trypticase soy agar
  • Test Article Preparation Aseptic preparation was used for any sterile articles. Two test articles were prepared for each rabbit .
  • a pocket surrounding each device was created using a continuous stitch and prolene sutures reconnecting the subcutaneous tissues around the device, The subcutaneous tissues were closed using vicryl sutures and interrupted stitches and the cutaneous tissues were closed, leaving only the distal end of the catheter in the pocket.
  • the previously prepared syringe was used to inject the determined dose of S. aureus, S. epidermidis, S. capitis or E. coli, into each pocket using the catheter followed by 1.0 mL of sterile saline from a separate sterile syringe to flush the catheter. The catheter was removed and the purse-string suture was closed to seal the pocket. Animals were observed daily over the course of 7 days .
  • Clinical Observations Clinical observations were recorded daily for each animal. Observations were typically cage side, looking for signs of illness, injury, or abnormal behavior .
  • the anti-bacterial pouch or shell (AIGIS Rx TM) was aseptically removed from each device, if present, and placed into a labeled, saline-filled container.
  • the cardiac pacing devices were placed in freshly prepared 2.5% glutaraldehyde or phosphate-buffered saline.
  • the implant pockets were swabbed once with a sterile cotton swab, and were placed into sterile labeled Whirlpack bags and given to the microbiologist for streaking onto TSA plates.
  • the cardiac pacing devices from animals 9644 and 9645 were placed in 50 mL sterile saline with 0.5% Tween 80 and
  • the containers with each device were vigorously vortexed for 30 seconds, followed by placement in a sonicator bath and sonication for 5 minutes .
  • the sonicant solution was transferred to a labeled 50 mL sterile tube, and 50 mL fresh saline with 0.5% Tween-80 was added to the mesh in the original container.
  • This container was again vigorously vortexed for 30 seconds, followed by placement in a sonicator bath, and sonication for 5 minutes.
  • the sonicant solution was transferred to a labeled 50 mL sterile tube. The process was repeated resulting in three sonicant solutions per device.
  • Each sonication specimen to be plated was diluted 10 _1 , 10 ⁇ 2 and 1 0 " by serial dilution. Two hundred mL of each dilution and the undiluted sample were plated onto TSA plates, and incubated overnight up to 48 hours to quantify dislodged bacteria .
  • Bacterial Cultures for Inoculum The S. aureus, S. epidermidis, S. capitis, and E. coli overnight cultures created to prepare inoculum were successful and yielded viable, colony-forming bacteria. The cultures were diluted or concentrated to prepare each inoculum dose and were plated to quantify actual CFUs, both immediately after inoculum preparation, and again at the end of implant. The actual CFUs were 5.8 x 10 8 (S. aureus), 4.3 x 10 9 (S. epidermidis) , 1.3 x 10 10 (S. capitis), and 1.2 x 10 7 (E. coli) CFU/mL from the 4 doses, respectively, at pre-implant, and 5.5 x 10 6 , 4.9 x 109, 1.2 x 10 10 and 1.0 x 10 7 CFU/mL for the four doses,
  • post-implant which is slightly above the target inoculums of 1 x 10 10 and 1 x 10 7 for S. capitis and E. coli, and slightly below the target inoculum of 1.0 x 10 7 and for 1.0 x 10 10 for S. aureus and S. epidermidis.
  • preimplant CFUs were 1.5 x 10 9 CFU/mL (S.
  • the target inoculums have an inherent variability, and are expected within the bacteria inoculum studied. Mixed colonies were observed on the viability
  • Pacemaker with AIGIS Rx TM articles and control pacing devices for animals 8244, 8246, 8248, 8320, 9646 and 9642 were placed in 2.5% glutaraldehyde and submitted for SEM.
  • Pacemaker with AIGIS Rx TM articles and control pacing devices for animals 8245, 8247, 8251, and 8327 were placed in phosphate buffered saline and submitted for confocal microscopy.
  • Swabs and Tissue Samples A summary of bacterial colonization from swabs is presented in Tables 17-20. Swabs from the pacing device implants (right side) in Group 3 and 4 and the repeat of Group 2 resulted in bacterial growth.
  • Sonicant samples from the pacing device implants (right side) in Group 1 and 2 also resulted in bacterial growth.
  • Table 18 Summary of Microbiology Data of the Group Infected with $. epide ndis
  • Table 19 Summary of Microbiology Data of the Groups Iitfected witli S, capitis and E.coli
  • Table 20 Summary of CFU Data by Group [0264] Confocal Microscopy: The devices without the AIGIS Rx envelope were observed to have bacterial infections, whereas the devices with the AIGIS Rx TM envelope appeared to have minimal viable bacteria, see FIG. 18.
  • test procedure is a modified version of a standard method for measuring the antimicrobial effectiveness of material surfaces as described by the
  • the standard method is a procedure for assessing the antimicrobial effectiveness of a material surface by measuring the log reduction in bacterial
  • device Type 1 the mesh substrate was not resorabable. It was made from polypropylene fibers.
  • device type 2 the mesh substrate was resorabable and made from a terpolymer of glycolide, caprolactone and trimethylene carbonate. In both types of cases, the mesh substrate was coated with a solution of a tyrosine polyarylate containing the two antimicrobials
  • the pass-fail criterion for the AATCC method is for the test product to exhibit a 3 log (103) reduction in bacterial growth. Both Type 1 and Type 2 devices passed the pre-selected pass criteria for all tested bacteria.
  • the antimicrobial activity is independent of the mesh substrate and any substrate that is coated with a composition that is equivalent to the one on the devices tested, should also exhibit similar antimicrobial activity .
  • the lowest innoculum dose that was used was 1 x 10 6 for MRSA and the highest innoculum dose was 1 x 10 10 for S. epidermidis. These inoculums are several thousand orders of magnitude higher than the number of bacteria that is recovered from cultures of infected implants.
  • AIGIS R is as effective as AIGIS in preventing infection with the challenge pathogens.
  • the studies encompassed 36 rabbits; 18 control rabbits and 18 test rabbits, with a total of 36 AIGIS R test devices and 36 control pacing devices without AIGIS R. The final result was that only 1/36 test devices was positive for infection, and only 1/36 positive controls was negative for infection.
  • a summary the efficacy results for AIGIS and Type 2 Device (AIGIS R) is presented below in Table 17.
  • AIGIS R is substantially equivalent to AIGIS in eliminating the inoculated pathogens . Furthermore, to our knowledge, AIGIS R is the first device to show efficacy against S. lugdunensis, a tenacious pathogen that is becoming more prevalent in heart device infections.

