WO2015157681A1 - Microparticules pour le traitement de plaies - Google Patents

Microparticules pour le traitement de plaies Download PDF

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Publication number
WO2015157681A1
WO2015157681A1 PCT/US2015/025389 US2015025389W WO2015157681A1 WO 2015157681 A1 WO2015157681 A1 WO 2015157681A1 US 2015025389 W US2015025389 W US 2015025389W WO 2015157681 A1 WO2015157681 A1 WO 2015157681A1
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Prior art keywords
composition
microparticles
mammalian subject
microparticle
site
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PCT/US2015/025389
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English (en)
Inventor
Hobart W. HARRIS
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Vitruvian Medical Devices, Inc.
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Publication of WO2015157681A1 publication Critical patent/WO2015157681A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0094—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing macromolecular fillers
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/106—Fibrin; Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the invention relates to devices, compositions, and methods for treating a wound in a mammalian subject.
  • the invention relates to decreasing hernia recurrence and preventing incisional hernia formation.
  • Ventral hernias are areas of weakness in the anterior abdominal wall muscle.
  • a hernia is generally an abnormal protrusion or bulge of an organ through muscle or tissue in the body.
  • ventral hernias There are several different types of ventral hernias, including inguinal (groin), umbilical, and incisional (post-surgical) hernias.
  • Hernias of the anterior abdominal wall are extremely common and cause considerable patient discomfort and disability, resulting in more than 1.1 million reparative surgeries each year in the United States.
  • Many patients experience complications with hernia repair surgeries, including chronic post-operative pain and recurrence of the hernia.
  • hernia repair surgery fails in up to 40% of cases depending on the type of hernia, patient and surgical technique.
  • incisional hernias complicate 10-15% of all open abdominal operations. Recurrent hernias and the formation of incisional hernias following abdominal operations are both caused by inadequate wound healing from an operation.
  • the current state of the art for repairing hernias involves placing a prosthetic material or mesh in the area of the hernia defect to reinforce the weakened muscle. Sutures or tacks are used to initially fix the mesh in place, and the body's healing reaction to the prosthetic material is responsible for the long-term durability of the repair.
  • hernia mesh There are two basic types of hernia mesh, synthetic and biologic. Synthetic meshes are polymeric materials that can be further sub-divided into permanent versus absorbable (biodegradable) varieties. While permanent meshes remain in the patient's body forever, the absorbable meshes dissolve over time.
  • biologic meshes are derived from collagen-rich tissues (including skin, intestinal submucosa, and pericardium) of cadavers, pigs, cows and horses. Synthetic prosthetics have the advantages of durability, low cost and over fifty years of clinical experience. However, they can also cause bowel obstructions, fistulas and chronic pain, and are not approved for use when operating in a contaminated field. In contrast, biologic meshes are made of naturally occurring proteins, promote the ingrowth of the patient's own cells, and are resistant to infection. Yet, there are concerns about the long-term efficacy of biologic meshes and they are 20-30 times more expensive than the synthetic alternatives.
  • a device for administering a composition for treating a wound in a mammalian subject includes a cartridge containing microparticles composed of a biocompatible material, a cartridge containing thrombin, and a cartridge containing fibrinogen.
  • the device also includes an applicator to combine the microparticles, thrombin, and fibrinogen to create a mixture that is administered to a site of abdominal incision in the mammalian subject.
  • the applicator combines the thrombin and fibrinogen into a pre -mixture, and combines the pre- mixture with the microparticles to create the mixture.
  • the cartridges and/or the applicator are sterilized by one of any number of methods, including gamma radiation, vapor heating, solvent treatment, or detergent treatment.
  • the microparticles, thrombin, and/or fibrinogen are sterilized by vapor, heating, solvent treatment, ethylene oxide treatment, or detergent treatment.
  • the applicator includes a nozzle for delivering an aerosol spray.
  • the applicator includes a syringe.
  • the applicator is configured to deliver the composition by applying individual drops of the mixture to the site of abdominal incision.
  • the applicator is configured to deliver the composition by applying a continuous stream of the mixture to the site of abdominal incision.
  • the composition is in the form of a spray, powder, liquid, gel, fibrin sheet, or solid strip.
  • the composition is formulated to be administered by subcutaneous injection, subcutaneous application, or topical administration.
  • the composition comprises any microparticles composed of a biocompatible material.
