WO2003049782A1 - Implants biocompatibles revetus du facteur von willebrand - Google Patents

Implants biocompatibles revetus du facteur von willebrand Download PDF

Info

Publication number
WO2003049782A1
WO2003049782A1 PCT/IB2002/005284 IB0205284W WO03049782A1 WO 2003049782 A1 WO2003049782 A1 WO 2003049782A1 IB 0205284 W IB0205284 W IB 0205284W WO 03049782 A1 WO03049782 A1 WO 03049782A1
Authority
WO
WIPO (PCT)
Prior art keywords
vwf
collagen
composition
particles
tissue
Prior art date
Application number
PCT/IB2002/005284
Other languages
English (en)
Inventor
Andrew Stevens
Micheal W. Stewart
Original Assignee
Virexx Research Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Virexx Research Inc. filed Critical Virexx Research Inc.
Priority to AU2002366585A priority Critical patent/AU2002366585A1/en
Publication of WO2003049782A1 publication Critical patent/WO2003049782A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L27/60—Materials for use in artificial skin
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines

Definitions

  • the present invention is directed to compositions and methods for producing a therapeutic benefit by delivering VWF alone or in combination with other proteins and/or particles to target tissues. Delivery of VWF to the tissue increases the volume of the tissue through a bulking action. Perceived benefits include improved cosmetic appearance of the tissue, improved coaptation of sphincters and control of blood flow in various tissues.
  • Collagen implants have been employed successfully in many areas of the body to correct distensible acne scars, atrophy from disease or trauma, glabellar frown lines, nasolabial folds, or defects secondary to rhinoplasty, skin graft or other surgery, and other soft tissue defects.
  • Collagen is a protein product usually of dermal bovine origin, which is subject to degradation over time.
  • additional injections of collagen are usually required in order to restore the results originally obtained after the first injection.
  • Additional implantations at six to eighteen month intervals are usually required to maintain optimal correction of tissue defects. The interval at which further implantation is needed depends on the nature of the lesion, the amount of implant introduced, the plane of placement and the stresses that may exist at corrected sites. Ongoing mechanical stresses eventually cause these defects to recur. Correction tends to persist longer in areas in which mechanical stresses or disease processes are inactive.
  • Sensitization reactions to dermal injections of collagen occur in 1-2% of patients receiving implants. Most reactions involve hypersensitivity and consist of erythema, swelling, induration and/or urticaria at implantation sites. Abscess formation occurs on rare occasions at injection sites. In some cases, the reactions are associated with an elevated titer of anti-bovine collagen antibodies, and reactions can be multiple or recurrent. The reactions develop in the weeks to months following injection and may result in induration and/or scar formation. The likelihood of allergic reaction increases with multiple injections of collagen, which are normally required to achieve the desired results.
  • allergic reactions typically persist for one to nine months with an average duration of four months.
  • the reactions may be intermittent or continuous in nature. In rare instances, the reactions resolve in one or two weeks, or may persist for more than one year.
  • anti-allergic therapy anti-histamines; NSAIDs; oral, topical, and intra-lesional steroids
  • NSAIDs anti-histamines
  • oral, topical, and intra-lesional steroids have been tried, they usually result in only temporary improvement.
  • the resolution of sensitivity reactions occurs over a prolonged period of time. In some patients, residual firmness of the tissues remains at the site of a resolved sensitivity reaction.
  • Soft-tissue fillers such as injectable collagen have been used to fill in facial lines and creases thereby temporarily restoring a smoother, more youthful appearance. More medically related uses of such fillers include treatment of urinary incontinence and gastroesophageal reflux disease (GERD).
  • GFD gastroesophageal reflux disease
  • the lower esophageal sphincter is a ring of increased thickness in the circular smooth muscle layer of the esophagus.
  • the LES maintains a high-pressure zone while at rest (between 15 and 30 mm Hg above pressures in the stomach).