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Abstract

La présente invention concerne des treillis chirurgicaux biodégradables à revêtement polymère, en forme de poches, utilisables en association avec des dispositifs de régulation du rythme cardiaque et d'autres dispositifs médicaux implantables. Lesdits treillis se présentent sous la forme d'un contenant, par exemple une poche ou autre enveloppe, et se révèlent capables d'enfermer, d'entourer et/ou de contenir le dispositif de régulation du rythme cardiaque ou un autre dispositif médical implantable, ainsi que de prévenir ou de retarder la formation d'un biofilm.
PCT/US2013/077084 2013-03-07 2013-12-20 Procédés et compositions permettant d'inhiber l'assemblage de cellules microbiennes se liant de façon irréversible à la surface de dispositifs médicaux WO2014137454A1 (fr)

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WO2016048950A1 (fr) * 2014-09-22 2016-03-31 Tepha, Inc. Implants de p4hb orientés contenant des agents antimicrobiens
WO2017083485A1 (fr) 2015-11-10 2017-05-18 Mcjames Ii William Charles Dispositif et procédé de commande de libération d'agents bioactifs et thérapeutiques à partir d'un dispositif médical implantable
WO2018122442A1 (fr) * 2016-12-30 2018-07-05 Universitat De València Porte-supports pour biopfilms microbiens, système et réacteur à biofilms comprenant ledit porte-supports, et procédé d'utilisation dudit réacteur
EP3501559A1 (fr) * 2017-12-22 2019-06-26 BIOTRONIK SE & Co. KG Système avec implant intracardiaque et couvercle pour l'implant
EP3586886A1 (fr) * 2015-03-31 2020-01-01 Orchid Medical Pte Ltd Film élastique antimicrobien et douille fabriquée à partir de celui-ci
US10537743B2 (en) 2016-02-24 2020-01-21 Cochlear Limited Implant infection control
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