  • the biocompatible material is
  • the composition is a combination of fibrinogen, thrombin, and microparticles comprising silver, polypropylene,
  • the biocompatible material is biodegradable.
  • the microparticles are spherical, and each microparticle has a diameter between 5 and 1000 microns. In other embodiments, each microparticle is coated with silver or titanium. In other embodiments, each microparticle includes a hollow center.
  • the composition includes a sterile fibrin sealant.
  • the sterile fibrin sealant includes thrombin and fibrinogen.
  • the composition is formulated as a pharmaceutical composition.
  • a kit for treating a wound in a mammalian subject includes a sterile container containing microparticles composed of a biocompatible material, a sterile container containing a fibrin sealant, and instructions for administering the contents of the sterile container to a site of abdominal incision in a mammalian subject.
  • a method for treating a wound in a mammalian subject includes administering to the mammalian subject a therapeutic amount of the composition of microparticles composed of a biocompatible material.
  • the administering includes applying the composition to a site of abdominal incision in the mammalian subject.
  • the method further comprises applying a hernia mesh to a site of abdominal incision in the mammalian subject.
  • the composition includes a sterile fibrin sealant, which may comprise thrombin and fibrinogen.
  • the sterile fibrin is in the form of a liquid, a powder, a lyophilized powder, or a frozen liquid.
  • the composition is administered as a dosage of 1 ml of fibrin sealant per 2 cm 2 surface area at the site of abdominal incision.
  • FIG. 1 shows the incidence of anatomic hernias in rats treated with various microparticles, according to one embodiment.
  • FIG. 2 shows the anatomic hernia size in rats treated with various microparticles, according to one embodiment.
  • Disclosed herein are devices, methods, and compositions for treating a wound in a mammalian subject.
  • these devices, methods, and compositions are used to improve the results of hernia repair surgeries and to prevent incisional hernias from occurring.
  • These technologies are based on the idea that generating increased native tissue will improve wound healing and decrease initial and recurrent incisional hernia formation.
  • the effects of applying biodegradable and inert microparticles to a subject for myofascial wound healing are analyzed.
  • the analyzed effects include tensile strength of the repair, and hernia formation.
  • the Examples demonstrate that microparticles can be used to prevent and treat incisional hernias.
  • microparticles to sites of abdominal incisions is a novel approach for treating wounds.
  • hernia refers to a protrusion or bulge of an organ or the fascia of an organ that projects from the normal contours of the body.
  • incisional hernia refers to a hernia defined by a protrusion of the abdomen, generally caused by inadequate healing of a surgical wound.
  • microparticle refers to particles that are generally (but not limited to) between 0.1 and 100 ⁇ in diameter, composed of any of a variety of materials. In some embodiments, microparticles are between 0.1 and 1000 ⁇ in diameter. In other words, microparticles are between 0.1 and 1000 ⁇ in diameter. In other words, microparticles are between 0.1 and 1000 ⁇ in diameter.
  • microparticles are smaller than 0.1 ⁇ in diameter or larger than 1000 ⁇ in diameter. In other embodiments, microparticles are between 100 and 250 ⁇ in diameter. In some embodiments, microparticles are spherical in shape. In other embodiments, microparticles are oblong in shape. In some embodiments, microparticles do not comprise metals.
  • biocompatible refers to a compatibility of a particular material with a living host.
  • a living host can include a cell line, a tissue sample, or an organism.
  • biocompatibility means that the material is not toxic to the host.
  • ameliorating refers to any therapeutically beneficial result in the treatment of a disease state, e.g., a wound, an incisional hernia, or other disease state, including prophylaxis, lessening in the severity or progression, remission, or cure thereof.
  • mammal as used herein includes both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines.
  • patient or “subject” refers to a cell, tissue, or organism, human or non-human, whether in vivo, ex vivo, or in vitro, male or female.
  • the patient or subject can be a human patient or a non-human.
  • sufficient amount means an amount sufficient to produce a desired effect, e.g., an amount sufficient to modulate protein aggregation in a cell.
  • therapeutically effective amount is an amount that is effective to prevent or ameliorate a wound, an incisional hernia, or a symptom of a disease.
  • a therapeutically effective amount can be a “prophylactically effective amount” as prophylaxis can be considered therapy.
  • treatment refers to a method of ameliorating, healing, or preventing a condition in a subject.
  • compositions for treating a wound in a mammalian subject comprising microparticles composed of a biocompatible material.
  • the composition includes bioactive microparticles combined with a fibrin- based tissue sealant.