  • the LES relaxes before the esophagus contracts, and allows food to pass through to the stomach. After food passes into the stomach, the LES constricts to prevent the contents from regurgitating into the esophagus.
  • the resting tone of the LES is influenced by both muscle tone and specific innervation. After a meal, the LES usually remains closed. When it relaxes, it may allow acid and food particles to reflux into the esophagus.
  • Pathologic conditions associated with GERD include erythema, isolated erosion, confluent erosions, circumferential erosions, deep ulcers, esophageal stricture, replacement of normal esophageal epithelium with abnormal (Barrett's) epithelium, pulmonary aspiration, chronic cough, and reflux laryngitis.
  • GERD can be attributed to such factors as transient lower esophageal sphincter (LES) relaxations, decreased LES resting tone, delayed stomach emptying, ineffective esophageal clearance, and diminished salivation.
  • Other contributing factors include the potency of the refluxed material, and the inability of the esophageal tissue to resist injury and repair itself.
  • Urinary incontinence is defined as the uncontrolled loss of urine from the bladder. Stress and urge incontinence (SUI) are the most common types and are found in approximately 95% of the patients. Stress incontinence is caused by a sudden increase in intra-abdominal pressure, such as coughing or straining. The underlying problem is a malfunctioning internal urethral sphincter or weak pelvic muscular support to the bladder and urethra. The movement of the urethra causes a pressure gradient between the bladder and urethra, resulting in urinary leakage. Intrinsic sphinteric deficiency (ISD) is caused by the loss of the sealing effect of the internal sphincter.
  • ISD Intrinsic sphinteric deficiency
  • Urge urinary incontinence is defined as the inability to suppress a sudden urge to void, resulting in a bladder contraction and leakage. This is caused by bladder instability or hyperactivity.
  • Both esophageal reflux and urinary incontinence can be effectively treated by injecting a bulking agent such as collagen into the sphincter tissue thereby providing improved strength and stability of the closed sphincter.
  • a bulking agent such as collagen
  • Injections of various types of bulking agents have been used for cosmetic purposes to minimize facial lines and scaring.
  • the most widely used bulking agent is derived from bovine skin and is marketed under the trade names Zyderm®, Zyplast® and Contigen®.
  • the effects of these therapies are short-lived, i.e., from weeks to months.
  • both artificial skins are comprised of two membranes: an ultra-thin silicone rubber film serves as an outer protective layer (the substitute for epidermis) and an inner layer of either collagen-coated fabric or a layer of a collagen/glycosaminoglycan matrix that functions as scaffolding in which the new skin will grow (the dermal layer substitute).
  • BioBrane® is biosynthetic skin substitute first developed in 1979 and consists of an outer silicone film in which is partially imbedded an inner nylon fabric layer woven from tri-filament threads that forms a three-dimensional matrix.
  • Collagen (porcine type 1 ) is incorporated in both the silicone and nylon components by chemical cross-links.
  • the collagen peptides on the nylon bind to the fibrin and collagen of the burn wound surfaces resulting in an initial adherence of the artificial skin to the wound within a day or so.
  • a second phase of adherence occurs when the epidermal cells from the patient's tissue begin proliferating within the nylon matrix. Small pores in the membranes allow for drainage of exudate and provide for permeability of topical antibiotics to treat infections.
  • the dressing remains in place until autografting of partial thickness skin grafts becomes possible.
  • Integra® is described as a dermal regeneration template.
  • the inner or dermal layer consists of a porous matrix of cross-linked bovine tendon collagen and chondroitin-6-sulfate bonded to the outer or epidermal layer of silicone film.
  • the dermal layer acts as a biodegradable template that facilitates the dermal tissue regeneration. Fibroblasts, macrophages, and lymphocytes as well as blood and lymph vessels migrate into the collagen matrix from the wound tissues. The fibroblasts degrade the bovine collagen layer and recreate a new human collagen matrix.