  • microparticles can be composed of any biocompatible material.
  • biocompatible material In an
  • the biocompatible material is biodegradable or completely resorbable.
  • permanent microparticles include polypropylene (Prolene),
  • biodegradable microparticles include polyglycolide-cotrimethylene carbonate (PGA-TMC) (example ratios including but not limited to 67/33 and 75/25), polyglycolic acid (PGA), PGA-caprolactone, PGA-poly (lactic-co-glycolic) acid aka poly lactide-co-glycolide;
  • PGA-TMC polyglycolide-cotrimethylene carbonate
  • PGA polyglycolic acid
  • PGA-caprolactone polyglycolic acid
  • PGA-poly (lactic-co-glycolic) acid aka poly lactide-co-glycolide
  • poly(lactic-co-glycolic acid) PLGA example ratios including but not limited to 85/15, 75/25 and 50/50
  • polyglactin 910 polydioxanone (poly-/?-dioxanone), and poly-4-hydroxybutyrate (P4HB)
  • P4HB poly-4-hydroxybutyrate
  • the microparticles are composed of a combination of any of the above materials.
  • the microparticles are spherical. In a further embodiment, each microparticle has a diameter between 0.1-1000 ⁇ . In other embodiments, each microparticle has a diameter between 5-1000 ⁇ , 0.1-500 ⁇ , 100-250 ⁇ , or 10-100 ⁇ . In some embodiments, the microparticles are coated with a metal, such as silver or titanium. In other embodiments, the microparticles have a hollow center.
  • the microparticles are combined with a sterile fibrin sealant.
  • the microparticles are present in the composition at a concentration between 0- 2500 mg/mL of sterile fibrin sealant.
  • the microparticles are present at a concentration of 25, 50, 75, 100, 200, 250, 300, 400, 500, 1000, 1500, 2000, or 2500 mg/mL of sterile fibrin sealant.
  • the fibrin sealant is composed of thrombin and fibrinogen (TISSEEL and ARTISS, Baxter (Deerfield, IL); EVICEL, Ethicon BioSurgery). Fibrinogen is a protein that forms a clot when combined with thrombin.
  • Thrombin is a specific protease that transforms fibrinogen into fibrin.
  • the fibrin sealant can be sterilized by one of a variety of methods, including but not limited to, a vapor heating method, a solvent treatment process, or a detergent treatment process.
  • the fibrin sealant can be prepared in a liquid form (such as a gel), or powder form, including lyophilized powder or frozen liquid.
  • the fibrin sealant is combined with the microparticles prior to application of the resulting composition to a site of abdominal incision.
  • the fibrin sealant is applied to the site of abdominal incision prior to application of the microparticles, or the microparticles are applied to the incision site before the fibrin sealant is applied.
  • the thrombin and fibrinogen can be combined and mixed before further combination with the microparticles, all prior to application of the resulting composition to a site of abdominal incision.
  • the thrombin, fibrinogen, and microparticles are all combined and mixed simultaneously prior to application of the resulting composition to the abdominal incision site.
  • the microparticles are combined with the thrombin before subsequent combination with the fibrinogen, or the microparticles are combined with the fibrinogen before subsequent combination with the thrombin.
  • the fibrin sealant is manufactured from pooled human plasma and provided as a single use kit including two packages.
  • the first package contains one vial of Sealant Protein X (SPX) and one vial of Thrombin.
  • the second package contains a sterile spray application device and Microparticle Applicator Cartridge.
  • the two components SPX and Thrombin
  • the SPX and Thrombin components appear as white to slightly yellowish opaque masses when frozen and as clear to slightly opalescent and colorless to slightly yellowish solutions when thawed.
  • the components contain no
  • SPX is provided as a sterile solution, pH 6.7-7.2, which mainly includes a concentrate of human fibrinogen.
  • SPX is composed of any combination of the following active ingredients: concentrate of human fibrinogen (65- 105 mg/ml), aprotinin (synthetic, 2250-3750 KlU/ml), and Factor XIII (45-70 ⁇ g/ml), and other ingredients: human albumin, histidine, tri-sodium citrate, niacinamide, polysorbate 80, and water for injection.
  • SPX does not include Factor XIII.
  • thrombin is provided as a sterile solution, pH 6.8-7.2, which contains purified human thrombin that activates clotting of the final combined product.
  • thrombin is composed of any combination of the following active ingredients: human thrombin (500-625 IU/ml), and calcium chrloride (36-44 ⁇ /ml), and other ingredients: human albumin, mannitol, sodium chloride and water for injection.
  • cryoprecipitate (the starting material for SPX), and cryo-poor plasma (the starting material for the production of thrombin) are both made from pooled human plasma obtained from US licensed plasma collection centers.
  • SPX is manufactured from pooled Human Source plasma and thrombin is manufactured from pooled Human Source or recovered plasma.
  • compositions of microparticles described herein can be formulated in
  • compositions can comprise, in addition to one or more of the microparticles, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.
  • the pharmaceutical compositions for administration can be in solid or liquid form.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can be included.
  • the pharmaceutical composition is in the form of a spray, powder, liquid, gel, fibrin sheet, or solid strip.
  • the pharmaceutical composition is formulated to be administered by topical administration or subcutaneous injection.
  • the active ingredient can be in the form of a parenterally acceptable aqueous solution which is pyrogen- free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen- free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives can be included, as required.
  • Administration is preferably in a "therapeutically effective amount" or
  • prophylactically effective amount (as the case can be, although prophylaxis can be considered therapy), this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of the wound or hernia being treated. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.
  • a composition can be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • compositions described above including a pharmaceutical composition
  • this composition is administered as an adjuvant to current hernia repair surgical techniques and materials.
  • the composition can be administered to treat or prevent an incisional hernia.
  • the composition further comprises the fibrin sealant as described above.
  • the composition is administered by applying the composition to a site of abdominal incision in the mammalian subject.
  • the method of administration can be via any application method, including applying the composition by dripping or continuous stream.
  • the composition is applied to a surface area of 1 cm 2 , 2 cm 2 , 3 cm 2 , 4 cm 2 , 5 cm 2 , 6 cm 2 , 7 cm 2 , 8 cm 2 , 9 cm 2 , 10, cm 2 11 cm 2 , 12 cm 2 , 13 cm 2 , 14 cm 2 , or 15 cm 2 or more.
  • the composition is administered at a dosage ratio of 1 ml of fibrin sealant per 2 cm 2 surface area at the site of abdominal incision.
  • the composition is administered at a dosage ratio of 1 ml fibrin sealant per 10 cm 2 surface area.
  • the composition is applied by dripping, and the tip of the applicator is kept as close to the tissue surface as possible without touching the tissue during application. Individual drops of the composition are applied to the incision, creating a 2 cm- wide band. The drops are allowed to separate from each other and from the tip of the applicator.
  • the composition is applied by a continuous stream, and the tip of the applicator is kept approximately 1-2 cm above the tissue surface during application.
  • a slow and continuous stream of the composition is applied to the incision following a zig-zag path to create a 2 cm-wide band of material.
  • the composition is an adjuvant to current surgical techniques for closing the abdominal wall following open surgery.
  • the composition is applied to the surface of the re-approximated myofascial incision after suture closure is complete.
  • the composition is not injected into the peritoneal cavity.
  • the composition is administered by dripping in short bursts (0.1-0.2 ml) or as a continuous stream onto the sutured myofascial incision to produce an even layer that covers the entire incision.
  • Standard surgical techniques are used for closing the myofascial layer of the abdominal wall, including placing a permanent or absorbable suture using a continuous or interrupted technique, prior to the application of the composition.
  • excess fluid is removed from the site of application.
  • a hernia mesh is affixed to the site of abdominal incision at the time the composition is applied. Once the hernia mesh has been affixed, the composition can be applied in a manner that coats the local surgical field including the hernia mesh, prior to wound closure. In some embodiments, the amount of the composition administered is based on the surface area to be covered.
  • the device includes at least: a cartridge containing
  • the device also includes a cartridge containing thrombin, a cartridge containing fibrinogen.
  • the device also includes an applicator configured to combine the microparticles, thrombin, and fibrinogen to create a mixture, and the applicator is also configured to deliver the mixture to a site of abdominal incision in a subject.
  • any or all of the cartridges, applicator, microparticles, fibrinogen, and thrombin are sterilized before use. Sterilization can be performed by using any sterilization technique, including gamma radiation, ethylene oxide treatment, vapor heating, solvent treatment, and detergent treatment.
  • the applicator is configured to combine the thrombin and fibrinogen into a pre-mixture before combining the pre-mixture with the microparticles to create the mixture for administration.