  • the outer silicone rubber layer functions as an epidermal barrier for a period of about two to three weeks. During this time, revascularization of the dermal layer occurs.
  • Artificial skin preparations may be used for skin replacement for superficial to mid-partial thickness burns once dead tissue has been debrided, for excised burn wounds with or without meshed autografts, for donor sites, and for partial thickness skin slough disorders.
  • the artificial skins have the following properties: (a) they are adherent to a clean, viable wound surface; (b) they are impermeable to bacteria; (c) they control the rate of water loss by evaporation and thus prevent the desiccation of the tissues; (d) they are flexible, durable, non-allergenic, and non-toxic; (e) they are permeable to topical antibiotics; (f) they provide an optimized healing environment; and (g) they decrease pain and wound exudate.
  • ECM extracellular matrix
  • subendothelium in the vicinity of blood vessels and capillaries.
  • the molecules making up the ECM provide scaffolding for the surrounding tissues thereby conferring both function and form.
  • These molecules include collagens, elastin, fibronectin, laminin, heparan sulfate, chondroitin sulfate, and von Willebrand factor (VWF).
  • VWF is a large glycoprotein found circulating in the blood stream as well as forming part of the subendothelial extracellular matrix (ECM). VWF has two primary functions in the body: 1 ) to protect Factor VIII (FVIII) from premature activation in the blood stream, and 2) to localize platelets to areas of vascular damage. The latter function is accomplished when VWF is either exposed as part of the ECM or when VWF circulating in the blood stream binds to exposed collagen (also a component of the ECM) after vascular trauma.
  • FVIII Factor VIII
  • VWF does not bind to platelets as it circulates in the blood stream; however, once immobilized on the ECM, VWF engages the glycoprotein Ib/IX/V receptor on the surface of the platelets, causing the platelets to adhere to the site of vascular injury. This in turn leads to platelet activation and platelet/platelet binding causing a 'platelet plug' to form at the site. This aggregate of platelets (thrombus) serves to prevent further blood loss from the damaged blood vessel.
  • the VWF molecule has binding sites for several constituents of the ECM. Different types of collagen (e.g., I, III, VI) have been shown to bind to specific peptide sequences of the A1 and A3 domains of VWF. A VWF binding site has also been identified for heparin suggesting that homologous proteins such as sulfated proteoglycans (e.g., heparan sulfate proteoglycans, chondroitin sulfate proteoglycans) might also bind. Binding of the VWF molecule to these ECM constituents would, in effect, localize the VWF to the site of injection.
  • sulfated proteoglycans e.g., heparan sulfate proteoglycans, chondroitin sulfate proteoglycans
  • the object of the present invention is to provide a von Willebrand Factor-coated collagen implant that can easily be injected, remains immobilized at the site where it has been introduced for an extended period of time, and is tolerated by the tissue with minimal side effects.
  • a histocompatible solid in the form of von Willebrand factor- coated collagen in various formats such as particles is used as an implant.
  • Particles of collagen of bovine origin may be coated with von Willebrand Factor.
  • the surface-bound von Willebrand Factor molecules will slowly cross-link with each other and eventually the coated collagen particles will be connected by a cohesive network of cross-linked fibers.
  • the cross-linked particles will therefore be more resistant to degradation by tissue enzymes and to phagocytosis by tissue macrophages.
  • the patient immune system will identify the von Willebrand Factor coated collagen particles as "self. Thus, the coated particles will be subjected to significantly reduced immune responses following administration. Consequently, the risk of inducing an inflammatory reaction in the patient tissues will be greatly diminished.
  • the bound Von Willebrand Factor may bind platelets in the plasma.
  • the platelets will adhere to the particles, undergo activation and degranulation, which will cause further platelet aggregation and recruitment.
  • fibrinogen will be converted to fibrin that will also bind to the platelets.
  • the aggregation of platelets and fibrin around the particles will further isolate the particles from the immune system.
  • the von Willebrand Factor-coated collagen implant may be used for administration to patients by injection into the mid to deep dermal tissues for correction of tissue contour deficiencies. Over a period of months, it is believed that host connective tissue cells will colonize the implant. The implant will therefore assume the texture and appearance of normal host tissue and will undergo the same stresses and aging processes.
  • the solid particles of von Willebrand Factor-coated collagen which are formed as a powder, preferably have an average diameter of about 10 ⁇ m. Such solid particles are too large to be phagocytized by tissue monocytes. It is also possible to use smaller solid particles in the range of 4 to 5 ⁇ m or 5 to 10 ⁇ m.
  • the solid particles preferably have an average diameter of about 15 to about 200 ⁇ m and more preferred from about 15 to about 60 ⁇ m. In this case, the solid particles are also small enough to be injected by means of a needle and syringe to the desired site.
  • the solid particles preferably have a diameter such that they are not carried away by lymph drainage or other tissue fluids from the site into which they have been introduced. Since the particles have a quasi-spherical form, they can form a closely packed arrangement at the site into which they have been introduced.
  • collagen proteins may be used as the basis for forming the particulate implant.
  • the particles are preferably suspended orslurried in an inert suspending agent.
  • an inert suspending agent for instance, water, buffer salts, and sodium chloride as well as mixtures thereof can be used as suspending agents.
  • the suspending agents used according to the present invention may contain a surfactant such as Tween 80.
  • a surfactant changes the surface tension of water so that the solid particles or aggregates may be suspended more easily.
  • a gel which can be degraded within the body such as gelatin, can also be used as a component of the suspending agent.
  • suspending agent By using a suspending agent, it is possible to inject the solid particles as used according to the present invention by means of a needle and syringe. For intracutaenous administration, it is possible to use a 20 to 27 gauge needle for such purposes.
  • the von Willebrand Factor-coated collagen particle with different diameters for instance from 40 to 80 ⁇ m as well as from 15 to 60 ⁇ m can been used.
  • the suspending agent which prevents the small beads from rapid settling in the injection syringe due to gravitation, are mixed with the beads just before the injection.
  • the von Willebrand Factor-coated collagen particles that have been inserted into the body will eventually be incorporated into connective tissue and will remain stationary in the tissue.
  • VWF would improve the initial adherence of the collagen (dermal) layer of the artificial skin to the tissues of the wound.
  • the VWF molecule has binding sites for several constituents of the ECM. Different types of collagen including collagen of porcine or bovine origin have been shown to bind to specific peptide sequences of the A1 and A3 domains of VWF. A VWF binding site has also been identified for heparin suggesting that homologous proteins such as sulfated proteoglycans (e.g., heparan sulfate proteoglycans, chondroitin sulfate proteoglycans) might also bind. VWF also binds weakly to fibronectin, fibrinogen and fibrin.
  • sulfated proteoglycans e.g., heparan sulfate proteoglycans, chondroitin sulfate proteoglycans
  • VWF Since VWF is known to bind to components of the extracellular matrix, VWF could be used to coat the inner layer of collagen or collagen peptides on these forms of artificial skin to the benefit of burn patients. Furthermore, if the exudate of the burn wounds contains platelets, VWF immobilized on the artificial skin will bind to the platelets through its interaction with the glycoprotein lb (GPIb) receptor on the surface of the platelets. Upon activation of the platelets, an additional receptor, glycoprotein llb/llla (GPIIb/llla), is altered, thus enabling the binding of several plasma proteins and thereby promoting additional platelet/platelet binding. Fibrinogen also binds to the activated GPIIb/llla receptor thereby becoming immobilized and capable of causing additional adherence of the tissues to the artificial skin.