  • the applicator is configured to deliver the composition by applying individual drops of the mixture to the site of abdominal incision, or deliver the composition by applying a continuous stream of the mixture to the site of abdominal incision.
  • the applicator is a syringe.
  • the barrel portion (cartridge) of the syringe device can be a single, double, or triple barrel, such that a plunger is configured to push material (such as microparticles, thrombin, and fibrinogen) through one, two, or three barrels simultaneously, or in a specific order.
  • material such as microparticles, thrombin, and fibrinogen
  • the microparticles can be contained in one cartridge, while the fibrin sealant (thrombin and fibrinogen) is contained in another cartridge.
  • the plunger is configured to push these materials through the barrels, and the microparticles and fibrin sealant are combined before being pushed out of the device to be applied to the site of abdominal incision.
  • the syringe is configured to push material from the barrel or barrels into a separate cartridge that holds another material, causing all of the material to be mixed before being delivered to an incision site.
  • the syringe can be configured to push thrombin and fibrinogen, both in different barrels, into a cartridge containing microparticles.
  • the thrombin and fibrinogen are pushed into the cartridge containing microparticles, the thrombin, fibrinogen, and microparticles are all mixed and combined in the cartridge to form a composition, and the plunger is further configured to push the composition out of the device to apply to the abdominal incision site.
  • the applicator is a nozzle that is configured to deliver the composition by an aerosol spray.
  • the cartridges of the nozzle device are configured to combine and mix the microparticles, thrombin, and fibrinogen in various combinations and order prior to administering the aerosol spray to a site of abdominal incision.
  • the cartridges of the nozzle device can be configured to combine thrombin and fibrinogen into a mixture, and subsequently add microparticles to the mixture.
  • the microparticles, fibrinogen, and thrombin can all be mixed simultaneously.
  • the kit for administering a composition for treating a wound in a mammalian subject includes at least: a sterile container containing microparticles composed of a biocompatible material, a sterile container containing a fibrin sealant, and instructions for administering the contents of the sterile container to a site of abdominal incision in a mammalian subject.
  • the thrombin and fibrinogen components of the fibrin sealant are packaged separately in sterile containers.
  • the kit includes an applicator device for administering the composition.
  • the applicator device includes a syringe or a nozzle.
  • Example 1 shows the analysis of different dose-response relationships in order to determine the optimal dose of microparticles in a rodent model of ventral abdominal wall incision healing and strength
  • Example 2 focuses on analyzing the impact of microparticles on treating incisional hernias in rats
  • Example 3 shows the impact of varying the types of microparticles used to reduce the incidence of incisional hernias from forming.
  • Example 1 Ventral abdominal wall incision healing and strength analysis
  • This Example describes a method of determining the optimal dose of microparticles to augment myofascial wound healing as measured by tensile strength of the incision and incisional hernia formation.
  • Treatment doses reflect the volume of synthetic mesh products currently in use.
  • Four concentrations of microparticles; 0, 25, 250 and 2,500 mg/ml fibrin tissue sealant are analyzed.
  • Sprague-Dawley rats male, 250-300 g
  • a ventral abdominal wall incisional hernia is produced in a rat by making a full-thickness, 3-cm x 6-cm paramedian skin incision that has been raised through the avascular, prefascial plane, thereby separating the skin incision from the underlying fascial wound-healing environment.
  • the 1 :2 ratio of flap length to width is maintained to prevent ischemia of the skin flap.
  • the intestines are briefly manipulated and the myofascial incision is closed with two interrupted 5-0 plain catgut sutures placed 5 mm from the cut myofascial edges and -1.5 cm from the cranial and caudal ends of the midline laparotomy incision.
  • the incision can also be closed with a continuous 4-0 vicryl suture, or two rapidly absorbing 5-0 plain catgut sutures placed -1.5 cm from either end of the incision.
  • the skin flap is then closed using a running 4-0 vicryl suture.
  • a 5-cm, full-thickness, midline laparotomy incision is made.
  • Animals in the treatment groups have 0 - 2,500 mg microparticles/ml of sterile fibrin tissue sealant (TISSEEL®, Baxter Healthcare Corp., Hayward, CA) topically applied to their sutured myofascial incisions before skin closure.
  • the treatment is administered by volume per surface area; i.e. 1 ml/10 cm 2 or 0.5 ml/5-cm myofascial incision, covering a total surface area of 5 cm 2 .
  • the skin flap is then closed with a continuous 4-0 vicryl suture to prevent intestinal evisceration.
  • Animals in the control group have an equal volume of sterile saline (0.5 ml) applied to their sutured myofascial incisions before skin closure.
  • bupivacaine 0.25% is infused subcutaneously around the abdominal incision.
  • the rats are observed every 2 minutes until awake and resuming normal activity; rats are then returned to individual cages and monitored twice daily. If the rat fails to display appropriate postoperative progression (fails to respond to tactile stimulus, displays moribund behavior or has overt bleeding) between 2 minute intervals, it is euthanized immediately.
  • 0.05 mg/kg buprenorphine is injected subcutaneously.
  • MicroTester® Instron Corporation, Canton, MA
  • the fascial strips are mounted into the load frame via pneumatic graspers, preloaded to 0.1 Newtons with the gauge length measured between the grips.
  • the load frame applies testing loads to the fascial strips until mechanical tissue disruption occurs.
  • the anatomic location of the tissue break is noted for each specimen.
  • Force and tissue deformation data are simultaneously captured via computer and data analysis performed using Bluehill® Software (Instron Corporation, Canton, MA). Failure of the specimen is defined at the yield point, rather than at the point of ultimate tissue disruption.
  • This Example describes a method of determining the impact of microparticles on treating incisional hernias in rats using the optimal dose determined in Example 1.
  • Sprague- Dawley rats male, 250-300 g
  • Rats in the treatment groups have their fascial closure (hernia repair) reinforced with either synthetic mesh or microparticles.
  • hernia repair a 5 cm x 1 cm strip of mesh is centered over the fascial incision and attached using 0.5 ml fibrin sealant before closing the skin with a continuous 4-0 vicryl suture.
  • the optimal dose of microparticles dispersed in fibrin sealant (0.5 ml/5-cm myofascial incision) is applied to the fascial repair before closing the skin with a continuous 4-0 vicryl suture.
  • the strips used to reinforce the hernia repair include absorbable synthetic meshes (Vicryl mesh, Ethicon Inc., Somerville, NJ; BioATM mesh, W.L. Gore & Associates, Inc., Flagstaff, AZ), (PhasixTM mesh, C.R. Bard, Inc. [Davol], Warwick, RI and permanent, synthetic meshes (UltraproTM, Ethicon; plain prolene mesh, Bard [Davol]).
  • the particles used to reinforce the hernia repair include biodegradable microparticles [polyglycolic acid (PGA), polyglactin 910, polyglycolide-cotrimethylene carbonate (PGA-TMC, 67/33 and 75/25), poly (lactic-co- glycolic) acid (PLGA 85/15, 75/25 and 50/50), PGA-caprolactone and polydioxanone] and inert microparticles (polypropylene, titanium, PTFE, ePTFE, and PMMA). Animals in the sham control group have an equal volume of sterile saline (0.5 ml) applied to their hernia repairs.
  • PGA polyglycolic acid
  • PGA-TMC polyglycolide-cotrimethylene carbonate
  • PLGA 85/15, 75/25 and 50/50 poly (lactic-co- glycolic) acid
  • PGA-caprolactone and polydioxanone polypropylene, titanium, PTFE, e
  • Example 3 Microparticles reduce the incidence of incisional hernias
  • This Example describes a method of determining the impact of microparticles on reducing the incidence of incisional hernia formation in rats by using varying microparticles.
  • Sprague-Dawley rats male, 250-300 g underwent an incisional hernia model. The animals were placed under isoflurane anesthesia, the ventral abdominal wall hair was shaved with electric clippers, and the surgical field was prepared with chlorhexidine or betadine.
  • a 3-cm, full-thickness, upper (epigastric) midline ventral skin incision was made, followed by a 5-cm midline laparotomy incision through which the intestines were briefly manipulated before the myofascial incision was closed with two interrupted 5-0 plain catgut sutures placed 5 mm from the cut myofascial edges and approximately 1.5 cm from the cranial and caudal ends of the midline laparotomy incision, respectively.
  • mice were randomly assigned to each of eight treatment groups and a sham control group before closing the skin flap with a continuous 3-0/4-0 prolene/vicryl suture to prevent intestinal evisceration.
  • Animals in the treatment groups received a dose of microparticle composition with a total particle surface area of 11.44 cm 2 mixed within a fibrin tissue sealant (1 ml/10 cm 2 or 0.5 ml/5-cm myofascial incision) topically applied to their sutured myofascial incisions before skin closure using a subcuticular suture.