  • GPIIb/llla glycoprotein llb/llla
  • von Willebrand Factor coated-collagen in artificial skin preparations would significantly improve the initial binding phase of the artificial skin to the burn wound tissues. This would be as a result of an increase in the amount or degree of the adherence as well as an increase in the rate of the binding interaction. This being the case, the period of time between the application of the artificial skin and the migration of fibroblasts and other tissue cells migrate into the artificial skin would be significantly reduced.
  • the present invention provides compositions and methods for delivering von Willebrand factor of mammalian or recombinant origin either alone, or in combination with other proteins to target tissues for the purpose of bulking the tissue at the site of injection.
  • VWF delivered to the tissue would bind to constituents of the extracellular matrix (ECM) allowing specific localization of the injected agents.
  • ECM extracellular matrix
  • VWF bound to or found within exposed ECM is responsible for tethering and inducing irreversible adhesion of circulating platelets to damaged areas of blood vessels. VWF- mediated platelet capture is accomplished in spite of high blood flow velocity and associated shearing effects in the arterial circuit.
  • the present invention provides compositions and methods for bulking tissue at a selected site by injecting VWF alone, or in combination with other proteins and/or materials.
  • the VWF is of mammalian origin. In a most preferred embodiment of the invention the VWF is of human origin.
  • the VWF is mixed with collagen prior to injection.
  • the VWF or VWF/collagen mixture is bound to or injected with inert particles.
  • Particles could take the form of aggregated proteins such as albumin or gelatin.
  • Particles could also be constructed of materials such as polyvinyl alcohol (PVA), polystyrene, polycarbonate, polylactide, polyglycolide, lactide-glycolide copolymers, polycaprolactone, lactide- caprolactone copolymer, polyhydroxybutyrate, polyalkylcyanoacrylates, polyanhydrides, polyorthoesters, albumin, collagen, gelatin, polysaccharides, dextrans, starches, methyl methacrylate, methacrylicacid, hydroxylalkyl acrylates, hydroxylalkyl methacrylates, methylene glycol dimethacrylate, acrylamide, bisacrylamide, nylon, cellulose-based polymers, ethylene glycol polymers and copolymers, oxyethylene and oxypropy
  • PVA poly
  • the particles are at least 10 ⁇ m in diameter.
  • the particles have a diameter of 10 ⁇ m to 500 ⁇ m. In a most preferred embodiment of the invention the particles will have an average diameter of 15 to 60 ⁇ m.
  • the particles are spherical or ovoid in nature.
  • the VWF/particle and/or VWF/collagen and/or VWF/collagen/particle mixture is supplied in the form of a powder.
  • the target tissue functions to control the movement of material into and/or out of an organ.
  • examples include sphincters, arteries, arterioles, metarterioles, veins, venules, airway smooth muscle, smooth muscle in general and blood sinuses.
  • the target tissue is amenable to cosmetic improvement.
  • the target tissue either controls or is associated with tissue that controls the movement of urine from the bladder.
  • the target tissue either controls or is associated with tissue that controls the movement of stomach contents into the esophagus or out of the stomach to the duodenum.
  • the target tissue has a microvascular component including an extensive capillary network.
  • the target tissue either controls or is associated with tissue that controls the movement of blood through blood vessels.
  • the target tissue either controls or is associated with tissue that controls the pooling of blood within penile tissue.
  • the VWF is bound passively to collagen.
  • the VWF is bound covalently to collagen.
  • the VWF is injected into the tissue prior to collagen injection
  • the VWF is premixed with collagen prior to injection.
  • the VWF is injected after collagen injection.
  • VWF is incorporated into artificial skin materials.
  • the VWF-containing artificial skin is used to treat burn patients.
  • a selected site, a pre-determined sited, targeting, and pre-targeting all refer to the location where the accumulation of VWF will provide a therapeutically beneficial result in an animal or human patient.