  • the microparticle composition included a combination of fibrinogen, thrombin, and
  • microparticles including silver, polypropylene, polymethylmethacrylate (PMMA), silver- coated PMMA, polylactic-co-glycolide (PLGA, 85/15), PLGA (porous), and poly-4- hydroxybutyrate (P4HB).
  • the total particle surface area of 11.44 cm 2 is the equivalent of using 500 mg/kg or 250 mg/ml of 250 ⁇ silver microparticles.
  • Animals in the sham control group received an equal volume of sterile saline (0.5 ml) applied to their sutured myofascial incisions before skin closure using a subcuticular suture.
  • the tissue sealant (Tisseel ®, Baxter Biosurgery, Deerfield, IL) was mixed with apyrogenic microparticles to create final delivered concentrations as listed in Table 1 (below). After 28 days (+/- 3 days), the animals in each group were inspected for a visible hernia, and euthanized while under anesthesia. The abdominal wall was excised and the abdominal wall muscle was evaluated for a hernia defect (anatomic hernia). Samples from the wound-healing interface were fixed in formalin and paraffin-embedded in preparation for histology. The results showed that using microparticles in combination with fibrin tissue sealant is a feasible approach to preventing incisional hernias.
  • Table 1 Microparticle compositions and dosing
  • FIG. 1 shows the incidence of anatomic hernias in rats treated with various microparticles. Fisher's exact test was performed. * denotes a p value of 0.0004 between control and silver microparticles. There was no statistically significant difference between control and the other microparticles tested, however important trends were observed. P values were: control versus polypropylene 230 micron: 0.3034, control versus
  • FIG. 2 shows the anatomic hernia size in rats treated with various microparticles. Hernia sizes of various treatment groups were compared. A Kruskal-Wallis test was performed, with a p value of 0.0654. Dunn's post-test demonstrated a significant difference between control versus silver, * denotes a p value of ⁇ 0.05. It was concluded that all of the hernias formed were essentially of the same size.

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Abstract

La présente invention concerne des dispositifs, des méthodes et des compositions destinées au traitement d'une plaie chez un mammifère. Selon l'invention, le traitement d'une plaie consiste à administrer audit mammifère une quantité thérapeutique d'une composition. Ladite composition comprend des microparticules constituées d'un matériau biocompatible. Dans certains modes de réalisation, la composition comprend également une colle de fibrine stérile.
PCT/US2015/025389 2014-04-11 2015-04-10 Microparticules pour le traitement de plaies WO2015157681A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022047367A1 (fr) * 2020-08-31 2022-03-03 Vitruvian Medical Devices, Inc. Films stables au stockage comprenant de la fibrine et/ou du fibrinogène
US11845248B2 (en) 2020-02-14 2023-12-19 Donaldson Company, Inc. Expanded polytetrafluoroethylene composite

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100291058A1 (en) * 2002-10-04 2010-11-18 Virginia Commonwealth University Sealants for Skin and Other Tissues
US20120225052A1 (en) * 2008-09-26 2012-09-06 Rousseau Robert A Composition and method for treating tissue defects
WO2013138238A1 (fr) * 2012-03-12 2013-09-19 The Regents Of The University Of California Méthodes et compositions destinées au traitement de lésions et à la réduction du risque de hernies cicatricielles
US20130251764A1 (en) * 2006-12-04 2013-09-26 Abbott Cardiovascular Systems Inc. Methods and compositions for treating tissue using silk proteins

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100291058A1 (en) * 2002-10-04 2010-11-18 Virginia Commonwealth University Sealants for Skin and Other Tissues
US20130251764A1 (en) * 2006-12-04 2013-09-26 Abbott Cardiovascular Systems Inc. Methods and compositions for treating tissue using silk proteins
US20120225052A1 (en) * 2008-09-26 2012-09-06 Rousseau Robert A Composition and method for treating tissue defects
WO2013138238A1 (fr) * 2012-03-12 2013-09-19 The Regents Of The University Of California Méthodes et compositions destinées au traitement de lésions et à la réduction du risque de hernies cicatricielles

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11845248B2 (en) 2020-02-14 2023-12-19 Donaldson Company, Inc. Expanded polytetrafluoroethylene composite
WO2022047367A1 (fr) * 2020-08-31 2022-03-03 Vitruvian Medical Devices, Inc. Films stables au stockage comprenant de la fibrine et/ou du fibrinogène

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