  • Selected sites include sphincters, arteries, arterioles, metarterioles, veins, venules, airway smooth muscle, blood sinuses, lips, ears and other parts of the face, and other parts of the body where tissue augmentation provides a cosmetic and or therapeutic benefit.
  • therapeutically beneficial refers to a desirable change in the physiology of the recipient human or animal.
  • the change is detectable.
  • any biological mechanism that involves localization of VWF within target tissues to achieve tissue bulking may be used or harnessed to achieve a beneficial therapeutic result.
  • Exemplary therapeutic benefits produced in accordance with the present invention include but are not limited to minimizing or removing skin irregularities such as lines, scars and wrinkles, bulking of the tissue of the lower esophageal sphincter (LES) to reduce or eliminate gastroesophageal reflux disease (GERD), and bulking of the internal urethral sphincter to reduce or eliminate urinary incontinence.
  • administering refers to any action that results in exposing or contacting a composition containing VWF with a pre-determined cell, cells, or tissue, typically mammalian. Administering may be conducted in vivo, in vitro, or ex vivo. For example, a composition may be administered by injection or through an endoscope or catheter.
  • Exemplary proteins useful in the practice of this invention include but are not limited to proteins corresponding to known to be components of the extracellular matrix or subendothelium such as collagen, fibronectin, fibrinogen, laminin, osteopontin, von Willebrand factor, heparan sulfate, and chondroitin sulfate.
  • compositions may also include pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers include but are not limited to saline, sterile water, phosphate buffered saline, and the like.
  • Other buffering agents, dispersing agents, and inert non-toxic substances suitable for delivery to a patient may be included in the compositions of the present invention.
  • Other components such as surfactants and topical anesthetics may be included in the composition.
  • the compositions may be solutions suitable for administration, and are typically sterile and free of undesirable foreign particulate matter.
  • the compositions may be sterilized by conventional sterilization techniques.
  • Administration may be once, more than once, and over a prolonged period.
  • Actual methods and protocols for administering pharmaceutical compositions including dilution techniques for injections of the present compositions, are well known or will be apparent to one skilled in the art. Some of these methods and protocols are described in Remington's Pharmaceutical Science, Mack Publishing Co. (1982).
  • the VWF bulking agent may be administered in combination with other agents, or may be administered in combination with other treatment protocols or agents.
  • liposomes, nanospheres, micelles, or microspheres may be used to administer a composition, and that such administration may result in a therapeutically desirable benefit.
  • a widely employed treatment option to improve the lip profile and wrinkles around the lips involves the injection of natural-source injectable tissue fillers, of which bovine-origin collagen is among the most commonly employed. Injectable collagen is often injected into the upper and lower lips, deep oral commissures (marionette lines) or the nasolabial folds as well as into the fine lines around the upper and lower lips or on the cheeks. Patients report that collagen injections produce soft, pliable, and natural feeling tissue augmentation.
  • tissue filler consisting of von Willebrand Factor-coated collagen particles.
  • This treatment would be designed to be performed in the physician's office. Once it was determined that the patient was not allergic to bovine collagen, the patient dose would be administered.
  • the patient dose of tissue filler would be supplied in a pre-filled syringe ready for injection.
  • the dose of tissue filler would consist of pre-formed particles or aggregates of collagen about 10-50 ⁇ m in diameter that have been mixed with sufficient von Willebrand Factor to permit the formation of complete coat of the protein over the surface of the particles.
  • the von Willebrand Factor-coated collagen particles would be washed to remove unbound VWF. The particles would then be resuspended in a pharmaceutical vehicle that was suitable for injection, most commonly a buffered saline solution.
  • Ice would be placed on the areas to be injected, and a fine needle utilized to inject the VWF/collagen mixture into the desired areas.
  • a slight overfill may be performed of about 10%.
  • Urinary incontinence (a loss of bladder control) affects approximately 25 million Americans. Stress urinary incontinence in women is most often caused by changes in the pelvic floor associated with child bearing that can result in an uncontrolled loss of urine during exercise. Because of the changes in the architecture of the pelvic floor that cause incontinence, surgery and/or injection of tissue bulking agents can produce significant improvement in these patients.
  • tissue bulking agents such as bovine origin collagen represent an important option for the treatment of urinary incontinence, because the procedure is cost effective and can be performed in an outpatient setting under local anesthesia.
  • a suitable injectable tissue bulking agent would consist of pre-formed particles or aggregates of collagen about 10-50 ⁇ m in diameter that have been mixed with sufficient von Willebrand Factor to permit the formation of complete coat of the latter protein over the surface of the collagen particles.
  • the von Willebrand Factor-coated collagen particles would be washed to remove unbound VWF. The particles would then be resuspended in a pharmaceutical vehicle that was suitable for injection, most commonly a buffered saline solution.
  • the von Willebrand Factor-coated collagen particles would be injected through a 25 gauge needle into the submucosal space of the bladder neck or around the urethral tissues to augment the natural sphincterfunction, thereby increasing resistance to urine flow. Injections could be performed in an outpatient setting.
  • Gastro-esophageal reflux disease is caused by acid regurgitation from the stomach into the esophagus. Normally, stomach acid and digestive enzymes are prevented from backing up into the esophagus by the lower esophageal sphincter. In patients with gastro-esophageal reflux disease, the valve undergoes inappropriate and periodic relaxation. Symptoms of heartburn result when the acidic contents of the stomach are pushed upwards into the lower esophagus and remain there for a extended period of time. VI. INDUSTRIAL APPLICABILITY
  • Gastro-esophageal reflux disease afflicts approximately 15-19 million Americans. In more advanced forms of the disease, patients may suffer from esophagitis, ulcers, strictures due to scarring, erosion of the lining of the esophagus, and Barrett's esophagus which may lead to cancer of the esophagus.
  • tissue bulking agents such as bovine origin collagen represents a attractive treatment option for the amelioration of gastro-esophageal reflux disease, because the procedure is cost effective and can be performed in an outpatient setting under local anesthesia.
  • a suitable injectable tissue bulking agent would consist of pre-formed particles or aggregates of collagen about 10-50 ⁇ m in diameter that have been mixed with sufficient von Willebrand Factor to permit the formation of complete coat of the protein over the surface of the particles.
  • the von Willebrand Factor-coated collagen particles would be washed to remove any unbound VWF.
  • the particles would be resuspended in a pharmaceutical vehicle that is suitable for injection, most commonly a buffered saline solution.
  • the von Willebrand Factor-coated collagen particles could be injected though a 25 gauge needle into the submucosa of the lower esophageal sphincter during an endoscopy procedure that would normally be performed in an outpatient setting.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Dermatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Biophysics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne de manière générale des méthodes et des compositions visant à améliorer l'apparence ou la cicatrisation de la peau ou la fonction des sphincters associés à des organes par administration d'un agent gonflant contenant le facteur Von Villebrand (VWF) seul ou combiné à du collagène.
PCT/IB2002/005284 2001-12-13 2002-12-11 Implants biocompatibles revetus du facteur von willebrand WO2003049782A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002366585A AU2002366585A1 (en) 2001-12-13 2002-12-11 Von willebrand factor-coated biocompatible implants

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33913401P 2001-12-13 2001-12-13
US60/339,134 2001-12-13

Publications (1)

Publication Number Publication Date
WO2003049782A1 true WO2003049782A1 (fr) 2003-06-19

Family

ID=23327647

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2002/005284 WO2003049782A1 (fr) 2001-12-13 2002-12-11 Implants biocompatibles revetus du facteur von willebrand

Country Status (2)

Country Link
AU (1) AU2002366585A1 (fr)
WO (1) WO2003049782A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007045616A1 (fr) * 2005-10-18 2007-04-26 Cinvention Ag Particules thermodurcies et procédés pour la production de celles-ci
JP2018520126A (ja) * 2015-06-10 2018-07-26 エボニック レーム ゲゼルシャフト ミット ベシュレンクテル ハフツングＥｖｏｎｉｋ Ｒｏｅｈｍ ＧｍｂＨ ヒト凝固因子タンパク質と乳酸ポリマーを含む粉末を製造する方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013003A1 (fr) * 1991-01-18 1992-08-06 University College London Proteine d'adhesion cellulaire a orientation macroscopique pour le traitement des blessures
US5834232A (en) * 1996-05-01 1998-11-10 Zymogenetics, Inc. Cross-linked gelatin gels and methods of making them
WO2001006949A2 (fr) * 1999-07-28 2001-02-01 Interface Biotech A/S Reparation in vivo de defauts osseux et/ou du cartilage
WO2001066161A1 (fr) * 2000-03-06 2001-09-13 Surmodics, Inc. Revetements d'implants endovasculaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992013003A1 (fr) * 1991-01-18 1992-08-06 University College London Proteine d'adhesion cellulaire a orientation macroscopique pour le traitement des blessures
US5834232A (en) * 1996-05-01 1998-11-10 Zymogenetics, Inc. Cross-linked gelatin gels and methods of making them
WO2001006949A2 (fr) * 1999-07-28 2001-02-01 Interface Biotech A/S Reparation in vivo de defauts osseux et/ou du cartilage
WO2001066161A1 (fr) * 2000-03-06 2001-09-13 Surmodics, Inc. Revetements d'implants endovasculaires

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007045616A1 (fr) * 2005-10-18 2007-04-26 Cinvention Ag Particules thermodurcies et procédés pour la production de celles-ci
JP2018520126A (ja) * 2015-06-10 2018-07-26 エボニック レーム ゲゼルシャフト ミット ベシュレンクテル ハフツングＥｖｏｎｉｋ Ｒｏｅｈｍ ＧｍｂＨ ヒト凝固因子タンパク質と乳酸ポリマーを含む粉末を製造する方法

Also Published As

Publication number Publication date
AU2002366585A1 (en) 2003-06-23

Similar Documents

Publication Publication Date Title
Shekhter et al. Medical applications of collagen and collagen-based materials
JP6640808B2 (ja) 異なる密度の成分を有する粒子状組織グラフトならびにそれを作成および使用する方法
AU2009277252B2 (en) Tissue scaffolds derived from forestomach extracellular matrix
JP4137382B2 (ja) 膠原組織組成物
EP0526756B1 (fr) Composition pour revitaliser le tissu cicatrisé
Natsume et al. Porous collagen sponge for esophageal replacement
Jia et al. Urethral tissue regeneration using collagen scaffold modified with collagen binding VEGF in a beagle model
US20060246033A1 (en) Injectable bulking agent compositions
US20110097367A1 (en) Monolithic in-situ cross-linked alginate implants
JPH0789867A (ja) 瘢痕組織を賦活化するための方法および組成物
US20100239556A1 (en) Promoting ecm production by fibroblast cells and/or promoting migration of fibroblast cells in a biological system
US20110064810A1 (en) Tissue engineering method for organ reconstruction using injectable matrix
WO1994000484A1 (fr) Facteur inhibiteur de cicatrices et utilisation
WO2012024390A9 (fr) Échafaudage composite biohybride
Kimura et al. In situ adipogenesis in fat tissue augmented by collagen scaffold with gelatin microspheres containing basic fibroblast growth factor
Jelodari et al. Decellularization of small intestinal submucosa
Mandal et al. Collagen as Biomaterial for Medical Application--Drug Delivery and Scaffolds for Tissue Regeneration: A Review
WO2003049782A1 (fr) Implants biocompatibles revetus du facteur von willebrand
JP2013517854A (ja) 人間又は動物の器官を再構成するための縫合可能な組織移植片構造
JP2002541926A (ja) 長期安定性を有する体内プロテーゼ
Silver et al. Wound dressings and skin replacement
Kuroyanagi Tissue-engineered products for skin regenerative medicine
Markowicz et al. Enhanced dermal regeneration using modified collagen scaffolds: experimental porcine study
KR102671293B1 (ko) 생착 향상을 위한 접착성 이식재
KR20180134188A (ko) 다양한 생리활성인자들이 탑재된 낙엽 적층형 다공성 고분자 미세입자 및 이의 제조방법

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP