US20010002411A1 - Medical devices comprising ionically and non-ionically crosslinked polymer hydrogels having improved mechanical properties - Google Patents

Medical devices comprising ionically and non-ionically crosslinked polymer hydrogels having improved mechanical properties Download PDF

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US20010002411A1
US20010002411A1 US09/757,396 US75739601A US2001002411A1 US 20010002411 A1 US20010002411 A1 US 20010002411A1 US 75739601 A US75739601 A US 75739601A US 2001002411 A1 US2001002411 A1 US 2001002411A1
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hydrogel
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John Ronan
Samuel Thompson
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M27/00Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
    • A61M27/002Implant devices for drainage of body fluids from one part of the body to another
    • A61M27/008Implant devices for drainage of body fluids from one part of the body to another pre-shaped, for use in the urethral or ureteral tract
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/145Hydrogels or hydrocolloids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials 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
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145Hydrogels or hydrocolloids
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00Processes of treating or compounding macromolecular substances
    • C08J3/24Crosslinking, e.g. vulcanising, of macromolecules
    • C08J3/243Two or more independent types of crosslinking for one or more polymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08JWORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2300/00Characterised by the use of unspecified polymers
    • C08J2300/14Water soluble or water swellable polymers, e.g. aqueous gels
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S524/00Synthetic resins or natural rubbers -- part of the class 520 series
    • Y10S524/916Hydrogel compositions
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S525/00Synthetic resins or natural rubbers -- part of the class 520 series
    • Y10S525/903Interpenetrating network
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S623/00Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
    • Y10S623/901Method of manufacturing prosthetic device

Definitions

  • This invention relates to medical devices comprising polymer hydrogels having improved mechanical properties.
  • Medical devices adapted for implant into the body to facilitate the flow of bodily fluids, to serve as vascular grafts or for other purposes have been developed.
  • these devices include stents, catheters or cannulas, plugs, constrictors, tissue or biological encapsulants and the like.
  • many of these devices used as implants are made of durable, non-degradable plastic materials such as polyurethanes, polyacrylates, silicone polymers and the like, or more preferably from biodegradable polymers which remain stable in-vivo for a period of time but eventually biodegrade in-vivo into small molecules which are removed by the body by normal elimination in the urine or feces.
  • durable, non-degradable plastic materials such as polyurethanes, polyacrylates, silicone polymers and the like, or more preferably from biodegradable polymers which remain stable in-vivo for a period of time but eventually biodegrade in-vivo into small molecules which are removed by the body by normal elimination in the urine or feces.
  • Typical of such biodegradable polymers are polyesters, polyanhydrides and polyorthoesters which undergo hydrolytic chain cleavage, as disclosed in U.S. Pat. No. 5,085,629; crosslinked polysaccharide hydrogel polymers as disclosed in EPA 0507604 A-2 and U.S. Pat. No. 5,057,606 and other tonically crosslinked hydrogels as disclosed in U.S. Pat. Nos. 4,941,870, 4,286,341 and 4,878,907.
  • EPA 0645150 A-1 describes hydrogel medical devices prepared from ionically crosslinked anionic polymers, e.g. polysaccharides such as calcium alginate or ionically crosslinked cationic polymers such as chitosan, cationic guar, cationic starch and polyethylene amine. These devices are adapted for more rapid in-vivo disintegration upon the administration of a chemical trigger material which displaces crosslinking ions.
  • anionic polymers e.g. polysaccharides such as calcium alginate or ionically crosslinked cationic polymers such as chitosan, cationic guar, cationic starch and polyethylene amine.
  • Hydrogels offer excellent biocompatibility and have been shown to have reduced tendency for inducing thrombosis, encrustation, and inflammation.
  • the use of hydrogels in biomedical device applications has often been hindered by poor mechanical performance.
  • many medical device applications exist where minimal stresses are encountered by the device in-vivo most applications require that the device survive high stresses during implantation.
  • Hydrogels suffer from low modulus, low yield stress and low strength when compared to non-swollen polymer systems. Lower mechanical properties result from the swollen nature of hydrogels and the non-stress bearing nature of the swelling agent, e.g., aqueous fluids.
  • This invention provides a means of boosting the mechanical performance of shaped medical devices comprising polymer hydrogels, such as stents, so that they may be more easily inserted into the body, and at the same time provides a means to soften such devices in-vivo while retaining the structural integrity of the device.
  • the invention provides a process for improving the mechanical properties and structural integrity of a shaped medical device comprising a crosslinked polymeric hydrogel, said process comprising subjecting an ionically crosslinkable polymer composition to crosslinking conditions such that both ionic and non-ionic crosslinks are formed resulting in a polymeric hydrogel, wherein a medical device of improved structural integrity is obtained upon selective removal of said crosslinking ions from said polymeric hydrogel.
  • the invention also provides a process for improving the mechanical properties and structural integrity of a shaped medical device comprising a polymeric hydrogel, said process comprising:
  • a medical device substantially conforming to the primary shape of said hydrogel is obtained upon selective removal of the crosslinking ions from said crosslinked polymeric hydrogel, such as by removal of said ions after the device is implanted into the body.
  • the invention also provides a shaped medical device having improved mechanical properties comprising a cross-linked polymeric hydrogel, said hydrogel containing both an ionic and a non-ionic crosslink structure.
  • the device is characterized by improved structural integrity after selective removal of said ionic crosslinking ions as compared with an otherwise identical device containing only an ionic structure.
  • the invention further provides a medical procedure comprising insertion of the above-described medical device into a human or animal body to form an implant, followed by the selective removal of at least a portion of the crosslinking ions from the implant in-vivo to soften the implant. Where the implant is later surgically removed, it may be once again subjected to ionic crosslinking conditions to ionically re-crosslink the implant prior to removal from the body.
  • the ionically crosslinkable polymers from which the medical devices of this invention may be fabricated may be anionic or cationic in nature and include but are not limited to carboxylic, sulfate, hydroxy and amine functionalized polymers, normally referred to as hydrogels after being crosslinked.
  • hydrogel indicates a crosslinked, water insoluble, water containing material.
  • Suitable crosslinkable polymers which may be used in the present invention include but are not limited to one or a mixture of polymers selected from the group consisting of polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide, poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed polyacrylonitrile, polyacrylic acid, polymethacrylic acid, polyethylene amine, alginic acid, pectinic acid, carboxy methyl cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan, carboxymethyl chitosan, chitin, pullulan, gellan, xanthan, carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate, cationic guar, cationic starch as well as salts and esters thereof.
  • Polymers listed above which are not ionically crosslinkable are used in blends with polymers which are ionically crosslinkable
  • the most preferred polymers include one or a mixture of alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic acid, chitosan, polyvinyl alcohol and salts and esters thereof.
  • Preferred anionic polymers are alginic or pectinic acid; preferred cationic polymers include chitosan, cationic guar, cationic starch and polyethylene amine.
  • Preferred blends comprise alginic acid and polyvinylalcohol.
  • the crosslinking ions used to crosslink the polymers may be anions or cations depending on whether the polymer is anionically or cationically crosslinkable.
  • Appropriate crosslinking ions include but are not limited to cations selected from the group consisting of calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, cobalt, lead and silver ions.
  • Anions may be selected from but are not limited to the group consisting of phosphate, citrate, borate, succinate, maleate, adipate and oxalate ions. More broadly, the anions are derived from polybasic organic or inorganic acids.
  • Preferred crosslinking cations are calcium, iron, and barium ions.
  • the most preferred crosslinking cations are calcium and barium ions.
  • the most preferred crosslinking anion is phosphate.
  • Crosslinking may be carried out by contacting the polymers with an aqueous solution containing dissolved ions.
  • the polymer hydrogels forming the shaped medical device of this invention are also crosslinked by non-ionic crosslinking mechanisms to produce a device having a higher crosslink density and one which has improved mechanical properties, i.e., improved stiffness, modulus, yield stress and strength.
  • This may be accomplished by additionally subjecting the tonically crosslinkable polymer to non-ionic crosslinking mechanisms such as high energy radiation (gamma rays) or treatment with a chemical crosslinking agent reactive with groups present in the polymer such that covalent bonds are formed connecting the polymer network.
  • non-ionic crosslinking mechanisms such as high energy radiation (gamma rays) or treatment with a chemical crosslinking agent reactive with groups present in the polymer such that covalent bonds are formed connecting the polymer network.
  • Non-ionic crosslinking mechanism useful with respect to some classes of hydrogel polymers is physical crosslinking which is typically accomplished by crystal formation or similar association of polymer blocks such that the polymer molecules are physically tied together and prevented from complete dissolution. Non-ionic crosslinking may be carried out prior to, subsequent to or concurrently with ionic crosslinking.
  • the most preferred method for non-ionic crosslinking is contact of the tonically crosslinkable polymer with a chemical crosslinking agent, because the degree of crosslinking can be more readily controlled, mainly as a function of the concentration of the crosslinking agent in the reaction medium.
  • Suitable crosslinking agents are polyfunctional compounds preferably having at least two functional groups reactive with one or more functional groups present in the polymer.
  • the crosslinking agent contains one or more of carboxyl, hydroxy, epoxy, halogen or amino functional groups which are capable of undergoing facile nucleophilic or condensation reactions at temperatures up to about 100° C. with groups present along the polymer backbone or in the polymer structure.
  • Suitable crosslinking reagents include polycarboxylic acids or anhydrides; polyamines; epihalohydrins; diepoxides; dialdehydes; diols; carboxylic acid halides, ketenes and like compounds.
  • a particularly preferred crosslinking agent is glutaraldehyde.
  • One of the unique properties of the polymer hydrogels of this invention is that the ionic crosslinks can be easily and selectively displaced in-vivo after implantation of the device in the body, resulting in a swelling and softening of the device in the body which enhances patient comfort. Since the non-ionic crosslinks are not significantly displaced, the device will retain its original non-ionically crosslinked shape configuration to a large degree and will not disintegrate.
  • a biliary or urethral stent can be fabricated which has improved modulus (stiffness) properties due to the dual crosslinking treatment of this invention.
  • modulus stiffness
  • Such a stent will be robust enough and be sufficiently resistant to buckling such that it can be readily inserted into the appropriate part of the body with an endoscope.
  • the ionic crosslinks present in the device can be selectively at least partially stripped either directly by the physician, by dietary means or by means of natural body fluids such as bile or urine.
  • the modulus of the device will be lowered and the device will soften and swell in body fluids, resulting in a more comfortable and conformable element and a larger lumen through which body fluids-may flow.
  • An enlarged lumen is typically preferred in tubular shaped devices to allow higher flow rates, to provide anchoring force to the body and to decrease the likelihood of occlusion during service.
  • Displacement of the crosslinking ions can be accomplished by flowing a solution containing a stripping agent around and/or through the medical device in-vivo.
  • the stripping agent serves to displace, sequester or bind the crosslinking ions present in the ionically crosslinked polymer, thereby removing the ionic crosslinks.
  • the choice of any particular stripping agent will depend on whether the ion to be displaced is an anion or a cation.
  • Suitable stripping agents include but are not limited to organic acids and their salts or esters, phosphoric acid and salts or esters thereof, sulfate salts and alkali metal or ammonium salts.
  • stripping agents include, but are not limited to, ethylene diamine tetraacetic acid, ethylene diamine tetraacetate, citric acid and its salts, organic phosphates such as cellulose phosphate, inorganic phosphates, as for example, pentasodium tripolyphosphate, mono and dibasic potassium phosphate, sodium pyrophosphate, phosphoric acid, trisodium carboxymethyloxysuccinate, nitrilotriacetic acid, maleic acid, oxalate, polyacrylic acid, as well as sodium, potassium, lithium, calcium and magnesium ions.
  • Preferred agents are citrate, inorganic phosphates and sodium, potassium and magnesium ions. The most preferred agents are inorganic phosphates and magnesium ions.
  • Specific methods for introduction of the stripping agent include introduction through the diet of the patient or through parenteral feeding, introduction of a solution directly onto the device such as by insertion of a catheter-which injects the. agent within the device, or through an enema.
  • one dietary technique for stripping urinary device such as an implanted calcium alginate ureteral stent strippable by phosphate anions would be to include in the patient's diet materials which bind phosphate e.g., calcium salts, to lower the content of PO 4 ⁇ 3 present in the urine which can be normally up to about 0.1%.
  • phosphate binders can be eliminated from the diet and also replaced by foods or substances which generate phosphate ions in the urine. Achievement of levels of phosphate in the urine of from 0.2 to 0.3% will result in the in-vivo stripping of the calcium ions from the calcium alginate stent. Lower levels of phosphate in the urine will also result in a more gradual stripping of the calcium ions, but higher levels are preferred for rapid stripping of the calcium.
  • stripping process may be reversed to re-stiffen the medical device which facilitates surgical removal of the device from the body. This may be accomplished by flowing a source of crosslinking ions through and/or around the implant to ionically re-crosslink the implant, essentially the reverse of the stripping process described above. Dietary modifications can also be used to re-crosslink the medical device in-vivo.
  • a secondary shape can be imparted to the medical device prior to implant in the body. This is accomplished by deforming the primary shape of a device which is crosslinked at least non-ionically, setting the device in the deformed shape by ionic crosslinking and implanting the device in the body in the deformed shape. Stripping the ions in-vivo as described above will cause the device to revert in-vivo to its primary non-ionically crosslinked shape.
  • an tonically crosslinkable polymer is formed into a primary shape and subjected to non-ionic crosslinking conditions to form a non-ionically crosslinked hydrogel having said primary shape.
  • Non-ionic crosslinking can be carried out by the methods described above, and is preferably carried out by extruding the polymer into a bath containing a sufficient amount of one or more of the non-ionic crosslinking agents to-form a shape-retaining hydrogel. Next, a secondary shape is imparted to the non-ionically crosslinked hydrogel and the hydrogel is then subjected to ionic crosslinking conditions to ionically crosslink the hydrogel while retaining this secondary shape.
  • an ionically crosslinkable polymer is formed into a primary shape and subjected to both non-ionic and ionic crosslinking conditions to form a hydrogel having said primary shape and containing both an ionic and non-ionic crosslink structure.
  • an ionically and non-ionically crosslinked shaped hydrogel is prepared as above.
  • the shaped hydrogel is selectively stripped ex-vivo of at least a portion or essentially all of the crosslinking ions; the shaped hydrogel is conformed to a secondary shape, e.g., bent around a wire, stretched, compressed or the like; and the shaped hydrogel is ionically re-crosslinked while retained in the secondary shape. Release of the crosslinking ions in-vivo will cause the implanted device to revert substantially to the original primary, non-ionically crosslinked shape.
  • the stripping step described above can occur immediately prior to or subsequent to the secondary shaping step, but preferably subsequent such step but prior to the ionic recrosslink step.
  • the medical device is of hollow, tubular configuration, such as a stent.
  • the stent is both ionically and non-ionically crosslinked, it is selectively stripped of the crosslinking ions.
  • the stent is stretched to form a narrower stent which facilitates insertion into the body, ionically crosslinked or re-crosslinked in the stretched state to fix the stent in the stretched state, implanted in the body and then re-stripped in-vivo of the ionic crosslinks to produce a softer implant having a wider lumen.
  • stent shapes such as pigtail ends, flaps, curves and the like can be developed in-vivo by subjecting devices having these primary initial shapes to the process described above, i.e., deforming the primary shape ex-vivo and reforming the primary shape in-vivo.
  • the stripping step described above is preferably accomplished by dipping or spraying the crosslinked device with an aqueous electrolyte solution for an appropriate time to selectively strip the crosslinking ions from the device.
  • Preferred electrolytes for ex-vivo stripping are chlorides of monovalent cations such as sodium, potassium or lithium chloride, as well as other stripping salts described above.
  • the concentration of the electrolyte salt in the solution may range from about 1 wt % up to the solubility limit.
  • the solution may also contain plasticizing ingredients such as glycerol or sorbitol to facilitate inter and intra polymer chain motion during and after secondary shaping.
  • Secondary shaping of the medical device may be done by hand, i.e., using pinning boards or jig pins, or by using shaped presses or molds.
  • the device may be ionically crosslinked or re-crosslinked in the secondary shape by contacting the device, while retaining the secondary shape, with an aqueous solution containing the crosslinking ions described above. After crosslinking, the device will essentially retain the secondary shape.
  • Medical devices which may be fabricated in accordance with this invention include stents, catheters or cannulas, plugs and constrictors, for both human and animal use.
  • the invention is particularly applicable to medical stents of tubular configuration which come in contact with one or more body fluids such as blood, urine, gastrointestinal fluids and bile.
  • the devices are particularly applicable for use in gastrointestinal, urogenital, cardiovascular, lymphatic, otorhinolaryngological, optical, neurological, integument and muscular body systems.
  • the devices may optionally include fillers, disintegration agents, additives for medical treatment such as antiseptics, antibiotics, anticoagulants, or medicines, and additives for mechanical property adjustment of the device.
  • Linear device or pre-device -configurations -such as fibers, rods, tubes or ribbons can be manufactured in accordance with the present invention by using a spinning device in which an aqueous solution of an ionically crosslinkable matrix polymer is forced through a shaping die into a crosslinking bath containing the crosslinking ions.
  • the product after crosslinking is typically described as a hydrogel.
  • the hydrogel may be used as made, or further given a three dimensional shape through treatment in a crosslinking solution after being forced into the desired shape. After equilibration, the hydrogel will retain the new three dimension shape.
  • the device may be used in its hydrogel form or in a dehydrated form. During dehydration, the three dimensional shape is retained.
  • Another process for manufacturing the articles of the present invention comprises introducing a solution comprising ionically crosslinkable polymer through a die to form a tube, simultaneously pumping a solution comprising crosslinking ion through the formed tube, and extruding the formed tube from said die into a solution comprising crosslinking ion.
  • the crosslinking step may involve shaping of the device as in wet spinning of a tubular device.
  • the device may be prepared by molding a latent crosslinking composition using a one or two part reaction injection molding system.
  • tubular as used herein, includes not only cylindrical shaped devices having circular cross sections, but also devices having different cross sections as long as such articles have a hollow passageway, which distinguishes a tube from a rod.
  • the ionically crosslinked, shaped polymer prepared as above is then subjected to non-ionic crosslinking, e.g. high energy radiation or by contact under appropriate acidic or basic conditions with the appropriate chemical crosslinking agent.
  • Crosslinking is preferably carried out by soaking the polymer in an aqueous solution containing a water soluble crosslinking agent such as glutaraldehyde, ethylene diamine or a lower alkylene glycol.
  • a water soluble crosslinking agent such as glutaraldehyde, ethylene diamine or a lower alkylene glycol.
  • concentration of crosslinking agent in solution may range from about 0.25 to about 10 wt %, more preferably from about 0.5 to 5.0 wt %.
  • the degree of non-ionic crosslinking is controlled as a function of the concentration of the crosslinking agent in solution.
  • the level should be selected such that a stiffer, higher modulus device is produced which will revert to a soft, stretchy, shape retaining device after removal of the ionic crosslinks. Some trial and error may be required to determine optimum levels depending on the particular polymer and the identity of the crosslinking agent.
  • the crosslinking process may also be conducted by first crosslinking the polymer non-ionically, followed by ionic crosslinking, essentially the reverse of the process described above.
  • the ionically crosslinkable polymer composition includes polymers which are partially water soluble
  • additives such as borax, boric acid, alkali metal salts and/or a lower alcohol such as methanol.
  • the various steps may be performed at any suitable temperature, e.g., at room temperature or at temperatures up to about 100° C. Preferably, soaking steps are conducted at room temperature. Moreover, the steps may be performed one immediately after another, or a drying step (e.g., air-drying) may be interposed between one or more steps. Additionally, the shaped medical device may be sterilized after the sequence of secondary-shaping steps.
  • the medical device may be stored wet or dry.
  • the medical device may be stored in a suitable aqueous solution or may be dried prior to storage.
  • the medical device could be stored in deionized water, or in water containing water soluble agents such as glycerol, sorbitol, sucrose and the like.
  • Exemplary hydrogel systems which may be prepared in accordance with this invention can be prepared by the following procedures:
  • a solution of sodium alginate is extruded through a tube die into a calcium chloride bath while calcium chloride solution is simultaneously introduced through the lumen of the tube.
  • This ionically crosslinked tube is then covalently crosslinked by treatment with an aqueous solution containing glutaraldehyde.
  • the now covalently and tonically crosslinked gel has a higher crosslink density and therefore higher modulus than a similar tube having only the covalent or only the ionic crosslinks.
  • the tube therefore has higher stiffness and improved resistance to buckling than a tube having the covalent or ionic crosslinks alone.
  • Suitable ions which will displace the calcium crosslinking ions include phosphate, sulfate, carbonate, potassium, sodium and ammonium.
  • the implanted device may be stiffened and strengthened during removal from the body via exposure of the device to an infusion fluid which contains a solution of the crosslinking ions (calcium).
  • a blend of polyvinyl alcohol (PVA) and sodium alginate may be dispersed or dissolved in water, extruded into a bath containing calcium ions, said bath also containing non-solvent conditions for the polyvinyl alcohol.
  • the polyvinyl alcohol component of the formed article may then be covalently crosslinked with an aqueous solution containing glutaraldehyde.
  • the article is now ready for insertion or implantation. After implantation, the article may be softened and swollen by removal of the ionic crosslinks as above. Removal of the ionic crosslinks may also optionally allow the alginate to fully or partially dissolve in the body fluids, leaving behind a less dense, more porous hydrogel.
  • the morphology of the final hydrogel device may be controlled through judicious selection of polyvinyl alcohol molecular weight, degree of crosslinking, solvent composition, alginate molecular weight, alginate salt used, state of the alginate salt (dissolved, particulated, gel), alginate monomer makeup, temperature, pressure, mix time, solution age, and rheological factors during manufacture.
  • the blend of PVA and sodium alginate described in (b) above may be used to make a stent having a shape memory feature to gain increased lumen size after deployment in-vivo.
  • a tube is made by extruding the mixture through a tube die into a concentrated calcium chloride bath, optionally containing other salts and boric acid. The tube is then transferred into a bath which contains calcium chloride and a chemical crosslinker (glutaraldehyde). After allowing for reaction, the tube will become a covalently crosslinked PVA/calcium alginate system. The tube is immersed in concentrated potassium chloride solution to remove the calcium crosslinks from the alginate while preventing the alginate from dissolving.
  • the tube is then stretched to form a longer length tube having a more narrow lumen. While in this stretched configuration, the tube is immersed into concentrated calcium chloride solution to re-crosslink the alginate. The tube is frozen into the longer length, narrow lumen configuration. Upon insertion into the body, the tube will return to it's original shorter length, large lumen configuration as the calcium is stripped from the alginate. The alginate may eventually dissolve, leaving behind a more porous glutaraldehyde crosslinked PVA tube. Other imposed shapes may be used to accommodate body insertion in a compact form, followed by shape change upon displacement of the ionic crosslinks.
  • Propyleneglycol alginate may be covalently crosslinked with ethylene diamine under basic conditions and ionically crosslinked with calcium ions. This covalently and tonically crosslinked material will exhibit higher stiffness than the material crosslinked with covalent linkages only. Removal of the ionic crosslinks will occur in-vivo after deployment in body fluid. A stent, catheter or cannula can be manufactured from this material, implanted while both ionically and covalently crosslinked, then in-vivo the device will soften as the ionic crosslinks are displaced. A device of this construction would provide stiffness for implantation and softness for patient comfort.
  • This example illustrates the preparation of tubing from a mixture of sodium alginate (Protanol LF 10/60 from Pronova Bipolymers A. S., Drammen, Norway) and polyvinylalcohol (PVA).
  • PVA polyvinylalcohol
  • the deionized water was weighed into a 4 oz. jar, while stirring the water, the PVA and sodium alginate were added and mixed until uniform.
  • the jar was capped and heated to 100° C. to dissolve the ingredients.
  • the jar was cooled to 37° C., then the bismuth. subcarbonate (radiopaque filler) which had been sifted through a 325 mesh screen was added and the composition was mixed with a jiffy mixer until uniform.
  • the samples were loaded into 30 cc syringes, centrifuged to remove air, then extruded through a tubing die into a coagulant solution.
  • the coagulant solution was made from 100 grams of calcium chloride dihydrate, 30 grams of sodium chloride, 50 grams of boric acid and 820 grams of deionized water.
  • the spun tubing was left in the coagulant solution overnight. Lengths of tubing were then soaked in a glutaraldehyde/coagulant solution mixture to covalently crosslink the sample. Glutaraldehyde levels were tested from 0.5% by weight to 12.5% by weight. pH was adjusted to 1.5 using 20% HCL solution. After reacting overnight at room temperature, the tubes were examined and then immersed in 0.4% sodium phosphate solution to strip the ionic crosslinks. Results are recorded in Table 2.

Abstract

Shaped-medical devices, e.g. stents, having improved mechanical properties and structural integrity are disclosed. The devices comprise shaped polymeric hydrogels which are both tonically and non-ionically crosslinked and which exhibit improved structural integrity after selective removal of the crosslinking ions. Process for making such devices are also disclosed wherein an ionically crosslinkable polymer is both ionically and non-ionically crosslinked to form a shaped medical device. When implanted in the body, selective in-vivo stripping of the crosslinking ions produces a softer, more flexible implant having improved structural integrity.

Description

    BACKGROUND OF THE INVENTION
  • 1. Field of the Invention [0001]
  • This invention relates to medical devices comprising polymer hydrogels having improved mechanical properties. [0002]
  • 2. Description of Related Art [0003]
  • Medical devices adapted for implant into the body to facilitate the flow of bodily fluids, to serve as vascular grafts or for other purposes have been developed. Typically, these devices include stents, catheters or cannulas, plugs, constrictors, tissue or biological encapsulants and the like. [0004]
  • Typically, many of these devices used as implants are made of durable, non-degradable plastic materials such as polyurethanes, polyacrylates, silicone polymers and the like, or more preferably from biodegradable polymers which remain stable in-vivo for a period of time but eventually biodegrade in-vivo into small molecules which are removed by the body by normal elimination in the urine or feces. [0005]
  • Typical of such biodegradable polymers are polyesters, polyanhydrides and polyorthoesters which undergo hydrolytic chain cleavage, as disclosed in U.S. Pat. No. 5,085,629; crosslinked polysaccharide hydrogel polymers as disclosed in EPA 0507604 A-2 and U.S. Pat. No. 5,057,606 and other tonically crosslinked hydrogels as disclosed in U.S. Pat. Nos. 4,941,870, 4,286,341 and 4,878,907. [0006]
  • EPA 0645150 A-1 describes hydrogel medical devices prepared from ionically crosslinked anionic polymers, e.g. polysaccharides such as calcium alginate or ionically crosslinked cationic polymers such as chitosan, cationic guar, cationic starch and polyethylene amine. These devices are adapted for more rapid in-vivo disintegration upon the administration of a chemical trigger material which displaces crosslinking ions. [0007]
  • Hydrogels offer excellent biocompatibility and have been shown to have reduced tendency for inducing thrombosis, encrustation, and inflammation. Unfortunately, the use of hydrogels in biomedical device applications has often been hindered by poor mechanical performance. Although many medical device applications exist where minimal stresses are encountered by the device in-vivo, most applications require that the device survive high stresses during implantation. Hydrogels suffer from low modulus, low yield stress and low strength when compared to non-swollen polymer systems. Lower mechanical properties result from the swollen nature of hydrogels and the non-stress bearing nature of the swelling agent, e.g., aqueous fluids. [0008]
  • Accordingly, there is a need in the art to provide shaped medical devices which not only offer the advantages of polymer hydrogels in terms of biological compatibility, but which also have improved mechanical properties, e.g. improved strength and modulus properties, such that they retain their shape and stiffness during insertion into the body, such as by delivery through an endoscope, and which also can swell and soften inside the body to enhance patient comfort. [0009]
  • SUMMARY OF THE INVENTION
  • This invention provides a means of boosting the mechanical performance of shaped medical devices comprising polymer hydrogels, such as stents, so that they may be more easily inserted into the body, and at the same time provides a means to soften such devices in-vivo while retaining the structural integrity of the device. [0010]
  • The invention provides a process for improving the mechanical properties and structural integrity of a shaped medical device comprising a crosslinked polymeric hydrogel, said process comprising subjecting an ionically crosslinkable polymer composition to crosslinking conditions such that both ionic and non-ionic crosslinks are formed resulting in a polymeric hydrogel, wherein a medical device of improved structural integrity is obtained upon selective removal of said crosslinking ions from said polymeric hydrogel. [0011]
  • In addition, the invention also provides a process for improving the mechanical properties and structural integrity of a shaped medical device comprising a polymeric hydrogel, said process comprising: [0012]
  • a) providing a crosslinked polymeric hydrogel composition containing a non-ionic crosslink structure, said hydrogel polymer characterized as being ionically crosslinkable and having a primary shape; [0013]
  • b) imparting a secondary shape to said hydrogel polymer composition; and [0014]
  • c) subjecting said hydrogel polymer to ionic crosslinking conditions to tonically crosslink said hydrogel polymer while retaining said secondary shape. [0015]
  • A medical device substantially conforming to the primary shape of said hydrogel is obtained upon selective removal of the crosslinking ions from said crosslinked polymeric hydrogel, such as by removal of said ions after the device is implanted into the body. [0016]
  • The invention also provides a shaped medical device having improved mechanical properties comprising a cross-linked polymeric hydrogel, said hydrogel containing both an ionic and a non-ionic crosslink structure. The device is characterized by improved structural integrity after selective removal of said ionic crosslinking ions as compared with an otherwise identical device containing only an ionic structure. [0017]
  • The invention further provides a medical procedure comprising insertion of the above-described medical device into a human or animal body to form an implant, followed by the selective removal of at least a portion of the crosslinking ions from the implant in-vivo to soften the implant. Where the implant is later surgically removed, it may be once again subjected to ionic crosslinking conditions to ionically re-crosslink the implant prior to removal from the body. [0018]
  • DETAILED DESCRIPTION OF THE INVENTION
  • The ionically crosslinkable polymers from which the medical devices of this invention may be fabricated may be anionic or cationic in nature and include but are not limited to carboxylic, sulfate, hydroxy and amine functionalized polymers, normally referred to as hydrogels after being crosslinked. The term “hydrogel” indicates a crosslinked, water insoluble, water containing material. [0019]
  • Suitable crosslinkable polymers which may be used in the present invention include but are not limited to one or a mixture of polymers selected from the group consisting of polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide, poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed polyacrylonitrile, polyacrylic acid, polymethacrylic acid, polyethylene amine, alginic acid, pectinic acid, carboxy methyl cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan, carboxymethyl chitosan, chitin, pullulan, gellan, xanthan, carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate, cationic guar, cationic starch as well as salts and esters thereof. Polymers listed above which are not ionically crosslinkable are used in blends with polymers which are ionically crosslinkable. [0020]
  • The most preferred polymers include one or a mixture of alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic acid, chitosan, polyvinyl alcohol and salts and esters thereof. Preferred anionic polymers are alginic or pectinic acid; preferred cationic polymers include chitosan, cationic guar, cationic starch and polyethylene amine. [0021]
  • Other preferred polymers include esters of alginic, pectinic or hyaluronic acid and C[0022] 2 to C4 polyalkylene glycols, e.g. propylene glycol, as well as blends containing 1 to 99 wt % of alginic,-pectinic or hyaluronic acid with 99 to 1 wt % polyacrylic acid, polymethacrylic acid or polyvinylalcohol. Preferred blends comprise alginic acid and polyvinylalcohol.
  • The crosslinking ions used to crosslink the polymers may be anions or cations depending on whether the polymer is anionically or cationically crosslinkable. Appropriate crosslinking ions include but are not limited to cations selected from the group consisting of calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, cobalt, lead and silver ions. Anions may be selected from but are not limited to the group consisting of phosphate, citrate, borate, succinate, maleate, adipate and oxalate ions. More broadly, the anions are derived from polybasic organic or inorganic acids. Preferred crosslinking cations are calcium, iron, and barium ions. The most preferred crosslinking cations are calcium and barium ions. The most preferred crosslinking anion is phosphate. Crosslinking may be carried out by contacting the polymers with an aqueous solution containing dissolved ions. [0023]
  • As indicated above, the polymer hydrogels forming the shaped medical device of this invention are also crosslinked by non-ionic crosslinking mechanisms to produce a device having a higher crosslink density and one which has improved mechanical properties, i.e., improved stiffness, modulus, yield stress and strength. This may be accomplished by additionally subjecting the tonically crosslinkable polymer to non-ionic crosslinking mechanisms such as high energy radiation (gamma rays) or treatment with a chemical crosslinking agent reactive with groups present in the polymer such that covalent bonds are formed connecting the polymer network. Another non-ionic crosslinking mechanism useful with respect to some classes of hydrogel polymers is physical crosslinking which is typically accomplished by crystal formation or similar association of polymer blocks such that the polymer molecules are physically tied together and prevented from complete dissolution. Non-ionic crosslinking may be carried out prior to, subsequent to or concurrently with ionic crosslinking. [0024]
  • The most preferred method for non-ionic crosslinking is contact of the tonically crosslinkable polymer with a chemical crosslinking agent, because the degree of crosslinking can be more readily controlled, mainly as a function of the concentration of the crosslinking agent in the reaction medium. Suitable crosslinking agents are polyfunctional compounds preferably having at least two functional groups reactive with one or more functional groups present in the polymer. Preferably the crosslinking agent contains one or more of carboxyl, hydroxy, epoxy, halogen or amino functional groups which are capable of undergoing facile nucleophilic or condensation reactions at temperatures up to about 100° C. with groups present along the polymer backbone or in the polymer structure. Suitable crosslinking reagents include polycarboxylic acids or anhydrides; polyamines; epihalohydrins; diepoxides; dialdehydes; diols; carboxylic acid halides, ketenes and like compounds. A particularly preferred crosslinking agent is glutaraldehyde. [0025]
  • One of the unique properties of the polymer hydrogels of this invention is that the ionic crosslinks can be easily and selectively displaced in-vivo after implantation of the device in the body, resulting in a swelling and softening of the device in the body which enhances patient comfort. Since the non-ionic crosslinks are not significantly displaced, the device will retain its original non-ionically crosslinked shape configuration to a large degree and will not disintegrate. [0026]
  • For example, a biliary or urethral stent can be fabricated which has improved modulus (stiffness) properties due to the dual crosslinking treatment of this invention. Such a stent will be robust enough and be sufficiently resistant to buckling such that it can be readily inserted into the appropriate part of the body with an endoscope. Once inserted, the ionic crosslinks present in the device can be selectively at least partially stripped either directly by the physician, by dietary means or by means of natural body fluids such as bile or urine. As the ionic crosslinks are removed, the modulus of the device will be lowered and the device will soften and swell in body fluids, resulting in a more comfortable and conformable element and a larger lumen through which body fluids-may flow. An enlarged lumen is typically preferred in tubular shaped devices to allow higher flow rates, to provide anchoring force to the body and to decrease the likelihood of occlusion during service. [0027]
  • Displacement of the crosslinking ions can be accomplished by flowing a solution containing a stripping agent around and/or through the medical device in-vivo. The stripping agent serves to displace, sequester or bind the crosslinking ions present in the ionically crosslinked polymer, thereby removing the ionic crosslinks. The choice of any particular stripping agent will depend on whether the ion to be displaced is an anion or a cation. Suitable stripping agents include but are not limited to organic acids and their salts or esters, phosphoric acid and salts or esters thereof, sulfate salts and alkali metal or ammonium salts. [0028]
  • Examples of stripping agents include, but are not limited to, ethylene diamine tetraacetic acid, ethylene diamine tetraacetate, citric acid and its salts, organic phosphates such as cellulose phosphate, inorganic phosphates, as for example, pentasodium tripolyphosphate, mono and dibasic potassium phosphate, sodium pyrophosphate, phosphoric acid, trisodium carboxymethyloxysuccinate, nitrilotriacetic acid, maleic acid, oxalate, polyacrylic acid, as well as sodium, potassium, lithium, calcium and magnesium ions. Preferred agents are citrate, inorganic phosphates and sodium, potassium and magnesium ions. The most preferred agents are inorganic phosphates and magnesium ions. [0029]
  • Specific methods for introduction of the stripping agent include introduction through the diet of the patient or through parenteral feeding, introduction of a solution directly onto the device such as by insertion of a catheter-which injects the. agent within the device, or through an enema. [0030]
  • For example, one dietary technique for stripping urinary device such as an implanted calcium alginate ureteral stent strippable by phosphate anions would be to include in the patient's diet materials which bind phosphate e.g., calcium salts, to lower the content of PO[0031] 4 −3 present in the urine which can be normally up to about 0.1%. When it is desired to strip the medical device, phosphate binders can be eliminated from the diet and also replaced by foods or substances which generate phosphate ions in the urine. Achievement of levels of phosphate in the urine of from 0.2 to 0.3% will result in the in-vivo stripping of the calcium ions from the calcium alginate stent. Lower levels of phosphate in the urine will also result in a more gradual stripping of the calcium ions, but higher levels are preferred for rapid stripping of the calcium.
  • Another advantage of the invention is that the stripping process may be reversed to re-stiffen the medical device which facilitates surgical removal of the device from the body. This may be accomplished by flowing a source of crosslinking ions through and/or around the implant to ionically re-crosslink the implant, essentially the reverse of the stripping process described above. Dietary modifications can also be used to re-crosslink the medical device in-vivo. [0032]
  • In another embodiment of the invention, a secondary shape can be imparted to the medical device prior to implant in the body. This is accomplished by deforming the primary shape of a device which is crosslinked at least non-ionically, setting the device in the deformed shape by ionic crosslinking and implanting the device in the body in the deformed shape. Stripping the ions in-vivo as described above will cause the device to revert in-vivo to its primary non-ionically crosslinked shape. In accordance with one aspect of this embodiment, an tonically crosslinkable polymer is formed into a primary shape and subjected to non-ionic crosslinking conditions to form a non-ionically crosslinked hydrogel having said primary shape. Non-ionic crosslinking can be carried out by the methods described above, and is preferably carried out by extruding the polymer into a bath containing a sufficient amount of one or more of the non-ionic crosslinking agents to-form a shape-retaining hydrogel. Next, a secondary shape is imparted to the non-ionically crosslinked hydrogel and the hydrogel is then subjected to ionic crosslinking conditions to ionically crosslink the hydrogel while retaining this secondary shape. [0033]
  • In another aspect of this embodiment, an ionically crosslinkable polymer is formed into a primary shape and subjected to both non-ionic and ionic crosslinking conditions to form a hydrogel having said primary shape and containing both an ionic and non-ionic crosslink structure. In accordance with this second aspect, an ionically and non-ionically crosslinked shaped hydrogel is prepared as above. Then, the shaped hydrogel is selectively stripped ex-vivo of at least a portion or essentially all of the crosslinking ions; the shaped hydrogel is conformed to a secondary shape, e.g., bent around a wire, stretched, compressed or the like; and the shaped hydrogel is ionically re-crosslinked while retained in the secondary shape. Release of the crosslinking ions in-vivo will cause the implanted device to revert substantially to the original primary, non-ionically crosslinked shape. The stripping step described above can occur immediately prior to or subsequent to the secondary shaping step, but preferably subsequent such step but prior to the ionic recrosslink step. [0034]
  • This embodiment is particularly useful where the medical device is of hollow, tubular configuration, such as a stent. Where the stent is both ionically and non-ionically crosslinked, it is selectively stripped of the crosslinking ions. The stent is stretched to form a narrower stent which facilitates insertion into the body, ionically crosslinked or re-crosslinked in the stretched state to fix the stent in the stretched state, implanted in the body and then re-stripped in-vivo of the ionic crosslinks to produce a softer implant having a wider lumen. Other stent shapes such as pigtail ends, flaps, curves and the like can be developed in-vivo by subjecting devices having these primary initial shapes to the process described above, i.e., deforming the primary shape ex-vivo and reforming the primary shape in-vivo. [0035]
  • The stripping step described above is preferably accomplished by dipping or spraying the crosslinked device with an aqueous electrolyte solution for an appropriate time to selectively strip the crosslinking ions from the device. Preferred electrolytes for ex-vivo stripping are chlorides of monovalent cations such as sodium, potassium or lithium chloride, as well as other stripping salts described above. The concentration of the electrolyte salt in the solution may range from about 1 wt % up to the solubility limit. The solution may also contain plasticizing ingredients such as glycerol or sorbitol to facilitate inter and intra polymer chain motion during and after secondary shaping. [0036]
  • Secondary shaping of the medical device may be done by hand, i.e., using pinning boards or jig pins, or by using shaped presses or molds. [0037]
  • The device may be ionically crosslinked or re-crosslinked in the secondary shape by contacting the device, while retaining the secondary shape, with an aqueous solution containing the crosslinking ions described above. After crosslinking, the device will essentially retain the secondary shape. [0038]
  • Medical devices which may be fabricated in accordance with this invention include stents, catheters or cannulas, plugs and constrictors, for both human and animal use. The invention is particularly applicable to medical stents of tubular configuration which come in contact with one or more body fluids such as blood, urine, gastrointestinal fluids and bile. The devices are particularly applicable for use in gastrointestinal, urogenital, cardiovascular, lymphatic, otorhinolaryngological, optical, neurological, integument and muscular body systems. [0039]
  • The devices may optionally include fillers, disintegration agents, additives for medical treatment such as antiseptics, antibiotics, anticoagulants, or medicines, and additives for mechanical property adjustment of the device. [0040]
  • Linear device or pre-device -configurations -such as fibers, rods, tubes or ribbons can be manufactured in accordance with the present invention by using a spinning device in which an aqueous solution of an ionically crosslinkable matrix polymer is forced through a shaping die into a crosslinking bath containing the crosslinking ions. The product after crosslinking is typically described as a hydrogel. The hydrogel may be used as made, or further given a three dimensional shape through treatment in a crosslinking solution after being forced into the desired shape. After equilibration, the hydrogel will retain the new three dimension shape. The device may be used in its hydrogel form or in a dehydrated form. During dehydration, the three dimensional shape is retained. [0041]
  • Another process for manufacturing the articles of the present invention comprises introducing a solution comprising ionically crosslinkable polymer through a die to form a tube, simultaneously pumping a solution comprising crosslinking ion through the formed tube, and extruding the formed tube from said die into a solution comprising crosslinking ion. In this process, the crosslinking step may involve shaping of the device as in wet spinning of a tubular device. Alternatively, the device may be prepared by molding a latent crosslinking composition using a one or two part reaction injection molding system. The term “tubular” as used herein, includes not only cylindrical shaped devices having circular cross sections, but also devices having different cross sections as long as such articles have a hollow passageway, which distinguishes a tube from a rod. [0042]
  • The ionically crosslinked, shaped polymer prepared as above is then subjected to non-ionic crosslinking, e.g. high energy radiation or by contact under appropriate acidic or basic conditions with the appropriate chemical crosslinking agent. Crosslinking is preferably carried out by soaking the polymer in an aqueous solution containing a water soluble crosslinking agent such as glutaraldehyde, ethylene diamine or a lower alkylene glycol. Generally, the concentration of crosslinking agent in solution may range from about 0.25 to about 10 wt %, more preferably from about 0.5 to 5.0 wt %. The degree of non-ionic crosslinking is controlled as a function of the concentration of the crosslinking agent in solution. The level should be selected such that a stiffer, higher modulus device is produced which will revert to a soft, stretchy, shape retaining device after removal of the ionic crosslinks. Some trial and error may be required to determine optimum levels depending on the particular polymer and the identity of the crosslinking agent. [0043]
  • The crosslinking process may also be conducted by first crosslinking the polymer non-ionically, followed by ionic crosslinking, essentially the reverse of the process described above. [0044]
  • Where the ionically crosslinkable polymer composition includes polymers which are partially water soluble, it is preferred to include in the aqueous spinning solution and treatment solutions described above one or more additives which retard the tendency of the solution to dissolve the polymer, i.e., provide non-solvent conditions. Example of such conditions include high salt concentrations, or inclusion in the solution of additives such as borax, boric acid, alkali metal salts and/or a lower alcohol such as methanol. [0045]
  • The various steps may be performed at any suitable temperature, e.g., at room temperature or at temperatures up to about 100° C. Preferably, soaking steps are conducted at room temperature. Moreover, the steps may be performed one immediately after another, or a drying step (e.g., air-drying) may be interposed between one or more steps. Additionally, the shaped medical device may be sterilized after the sequence of secondary-shaping steps. [0046]
  • The medical device may be stored wet or dry. For example, the medical device may be stored in a suitable aqueous solution or may be dried prior to storage. For example, the medical device could be stored in deionized water, or in water containing water soluble agents such as glycerol, sorbitol, sucrose and the like. [0047]
  • Exemplary hydrogel systems which may be prepared in accordance with this invention can be prepared by the following procedures: [0048]
  • a) Alginate which has been covalently and ionically crosslinked. [0049]
  • A solution of sodium alginate is extruded through a tube die into a calcium chloride bath while calcium chloride solution is simultaneously introduced through the lumen of the tube. This ionically crosslinked tube is then covalently crosslinked by treatment with an aqueous solution containing glutaraldehyde. The now covalently and tonically crosslinked gel has a higher crosslink density and therefore higher modulus than a similar tube having only the covalent or only the ionic crosslinks. The tube therefore has higher stiffness and improved resistance to buckling than a tube having the covalent or ionic crosslinks alone. After insertion into the body, exposure of the tube to ions in body fluids will remove the calcium crosslinks, lower the modulus of the gel and therefore reduce the stiffness of the tube, allowing for maximum patient comfort and biocompatibility. Suitable ions which will displace the calcium crosslinking ions include phosphate, sulfate, carbonate, potassium, sodium and ammonium. The implanted device may be stiffened and strengthened during removal from the body via exposure of the device to an infusion fluid which contains a solution of the crosslinking ions (calcium). [0050]
  • b) Polyvinyl alcohol and alginate. [0051]
  • A blend of polyvinyl alcohol (PVA) and sodium alginate may be dispersed or dissolved in water, extruded into a bath containing calcium ions, said bath also containing non-solvent conditions for the polyvinyl alcohol. The polyvinyl alcohol component of the formed article may then be covalently crosslinked with an aqueous solution containing glutaraldehyde. The article is now ready for insertion or implantation. After implantation, the article may be softened and swollen by removal of the ionic crosslinks as above. Removal of the ionic crosslinks may also optionally allow the alginate to fully or partially dissolve in the body fluids, leaving behind a less dense, more porous hydrogel. The morphology of the final hydrogel device may be controlled through judicious selection of polyvinyl alcohol molecular weight, degree of crosslinking, solvent composition, alginate molecular weight, alginate salt used, state of the alginate salt (dissolved, particulated, gel), alginate monomer makeup, temperature, pressure, mix time, solution age, and rheological factors during manufacture. [0052]
  • c) Polyvinyl alcohol and alginate—shape memory. [0053]
  • The blend of PVA and sodium alginate described in (b) above may be used to make a stent having a shape memory feature to gain increased lumen size after deployment in-vivo. A tube is made by extruding the mixture through a tube die into a concentrated calcium chloride bath, optionally containing other salts and boric acid. The tube is then transferred into a bath which contains calcium chloride and a chemical crosslinker (glutaraldehyde). After allowing for reaction, the tube will become a covalently crosslinked PVA/calcium alginate system. The tube is immersed in concentrated potassium chloride solution to remove the calcium crosslinks from the alginate while preventing the alginate from dissolving. The tube is then stretched to form a longer length tube having a more narrow lumen. While in this stretched configuration, the tube is immersed into concentrated calcium chloride solution to re-crosslink the alginate. The tube is frozen into the longer length, narrow lumen configuration. Upon insertion into the body, the tube will return to it's original shorter length, large lumen configuration as the calcium is stripped from the alginate. The alginate may eventually dissolve, leaving behind a more porous glutaraldehyde crosslinked PVA tube. Other imposed shapes may be used to accommodate body insertion in a compact form, followed by shape change upon displacement of the ionic crosslinks. [0054]
  • d) Propyleneglycol alginate. [0055]
  • Propyleneglycol alginate may be covalently crosslinked with ethylene diamine under basic conditions and ionically crosslinked with calcium ions. This covalently and tonically crosslinked material will exhibit higher stiffness than the material crosslinked with covalent linkages only. Removal of the ionic crosslinks will occur in-vivo after deployment in body fluid. A stent, catheter or cannula can be manufactured from this material, implanted while both ionically and covalently crosslinked, then in-vivo the device will soften as the ionic crosslinks are displaced. A device of this construction would provide stiffness for implantation and softness for patient comfort. [0056]
  • EXAMPLE 1
  • This example illustrates the preparation of tubing from a mixture of sodium alginate (Protanol LF 10/60 from Pronova Bipolymers A. S., Drammen, Norway) and polyvinylalcohol (PVA). A series of four different formulations were prepared as shown in Table 1. [0057]
    TABLE 1
    PVA/alginate (wt. rat.) 15/5 20/5 15/7.5 20/5
    Deionized water   72 g 67.5 g 69.7 g 74.25 g
    PVA 13.5 g 18.0 g 13.5 g  19.8 g
    Sodium alginate  4.5 g  4.5 g 6.75 g  4.95 g
    Bismuth subcarbonate 9.68 g 9.77 g 9.69 g  9.9 g
  • The deionized water was weighed into a 4 oz. jar, while stirring the water, the PVA and sodium alginate were added and mixed until uniform. The jar was capped and heated to 100° C. to dissolve the ingredients. The jar was cooled to 37° C., then the bismuth. subcarbonate (radiopaque filler) which had been sifted through a 325 mesh screen was added and the composition was mixed with a jiffy mixer until uniform. The samples were loaded into 30 cc syringes, centrifuged to remove air, then extruded through a tubing die into a coagulant solution. The coagulant solution was made from 100 grams of calcium chloride dihydrate, 30 grams of sodium chloride, 50 grams of boric acid and 820 grams of deionized water. The spun tubing was left in the coagulant solution overnight. Lengths of tubing were then soaked in a glutaraldehyde/coagulant solution mixture to covalently crosslink the sample. Glutaraldehyde levels were tested from 0.5% by weight to 12.5% by weight. pH was adjusted to 1.5 using 20% HCL solution. After reacting overnight at room temperature, the tubes were examined and then immersed in 0.4% sodium phosphate solution to strip the ionic crosslinks. Results are recorded in Table 2. [0058]
    TABLE 2
    Glutaraldehyde (wt %) 0.5% 1.0% 5.0% 12.5%
    15/5 (PVA/Alginate soft, slightly stiffer, stiff,
    wt. ratio) stretchy stiffer but still brittle
    soft
    15/7.5 (PVA/Alginate soft, slightly much stiff,
    wt. ratio) stretchy stiffer stiffer brittle
    20/5 (PVA/Alginate soft, slightly stiff, stiff,
    wt. ratio) stretchy stiffer brittle brittle
  • Control samples which were not treated with glutaraldehyde were swollen and broken apart in the phosphate solution. [0059]

Claims (64)

What is claimed is:
1. A process for improving the mechanical properties and structural integrity of a shaped medical device comprising a crosslinked polymeric hydrogel, said process comprising subjecting an ionically crosslinkable polymer composition to crosslinking conditions such that both ionic and non-ionic crosslinks are formed resulting in a polymeric hydrogel.
2. The process of
claim 1
wherein said ionic crosslinks are formed by contacting said ionically crosslinkable polymer with a source of ions.
3. The process of
claim 2
wherein said polymer comprises one or a mixture of polymers selected from the group consisting of polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide, poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed polyacrylonitrile, polyacrylic acid, polymethacrylic acid, polyethylene amine, alginic acid, pectinic acid, carboxy methyl cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan, carboxymethyl chitosan, chitin, pullulan, gellan, xanthan, carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate, cationic guar, cationic starch as well as salts and esters thereof.
4. The process of
claim 2
wherein said polymer comprises an anionic polymer and said ions are cations selected from the group consisting of calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, lead and silver ions.
5. The process of
claim 2
wherein said polymer comprises a cationic polymer and said ions are anions selected from the group consisting of phosphate, citrate, borate, succinate, maleate, adipate and oxalate ions.
6. The process of
claim 2
wherein said polymer comprises one or a mixture of cationic polymers selected from the group consisting of chitosan, cationic guar, cationic starch and polyethylene amine.
7. The process of
claim 1
wherein said non-ionic crosslinks are formed by contacting said ionically crosslinkable polymer under reaction conditions with a crosslinking agent having at least two functional groups reactive with one or more functional groups present in said hydrogel polymer to form covalent bonds.
8. The process of
claim 7
wherein said crosslinking agent contains carboxyl, hydroxy, epoxy, halogen or amino functional groups.
9. The process of
claim 8
wherein said crosslinking agent is selected from the group consisting of glutaraldehyde, epichlorohydrin, dianhydrides and diamines.
10. The process of
claim 9
wherein said crosslinking agent is glutaraldehyde.
11. The process of
claim 2
wherein said polymer comprises a polymer selected from the group consisting of one or a mixture of alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic acid, chitosan, polyvinylalcohol, and salts and esters thereof.
12. The process of
claim 11
wherein said polymer comprises alginic acid.
13. The process of
claim 11
wherein said polymer is an ester of alginic acid and a C2 to C4 alkylene glycol.
14. The process of
claim 13
wherein said alkylene glycol is propylene glycol.
15. The process of
claim 2
wherein said polymer comprises a mixture of alginic or pectinic acid and polyvinylalcohol.
16. The process of
claim 1
wherein said shaped medical device is in the form of a cylindrical hollow tube.
17. The process of
claim 1
wherein said shaped medical device is selected from the group consisting of stents, catheters or cannulas, plugs, constrictors and tissue or biological encapsulants.
18. A process for improving the mechanical properties and structural integrity of a shaped medical device comprising a polymeric hydrogel, said process comprising:
a) providing a crosslinked polymeric hydrogel composition containing a non-ionic crosslink structure, said hydrogel polymer characterized as being ionically crosslinkable and having a primary shape;
b) imparting a secondary shape to said hydrogel polymer composition; and
c) subjecting said hydrogel polymer to ionic crosslinking conditions to ionically crosslink said hydrogel polymer while retaining said secondary shape.
19. The process of
claim 18
wherein said crosslinked polymeric hydrogel contains both an ionic and non-ionic crosslink structure, and wherein at least a portion of the crosslinking ions are selectively stripped away either prior to or subsequent to step (b) but prior to step (c).
20. The process of
claim 19
wherein said crosslinking ions are selectively stripped away subsequent to step (b).
21. The process of
claim 19
wherein said crosslinking ions are selectively stripped away by contacting said crosslinked hydrogel polymer with an aqueous electrolytic solution containing monovalent cations.
22. The process of
claim 21
wherein said monovalent cations are selected from the group consisting of potassium, sodium and lithium.
23. The process of
claim 18
wherein said non-ionic crosslink structure present in said crosslinked polymeric hydrogel is formed by contact of said polymer under reaction conditions with a crosslinking agent having at least two functional groups reactive with one or more functional groups present in said polymer to form covalent bonds.
24. The process of
claim 23
wherein said crosslinking agent contains carboxyl, hydroxy, epoxy, halogen or amino functional groups.
25. The process of
claim 24
wherein said crosslinking agent is selected from the group consisting of glutaraldehyde, epichlorohydrin, dianhydrides and diamines.
26. The process of
claim 25
wherein said crosslinking agent is glutaraldehyde.
27. The process of
claim 18
wherein said step (c) is carried out by contacting said hydrogel polymer with an aqueous solution containing ions.
28. The process of
claim 27
wherein said hydrogel polymer comprises an anionic polymer and said ions are cations selected from the group consisting of calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, lead and silver.
29. The process of
claim 27
wherein said hydrogel polymer comprises a cationic polymer and said ions are anions selected from the group consisting of phosphate, citrate, borate, succinate, maleate, adipate and oxalate ions.
30. The process of
claim 18
wherein said shaped medical device is selected from the group consisting of stents, catheters or cannulas, plugs, constrictors and tissue or biological encapsulants.
31. A shaped medical device having improved mechanical properties comprising a crosslinked polymeric hydrogel, said hydrogel containing both an ionic and a non-ionic crosslink structure.
32. The device of
claim 31
wherein said non-ionic crosslink structure is a covalent crosslink structure.
33. The device of
claim 31
wherein, upon selective removal of the ionic crosslinks, said device reconfigures substantially to the non-ionically crosslinked shape.
34. The device of
claim 31
wherein said hydrogel comprises one or a mixture of polymers selected from the group consisting of polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide, poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed polyacrylonitrile, polyacrylic acid, polymethacrylic acid, polyethylene amine, alginic acid, pectinic acid, carboxy methyl cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan, carboxymethyl chitosan, chitin, pullulan, gellan, xanthan, carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate, cationic guar, cationic starch as well as salts and esters thereof.
35. The device of
claim 31
wherein said hydrogel comprises an anionic polymer and said ions are cations selected from the group consisting of calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, lead and silver ions.
36. The device of
claim 31
wherein said hyrdrogel comprises a cationic polymer and said ions are anions selected from the group consisting of phosphate, citrate, borate, succinate, maleate, adipate and oxalate ions.
37. The device of
claim 31
wherein said hydrogel comprises one or a mixture of cationic polymers selected from the group consisting of chitosan, cationic guar, cationic starch and polyethylene amine.
38. The device of
claim 31
wherein said non-ionic crosslink structure is formed by contacting said tonically crosslinkable polymer under reaction conditions with a crosslinking agent having at least two functional groups reactive with one or more functional groups present in said hydrogel polymer to form covalent bonds.
39. The device of
claim 38
wherein said crosslinking agent contains carboxyl, hydroxy, epoxy, halogen or amino functional groups.
40. The device of
claim 39
wherein said crosslinking agent is selected from the group consisting of glutaraldehyde, epichlorohydrin, dianhydrides and diamines.
41. The device of
claim 40
wherein said crosslinking agent is glutaraldehyde.
42. The device of
claim 31
wherein said hydrogel comprises a polymer selected from the group consisting of one or a mixture of alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic acid, chitosan, polyvinylalcohol, and salts and esters thereof.
43. The device of
claim 42
wherein said hydrogel comprises alginic acid.
44. The device of
claim 42
wherein said hydrogel is an ester of alginic acid and a C2 to C4 alkylene glycol.
45. The device of
claim 44
wherein said alkylene glycol is propylene glycol.
46. The device of
claim 42
wherein said hydrogel comprises a mixture of alginic or pectinic acid and polyvinylalcohol.
47. The device of
claim 31
in the shape of a cylindrical, hollow tube.
48. The device of
claim 31
wherein said shaped medical device is selected from the group consisting of stents, catheters or cannulas, plugs, constrictors and tissue or biological encapsulants.
49. A medical procedure comprising:
a. inserting the medical device of
claim 31
into a human or animal body to form an implant; and
b. selectively removing at least a portion of said crosslinking ions from said implant in-vivo to soften said implant.
50. The procedure of
claim 49
further including the step:
c. subjecting said implant to ionic crosslinking conditions to ionically re-crosslink said implant prior to removal thereof from said body.
51. The procedure of
claim 49
wherein said implant is a cylindrical hollow tube.
52. The procedure of
claim 49
wherein said hydrogel comprises one or a mixture of polymers selected from the group consisting of polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide, poly (N-vinyl pyrolidone), polyethylene oxide, hydrolysed polyacrylonitrile, polyacrylic acid, polymethacrylic acid, polyethylene amine, alginic acid, pectinic acid, carboxy methyl cellulose, hyaluronic acid, heparin, heparin sulfate, chitosan, carboxymethyl chitosan, chitin, pullulan, gellan, xanthan, carboxymethyl starch, carboxymethyl dextran, chondroitin sulfate, cationic guar, cationic starch as well as salts and esters thereof.
53. The procedure of
claim 49
wherein said hydrogel comprises an anionic polymer and said ions are cations selected from the group consisting of calcium, magnesium, barium, strontium, boron, beryllium, aluminum, iron, copper, lead and silver ions.
54. The procedure of
claim 49
wherein said hydrogel comprises a cationic polymer and said ions are anions selected from the group consisting of phosphate, citrate, borate, succinate, maleate, adipate and oxalate ions.
55. The procedure of
claim 49
wherein said hydrogel comprises one or a mixture of cationic polymers selected from the group consisting of chitosan, cationic guar, cationic starch and polyethylene amine.
56. The procedure of
claim 49
wherein said non-ionic crosslink structure is formed by contacting said ionically crosslinkable polymer under reaction conditions with a crosslinking agent having at least two functional groups reactive with one or more functional groups present in said hydrogel polymer to form covalent bonds.
57. The procedure of
claim 56
wherein said crosslinking agent contains carboxyl, hydroxy, epoxy, halogen or amino functional groups.
58. The procedure of
claim 57
wherein said crosslinking agent is selected from the group consisting of glutaraldehyde, epichlorohydrin, dianhydrides and diamines.
59. The procedure of
claim 58
wherein said crosslinking agent is glutaraldehyde.
60. The procedure of
claim 49
wherein said hydrogel comprises a polymer selected from the group consisting of one or a mixture of alginic acid, pectinic acid, carboxymethyl cellulose, hyaluronic acid, chitosan, polyvinylalcohol, and salts and esters thereof.
61. The procedure of
claim 60
wherein said hydrogel comprises alginic acid.
62. The procedure of
claim 60
wherein said hydrogel is an ester of alginic acid and a C2 to C4 alkylene glycol.
63. The procedure of
claim 62
wherein said alkylene glycol is propylene glycol.
64. The procedure of
claim 60
wherein said hydrogel comprises a mixture of alginic or pectinic acid and polyvinylalcohol.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030046545A1 (en) * 2001-08-21 2003-03-06 Merkle James A. Systems and methods for media authentication
US20030044408A1 (en) * 2001-06-15 2003-03-06 The Children's Hospital Of Philadelphia Surface modification for improving biocompatibility
US20080071384A1 (en) * 2006-09-19 2008-03-20 Travis Deal Ureteral stent having variable hardness
US20080132991A1 (en) * 2006-11-30 2008-06-05 Leonard Pinchuk Method for Ionically Cross-Linking Gellan Gum for Thin Film Applications and Medical Devices Produced Therefrom
US20100234233A1 (en) * 2007-08-10 2010-09-16 Alessandro Sannino Polymer hydrogels and methods of preparation thereof
WO2011066340A1 (en) * 2009-11-24 2011-06-03 University Of Florida Research Foundation, Inc. Apparatus and methods for blocking needle and cannula tracts
US20110153030A1 (en) * 2001-08-27 2011-06-23 Synecor, Llc Positioning tools and methods for implanting medical devices
WO2013159757A1 (en) 2012-04-25 2013-10-31 Contipro Biotech S.R.O. Crosslinked hyaluronan derivative, method of preparation thereof, hydrogel and microfibers based thereon
WO2017112878A1 (en) * 2015-12-22 2017-06-29 Access Vascular, Inc. High strength biomedical materials
WO2020227705A1 (en) * 2019-05-09 2020-11-12 Soliman Sherif Hydrogel retinal tamponade agent
US11130823B2 (en) 2011-06-07 2021-09-28 Gelesis Llc Method for producing hydrogels
US11130824B2 (en) 2015-01-29 2021-09-28 Gelesis Llc Method for producing hydrogels coupling high elastic modulus and absorbance
US11577008B2 (en) 2017-06-21 2023-02-14 Access Vascular, Inc. High strength porous materials incorporating water soluble polymers

Families Citing this family (166)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6214331B1 (en) * 1995-06-06 2001-04-10 C. R. Bard, Inc. Process for the preparation of aqueous dispersions of particles of water-soluble polymers and the particles obtained
US6818018B1 (en) * 1998-08-14 2004-11-16 Incept Llc In situ polymerizable hydrogels
US6211296B1 (en) * 1998-11-05 2001-04-03 The B. F. Goodrich Company Hydrogels containing substances
US6348042B1 (en) * 1999-02-02 2002-02-19 W. Lee Warren, Jr. Bioactive shunt
GB9902412D0 (en) 1999-02-03 1999-03-24 Fermentech Med Ltd Process
GB9902652D0 (en) * 1999-02-05 1999-03-31 Fermentech Med Ltd Process
AU3503700A (en) * 1999-02-25 2000-09-14 Scimed Life Systems, Inc. Medical devices comprising hydrogel polymers having improved mechanical properties
AU1375301A (en) * 1999-11-15 2001-05-30 Bio Syntech Canada Inc Temperature-controlled and ph-dependant self-gelling biopolymeric aqueous solution
DE60004710T2 (en) * 1999-12-09 2004-07-08 Biosyntech Canada Inc., Laval MINERAL-POLYMER HYBRID COMPOSITION
US20030158302A1 (en) * 1999-12-09 2003-08-21 Cyric Chaput Mineral-polymer hybrid composition
US6355058B1 (en) * 1999-12-30 2002-03-12 Advanced Cardiovascular Systems, Inc. Stent with radiopaque coating consisting of particles in a binder
DE60137489D1 (en) * 2000-02-03 2009-03-12 Tissuemed Ltd DEVICE FOR CLOSING A SURGICAL PUNKING WOMAN
EP1263801B1 (en) * 2000-03-13 2006-05-24 BioCure, Inc. Tissue bulking and coating compositions
US6652883B2 (en) 2000-03-13 2003-11-25 Biocure, Inc. Tissue bulking and coating compositions
AU4566001A (en) 2000-03-13 2001-09-24 Biocure Inc Embolic compositions
DE60117984T8 (en) * 2000-06-29 2007-06-14 Bio Syntech Canada Inc., Laval COMPOSITION AND METHOD FOR REPAIRING AND REGENERATING CARTIL AND OTHER WOVEN FABRICS
DK1328300T3 (en) * 2000-10-23 2005-03-21 Tissuemed Ltd Self-adhesive hydrating matrix for topical therapeutic use
CA2425935C (en) 2000-11-07 2011-03-29 Cryolife, Inc. Expandable foam-like biomaterials and methods
US20040091540A1 (en) * 2000-11-15 2004-05-13 Desrosiers Eric Andre Method for restoring a damaged or degenerated intervertebral disc
US6664335B2 (en) 2000-11-30 2003-12-16 Cardiac Pacemakers, Inc. Polyurethane elastomer article with “shape memory” and medical devices therefrom
US6635082B1 (en) * 2000-12-29 2003-10-21 Advanced Cardiovascular Systems Inc. Radiopaque stent
US6685626B2 (en) 2001-02-02 2004-02-03 Regeneration Technologies, Inc. Compositions, devices, methods, and kits for induction of adhesions
US6913765B2 (en) * 2001-03-21 2005-07-05 Scimed Life Systems, Inc. Controlling resorption of bioresorbable medical implant material
US20030004568A1 (en) * 2001-05-04 2003-01-02 Concentric Medical Coated combination vaso-occlusive device
US20020193813A1 (en) * 2001-05-04 2002-12-19 Concentric Medical Hydrogel filament vaso-occlusive device
US20020193812A1 (en) * 2001-05-04 2002-12-19 Concentric Medical Hydrogel vaso-occlusive device
US7201940B1 (en) * 2001-06-12 2007-04-10 Advanced Cardiovascular Systems, Inc. Method and apparatus for thermal spray processing of medical devices
US8252040B2 (en) * 2001-07-20 2012-08-28 Microvention, Inc. Aneurysm treatment device and method of use
US7572288B2 (en) * 2001-07-20 2009-08-11 Microvention, Inc. Aneurysm treatment device and method of use
US8715312B2 (en) * 2001-07-20 2014-05-06 Microvention, Inc. Aneurysm treatment device and method of use
US20030073961A1 (en) * 2001-09-28 2003-04-17 Happ Dorrie M. Medical device containing light-protected therapeutic agent and a method for fabricating thereof
US20030093111A1 (en) * 2001-10-26 2003-05-15 Concentric Medical Device for vaso-occlusion and interventional therapy
US6783721B2 (en) * 2001-10-30 2004-08-31 Howmedica Osteonics Corp. Method of making an ion treated hydrogel
US20040143180A1 (en) * 2001-11-27 2004-07-22 Sheng-Ping Zhong Medical devices visible under magnetic resonance imaging
US20030100830A1 (en) * 2001-11-27 2003-05-29 Sheng-Ping Zhong Implantable or insertable medical devices visible under magnetic resonance imaging
US8133501B2 (en) 2002-02-08 2012-03-13 Boston Scientific Scimed, Inc. Implantable or insertable medical devices for controlled drug delivery
US8685427B2 (en) * 2002-07-31 2014-04-01 Boston Scientific Scimed, Inc. Controlled drug delivery
GB0210216D0 (en) * 2002-05-03 2002-06-12 First Water Ltd Ionically crosslinked alginate hydrogels, process for their manufacture and their use in medical devices
US20030215395A1 (en) * 2002-05-14 2003-11-20 Lei Yu Controllably degradable polymeric biomolecule or drug carrier and method of synthesizing said carrier
US7794743B2 (en) 2002-06-21 2010-09-14 Advanced Cardiovascular Systems, Inc. Polycationic peptide coatings and methods of making the same
US7217426B1 (en) 2002-06-21 2007-05-15 Advanced Cardiovascular Systems, Inc. Coatings containing polycationic peptides for cardiovascular therapy
US8506617B1 (en) 2002-06-21 2013-08-13 Advanced Cardiovascular Systems, Inc. Micronized peptide coated stent
US7396539B1 (en) * 2002-06-21 2008-07-08 Advanced Cardiovascular Systems, Inc. Stent coatings with engineered drug release rate
US7033602B1 (en) 2002-06-21 2006-04-25 Advanced Cardiovascular Systems, Inc. Polycationic peptide coatings and methods of coating implantable medical devices
US7056523B1 (en) 2002-06-21 2006-06-06 Advanced Cardiovascular Systems, Inc. Implantable medical devices incorporating chemically conjugated polymers and oligomers of L-arginine
US8920826B2 (en) * 2002-07-31 2014-12-30 Boston Scientific Scimed, Inc. Medical imaging reference devices
US8227411B2 (en) * 2002-08-20 2012-07-24 BioSurface Engineering Technologies, Incle FGF growth factor analogs
US7598224B2 (en) * 2002-08-20 2009-10-06 Biosurface Engineering Technologies, Inc. Dual chain synthetic heparin-binding growth factor analogs
US20040063805A1 (en) * 2002-09-19 2004-04-01 Pacetti Stephen D. Coatings for implantable medical devices and methods for fabrication thereof
EP2260882B1 (en) * 2002-10-11 2020-03-04 Boston Scientific Limited Implantable medical devices
US7468210B1 (en) 2002-12-10 2008-12-23 Biosurface Engineering Technologies, Inc. Cross-linked heparin coatings and methods
US7094256B1 (en) * 2002-12-16 2006-08-22 Advanced Cardiovascular Systems, Inc. Coatings for implantable medical device containing polycationic peptides
US20040115164A1 (en) * 2002-12-17 2004-06-17 Pierce Ryan K. Soft filament occlusive device delivery system
WO2004069169A2 (en) * 2003-01-31 2004-08-19 Scimed Life Systems, Inc. Localized drug delivery using drug-loaded nanocapsules and implantable device coated with the same
EP1610829B1 (en) * 2003-04-04 2010-01-20 Tissuemed Limited Tissue-adhesive formulations
US7241455B2 (en) 2003-04-08 2007-07-10 Boston Scientific Scimed, Inc. Implantable or insertable medical devices containing radiation-crosslinked polymer for controlled delivery of a therapeutic agent
CA2523246C (en) * 2003-04-25 2009-12-01 Kos Life Sciences, Inc. Formation of strong superporous hydrogels
US8791171B2 (en) * 2003-05-01 2014-07-29 Abbott Cardiovascular Systems Inc. Biodegradable coatings for implantable medical devices
US6923996B2 (en) * 2003-05-06 2005-08-02 Scimed Life Systems, Inc. Processes for producing polymer coatings for release of therapeutic agent
US7364585B2 (en) * 2003-08-11 2008-04-29 Boston Scientific Scimed, Inc. Medical devices comprising drug-loaded capsules for localized drug delivery
US20050074406A1 (en) * 2003-10-03 2005-04-07 Scimed Life Systems, Inc. Ultrasound coating for enhancing visualization of medical device in ultrasound images
US20050107867A1 (en) * 2003-11-17 2005-05-19 Taheri Syde A. Temporary absorbable venous occlusive stent and superficial vein treatment method
CA2549295C (en) * 2003-12-04 2016-05-03 University Of Utah Research Foundation Modified macromolecules and methods of making and using thereof
WO2005077013A2 (en) 2004-02-06 2005-08-25 Georgia Tech Research Corporation Surface directed cellular attachment
CA2558661C (en) 2004-02-06 2012-09-04 Georgia Tech Research Corporation Load bearing biocompatible device
US20080227696A1 (en) * 2005-02-22 2008-09-18 Biosurface Engineering Technologies, Inc. Single branch heparin-binding growth factor analogs
JP4895826B2 (en) 2004-02-20 2012-03-14 バイオサーフェス エンジニアリング テクノロジーズ,インク. Bone morphogenetic protein-2 positive modulator
US8426528B2 (en) * 2004-02-23 2013-04-23 E I Du Pont De Nemours And Company Preparation of crosslinked polymers containing biomass derived materials
US20050220882A1 (en) * 2004-03-04 2005-10-06 Wilson Pritchard Materials for medical implants and occlusive devices
US8067073B2 (en) 2004-03-25 2011-11-29 Boston Scientific Scimed, Inc. Thermoplastic medical device
US7282165B2 (en) * 2004-04-27 2007-10-16 Howmedica Osteonics Corp. Wear resistant hydrogel for bearing applications
EP1595534A1 (en) * 2004-05-13 2005-11-16 Universiteit Utrecht Holding B.V. Gel composition comprising charged polymers
US7651702B2 (en) 2004-05-20 2010-01-26 Mentor Corporation Crosslinking hyaluronan and chitosanic polymers
CA2567532C (en) * 2004-05-20 2013-10-01 Mentor Corporation Methods for making injectable polymer hydrogels
CA2572363A1 (en) * 2004-06-29 2006-01-12 Biocure, Inc. Biomaterial
BRPI0514106A (en) * 2004-08-03 2008-05-27 Tissuemed Ltd fabric adhesive materials
US7402320B2 (en) * 2004-08-31 2008-07-22 Vnus Medical Technologies, Inc. Apparatus, material compositions, and methods for permanent occlusion of a hollow anatomical structure
US7244443B2 (en) 2004-08-31 2007-07-17 Advanced Cardiovascular Systems, Inc. Polymers of fluorinated monomers and hydrophilic monomers
DE102004045224B4 (en) * 2004-09-17 2010-12-30 Thilo Dr. Fliedner support prosthesis
US20060074182A1 (en) * 2004-09-30 2006-04-06 Depuy Products, Inc. Hydrogel composition and methods for making the same
US7972354B2 (en) * 2005-01-25 2011-07-05 Tyco Healthcare Group Lp Method and apparatus for impeding migration of an implanted occlusive structure
US20060222596A1 (en) * 2005-04-01 2006-10-05 Trivascular, Inc. Non-degradable, low swelling, water soluble radiopaque hydrogel polymer
KR100748348B1 (en) 2005-07-19 2007-08-09 한국원자력연구원 Method for the preparation of hydrogels for wound dressing using radiation irradiation
US9259439B2 (en) * 2005-10-21 2016-02-16 Ada Foundation Dual-phase cement precursor systems for bone repair
US9101436B2 (en) * 2005-10-21 2015-08-11 Ada Foundation Dental and endodontic filling materials and methods
US8048350B2 (en) * 2005-10-31 2011-11-01 Scott Epstein Structural hydrogel polymer device
US11896505B2 (en) 2005-10-31 2024-02-13 Scott M. Epstein Methods for making and using a structural hydrogel polymer device
WO2007059605A1 (en) * 2005-11-04 2007-05-31 Bio Syntech Canada Inc. Composition and method for efficient delivery of nucleic acids to cells using chitosan
US20070149641A1 (en) * 2005-12-28 2007-06-28 Goupil Dennis W Injectable bone cement
EP1996243B1 (en) 2006-01-11 2014-04-23 HyperBranch Medical Technology, Inc. Crosslinked gels comprising polyalkyleneimines, and their uses as medical devices
CA2640629A1 (en) 2006-02-03 2007-08-09 Tissuemed Limited Tissue-adhesive materials
US20070184087A1 (en) * 2006-02-06 2007-08-09 Bioform Medical, Inc. Polysaccharide compositions for use in tissue augmentation
FR2897775B1 (en) * 2006-02-24 2013-05-03 Elisabeth Laugier BIOMATERIAU, INJECTABLE IMPLANT COMPRISING IT, PROCESS FOR PREPARING THE SAME AND USES THEREOF
US20090018575A1 (en) * 2006-03-01 2009-01-15 Tissuemed Limited Tissue-adhesive formulations
US9017361B2 (en) 2006-04-20 2015-04-28 Covidien Lp Occlusive implant and methods for hollow anatomical structure
US7820172B1 (en) 2006-06-01 2010-10-26 Biosurface Engineering Technologies, Inc. Laminin-derived multi-domain peptides
CA2692240C (en) 2006-06-22 2018-03-13 Biosurface Engineering Technologies, Inc. Composition and method for delivery of bmp-2 amplifier/co-activator for enhancement of osteogenesis
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
EP2046288B1 (en) * 2006-07-14 2013-07-03 FMC Biopolymer AS Hydrogels containing low molecular weight alginates and biostructures made therefrom
CN101578520B (en) 2006-10-18 2015-09-16 哈佛学院院长等 Based on formed pattern porous medium cross flow and through biometric apparatus, and preparation method thereof and using method
WO2008095955A1 (en) * 2007-02-09 2008-08-14 Novartis Ag Cross-linkable polyionic coatings for contact lenses
JP5805369B2 (en) * 2007-03-20 2015-11-04 ボストン サイエンティフィック サイムド,インコーポレイテッドBoston Scientific Scimed,Inc. Urological medical devices for releasing therapeutic agents
CA2687281A1 (en) * 2007-03-20 2008-09-25 Boston Scientific Limited Urological medical devices for release of prostatically beneficial therapeutic agents
WO2008141059A2 (en) * 2007-05-11 2008-11-20 Aeris Therapeutics, Inc. Lung volume reduction therapy using crosslinked non-natural polymers
JP5734650B2 (en) 2007-06-25 2015-06-17 マイクロベンション インコーポレイテッド Self-expanding prosthesis
GB0715514D0 (en) * 2007-08-10 2007-09-19 Tissuemed Ltd Coated medical devices
US8066755B2 (en) 2007-09-26 2011-11-29 Trivascular, Inc. System and method of pivoted stent deployment
US8663309B2 (en) 2007-09-26 2014-03-04 Trivascular, Inc. Asymmetric stent apparatus and method
US8226701B2 (en) 2007-09-26 2012-07-24 Trivascular, Inc. Stent and delivery system for deployment thereof
EP2194921B1 (en) 2007-10-04 2018-08-29 TriVascular, Inc. Modular vascular graft for low profile percutaneous delivery
US7919542B2 (en) * 2007-11-12 2011-04-05 Zimmer Spine, Inc. Phase separated, branched, copolymer hydrogel
US8328861B2 (en) 2007-11-16 2012-12-11 Trivascular, Inc. Delivery system and method for bifurcated graft
US8083789B2 (en) 2007-11-16 2011-12-27 Trivascular, Inc. Securement assembly and method for expandable endovascular device
US8668863B2 (en) 2008-02-26 2014-03-11 Board Of Regents, The University Of Texas System Dendritic macroporous hydrogels prepared by crystal templating
US20090220578A1 (en) * 2008-02-28 2009-09-03 Depuy Products, Inc. Hydrogel composition and method for making the same
KR101649714B1 (en) 2008-03-21 2016-08-30 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 Self-aligned barrier layers for interconnects
CA2719320A1 (en) 2008-03-27 2009-10-01 President And Fellows Of Harvard College Three-dimensional microfluidic devices
WO2009121038A2 (en) * 2008-03-27 2009-10-01 President And Fellows Of Harvard College Shaped films of hydrogels fabricated using templates of patterned paper
WO2009120963A2 (en) * 2008-03-27 2009-10-01 President And Fellows Of Harvard College Paper-based cellular arrays
CN102016594B (en) * 2008-03-27 2014-04-23 哈佛学院院长等 Cotton thread as a low-cost multi-assay diagnostic platform
CA2719800A1 (en) 2008-03-27 2009-10-01 President And Fellows Of Harvard College Paper-based microfluidic systems
MY144571A (en) * 2008-04-24 2011-10-14 Univ Malaya Extracellular scaffold
US7959762B2 (en) * 2008-06-30 2011-06-14 Weyerhaeuser Nr Company Method for making biodegradable superabsorbent particles
US8641869B2 (en) * 2008-06-30 2014-02-04 Weyerhaeuser Nr Company Method for making biodegradable superabsorbent particles
US20090326180A1 (en) * 2008-06-30 2009-12-31 Weyerhaeuser Co. Biodegradable Superabsorbent Particles Containing Cellulose Fiber
US20090325797A1 (en) * 2008-06-30 2009-12-31 Weyerhaeuser Co. Biodegradable Superabsorbent Particles
US8101543B2 (en) * 2008-06-30 2012-01-24 Weyerhaeuser Nr Company Biodegradable superabsorbent particles
US7833384B2 (en) * 2008-06-30 2010-11-16 Weyerhaeuser Nr Company Method for making fiber having biodegradable superabsorbent particles attached thereto
US8084391B2 (en) * 2008-06-30 2011-12-27 Weyerhaeuser Nr Company Fibers having biodegradable superabsorbent particles attached thereto
DE102008053892A1 (en) 2008-10-30 2010-05-06 Fachhochschule Gelsenkirchen Medical implant with biofunctionalized surface
WO2010102279A1 (en) 2009-03-06 2010-09-10 President And Fellows Of Harvard College Microfluidic, electromechanical devices
KR101730203B1 (en) * 2009-10-23 2017-04-25 프레지던트 앤드 펠로우즈 오브 하바드 칼리지 Self-aligned barrier and capping layers for interconnects
EP2498763A4 (en) 2009-11-09 2015-10-07 Spotlight Technology Partners Llc Polysaccharide based hydrogels
AU2010314994B2 (en) 2009-11-09 2016-10-06 Spotlight Technology Partners Llc Fragmented hydrogels
EP2512540B1 (en) 2009-12-15 2019-08-07 Incept, LLC Implants and biodegradable fiducial markers
US8821810B2 (en) 2010-02-03 2014-09-02 President And Fellows Of Harvard College Devices and methods for multiplexed assays
US9232805B2 (en) 2010-06-29 2016-01-12 Biocure, Inc. In-situ forming hydrogel wound dressings containing antimicrobial agents
BR112012030842A2 (en) 2010-07-02 2016-11-08 Indian Council Medical Res non-composite superabsorbents and composites, and method for producing non-composite superabsorbents and composites
JP6042815B2 (en) 2010-10-08 2016-12-14 ザ ボード オブ リージェンツ オブ ザ ユニバーシティ オブ テキサス システム Anti-adhesion barrier membranes using alginate and hyaluronic acid for biomedical applications
US8946194B2 (en) 2010-10-08 2015-02-03 Board Of Regents, University Of Texas System One-step processing of hydrogels for mechanically robust and chemically desired features
EP2643020A4 (en) * 2010-11-26 2014-11-12 Univ Witwatersrand Jhb A drug delivery device
KR101303284B1 (en) 2011-04-06 2013-09-04 한국원자력연구원 Hydrogel having hyaluronic acid and condroitin sulfate and manufacturing method thereof
JP2014522263A (en) 2011-05-11 2014-09-04 マイクロベンション インコーポレイテッド Device for occluding a lumen
CA3048437C (en) 2011-05-26 2022-06-21 Cartiva, Inc. Tapered joint implant and related tools
WO2013010045A1 (en) 2011-07-12 2013-01-17 Biotime Inc. Novel methods and formulations for orthopedic cell therapy
US8968927B2 (en) 2011-07-15 2015-03-03 Covidien Lp Degradable implantable battery
US8968926B2 (en) 2011-07-15 2015-03-03 Covidien Lp Degradable implantable galvanic power source
EP3613413A1 (en) 2011-12-05 2020-02-26 Incept, LLC Medical organogel processes and compositions
US8992595B2 (en) 2012-04-04 2015-03-31 Trivascular, Inc. Durable stent graft with tapered struts and stable delivery methods and devices
US9498363B2 (en) 2012-04-06 2016-11-22 Trivascular, Inc. Delivery catheter for endovascular device
US11565027B2 (en) 2012-12-11 2023-01-31 Board Of Regents, The University Of Texas System Hydrogel membrane for adhesion prevention
KR101766679B1 (en) 2012-12-11 2017-08-09 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 Hydrogel membrane for adhesion prevention
EP2968825A4 (en) 2013-03-15 2016-09-07 Childrens Medical Center Gas-filled stabilized particles and methods of use
CN103446897B (en) * 2013-09-13 2015-03-11 天津工业大学 Chemical and ionic cross-linked alginate hydrogel flat membrane for filtration and preparation method thereof
AU2014240353A1 (en) * 2013-11-12 2015-05-28 Covidien Lp Degradable implantable battery
WO2015089197A2 (en) * 2013-12-12 2015-06-18 Hollister Incorporated Flushable catheters
EP3636226A1 (en) 2015-03-31 2020-04-15 Cartiva, Inc. Carpometacarpal (cmc) implants
WO2016161025A1 (en) 2015-03-31 2016-10-06 Cartiva, Inc. Hydrogel implants with porous materials and methods
WO2016168363A1 (en) 2015-04-14 2016-10-20 Cartiva, Inc. Tooling for creating tapered opening in tissue and related methods
KR101624511B1 (en) 2016-01-15 2016-05-26 전남대학교산학협력단 Antiadhesion coposition and comprising antiadhesion agent preparing method thereof
CN105797685A (en) * 2016-05-09 2016-07-27 江苏大学 Preparation method of sodium alginate-graphene oxide macroscopic sphere composite material
WO2018024794A1 (en) 2016-08-03 2018-02-08 Galderma Research & Development Double crosslinked glycosaminoglycans
ES2901326T3 (en) 2016-08-03 2022-03-22 Galderma Res & Dev Glycosaminoglycan cross-linking procedure
US20200254144A1 (en) * 2019-02-08 2020-08-13 The United States Of America, As Represented By The Secretary, Department Of Health And Human Servic Composite gels and methods of use thereof
CN114015074B (en) * 2021-10-20 2023-09-12 武汉理工大学 Carboxymethyl chitosan/polyacrylamide injectable self-healing hydrogel and preparation method and application thereof
US11911572B2 (en) 2022-05-05 2024-02-27 Innocare Urologics, Llc Soft tip drug-eluting urinary drainage catheter

Family Cites Families (127)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2485512A (en) 1941-10-21 1949-10-18 Alginate Ind Ltd Manufacture of transparent alginic films
GB674755A (en) 1949-08-04 1952-07-02 Courtaulds Ltd Improvements in and relating to the production of artificial protein fibres
US2689809A (en) 1951-10-08 1954-09-21 Permachem Corp Self-sterilizing article and its preparation
US2712672A (en) 1952-01-28 1955-07-12 Calcagno Luigi Process for preparing proteic sponges
US2791518A (en) 1955-03-21 1957-05-07 Permachem Corp Process for making a microbicidal article
US2847713A (en) 1955-05-13 1958-08-19 Weingand Richard Process for producing synthetic sausage skins and other laminar structures from alginates
US2897547A (en) 1955-05-27 1959-08-04 Weingand Richard Process for producing synthetic sausage casing from alginates or alginic acid
US3271496A (en) 1964-01-27 1966-09-06 Amicon Corp Method of shaping polyelectrolyte polymer
US3975350A (en) 1972-08-02 1976-08-17 Princeton Polymer Laboratories, Incorporated Hydrophilic or hydrogel carrier systems such as coatings, body implants and other articles
US4137921A (en) 1977-06-24 1979-02-06 Ethicon, Inc. Addition copolymers of lactide and glycolide and method of preparation
SE425372B (en) 1977-07-18 1982-09-27 Ird Biomaterial Ab SET TO HEPARINIZE AN ELECTRICALLY CHARGED SURFACE ON A MEDICAL ARTICLE INTENDED TO CONTACT WITH BLOOD AND MEDICINES TO PERFORM THE SET
DE2824893C2 (en) 1978-06-07 1980-04-24 Willy Ruesch Gmbh & Co Kg, 7053 Kernen Enteral treatment probe
US4339295A (en) 1978-12-20 1982-07-13 The United States Of America As Represented By The Secretary Of The Department Of Health & Human Services Hydrogel adhesives and sandwiches or laminates using microwave energy
US4286341A (en) * 1979-04-16 1981-09-01 Iowa State University Research Foundation, Inc. Vascular prosthesis and method of making the same
FR2484246A1 (en) 1980-06-17 1981-12-18 Europ Propulsion PROCESS FOR PRODUCING BIOACTIVE COATINGS ON BONE PROSTHESES, AND PROSTHESES THUS OBTAINED
JPS5714640A (en) 1980-07-02 1982-01-25 Toray Ind Inc Separating membrane of methyl methacrylate type
US4539234A (en) 1981-05-27 1985-09-03 Unitika Ltd. Urethral catheter capable of preventing urinary tract infection and process for producing the same
US4499154A (en) 1982-09-03 1985-02-12 Howard L. Podell Dipped rubber article
US4700704A (en) 1982-10-01 1987-10-20 Ethicon, Inc. Surgical articles of copolymers of glycolide and ε-caprolactone and methods of producing the same
US4613517A (en) 1983-04-27 1986-09-23 Becton, Dickinson And Company Heparinization of plasma treated surfaces
US4527293A (en) 1983-05-18 1985-07-09 University Of Miami Hydrogel surface of urological prosthesis
US4592920A (en) 1983-05-20 1986-06-03 Baxter Travenol Laboratories, Inc. Method for the production of an antimicrobial catheter
GB8318403D0 (en) 1983-07-07 1983-08-10 Sutherland I W Gel-forming polysaccharides
CA1238043A (en) 1983-12-15 1988-06-14 Endre A. Balazs Water insoluble preparations of hyaluronic acid and processes therefor
FR2559666B1 (en) 1984-02-21 1986-08-08 Tech Cuir Centre PROCESS FOR THE MANUFACTURE OF COLLAGEN TUBES, ESPECIALLY LOW-DIAMETER TUBES, AND APPLICATION OF THE TUBES OBTAINED IN THE FIELD OF VASCULAR PROSTHESES AND NERVOUS SUTURES
US4716224A (en) 1984-05-04 1987-12-29 Seikagaku Kogyo Co. Ltd. Crosslinked hyaluronic acid and its use
US4650488A (en) 1984-05-16 1987-03-17 Richards Medical Company Biodegradable prosthetic device
US4886870A (en) 1984-05-21 1989-12-12 Massachusetts Institute Of Technology Bioerodible articles useful as implants and prostheses having predictable degradation rates
SE442820B (en) 1984-06-08 1986-02-03 Pharmacia Ab GEL OF THE CROSS-BOND HYALURONIC ACID FOR USE AS A GLASS BODY SUBSTITUTE
US4863907A (en) 1984-06-29 1989-09-05 Seikagaku Kogyo Co., Ltd. Crosslinked glycosaminoglycans and their use
JPS6129720U (en) 1984-07-28 1986-02-22 高砂医科工業株式会社 Intestinal anastomosis aid
US4801475A (en) 1984-08-23 1989-01-31 Gregory Halpern Method of hydrophilic coating of plastics
US4674506A (en) 1984-11-29 1987-06-23 Kirk Alcond Surgical anastomosis stent
US4636524A (en) 1984-12-06 1987-01-13 Biomatrix, Inc. Cross-linked gels of hyaluronic acid and products containing such gels
US5128326A (en) 1984-12-06 1992-07-07 Biomatrix, Inc. Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same
US4582865A (en) 1984-12-06 1986-04-15 Biomatrix, Inc. Cross-linked gels of hyaluronic acid and products containing such gels
US4605691A (en) 1984-12-06 1986-08-12 Biomatrix, Inc. Cross-linked gels of hyaluronic acid and products containing such gels
US4871365A (en) 1985-04-25 1989-10-03 American Cyanamid Company Partially absorbable prosthetic tubular article having an external support
US4851521A (en) 1985-07-08 1989-07-25 Fidia, S.P.A. Esters of hyaluronic acid
US5202431A (en) 1985-07-08 1993-04-13 Fidia, S.P.A. Partial esters of hyaluronic acid
JPS6227169A (en) 1985-07-29 1987-02-05 Oki Electric Ind Co Ltd Printing position determining system for serial printer
AU589438B2 (en) 1985-08-26 1989-10-12 Hana Biologics, Inc. Transplantable artificial tissue and process
US4997443A (en) 1985-08-26 1991-03-05 Hana Biologics, Inc. Transplantable artificial tissue and process
US4902295A (en) 1985-08-26 1990-02-20 Hana Biologics, Inc. Transplantable artificial tissue
SE8504501D0 (en) 1985-09-30 1985-09-30 Astra Meditec Ab METHOD OF FORMING AN IMPROVED HYDROPHILIC COATING ON A POLYMER SURFACE
US5298569A (en) 1985-10-30 1994-03-29 Nippon Paint Co. Metallic ester acrylic compositions capable of releasing bioactive substance at a controlled rate
US4838876A (en) 1986-04-29 1989-06-13 The Kendall Company Silicone rubber catheter having improved surface morphology
FI81010C (en) 1986-09-05 1990-09-10 Biocon Oy Benomplaceringsimplants
ES2040719T3 (en) 1986-09-23 1993-11-01 American Cyanamid Company BIO-ABSORBABLE COATING FOR A SURGICAL ARTICLE.
IT1198449B (en) 1986-10-13 1988-12-21 F I D I Farmaceutici Italiani ESTERS OF POLYVALENT ALCOHOLS OF HYALURONIC ACID
JPH0696023B2 (en) * 1986-11-10 1994-11-30 宇部日東化成株式会社 Artificial blood vessel and method for producing the same
GB8630363D0 (en) 1986-12-19 1987-01-28 Igel Int Ltd Coloured hydrogel objects
JPS6425870A (en) 1987-04-30 1989-01-27 Ajinomoto Kk Support for anastomosis or bonding of living body
IL82834A (en) 1987-06-09 1990-11-05 Yissum Res Dev Co Biodegradable polymeric materials based on polyether glycols,processes for the preparation thereof and surgical artiicles made therefrom
US5059211A (en) 1987-06-25 1991-10-22 Duke University Absorbable vascular stent
US5527337A (en) 1987-06-25 1996-06-18 Duke University Bioabsorbable stent and method of making the same
US4923645A (en) 1987-11-16 1990-05-08 Damon Biotech, Inc. Sustained release of encapsulated molecules
US4916193A (en) * 1987-12-17 1990-04-10 Allied-Signal Inc. Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides
US4958038A (en) 1987-12-21 1990-09-18 E. I. Du Pont De Nemours And Company Organotitanium compositions useful for cross-linking
JP2561853B2 (en) 1988-01-28 1996-12-11 株式会社ジェイ・エム・エス Shaped memory molded article and method of using the same
US5147399A (en) 1988-02-01 1992-09-15 Dellon Arnold L Method of treating nerve defects through use of a bioabsorbable surgical device
US4888016A (en) 1988-02-10 1989-12-19 Langerman David W "Spare parts" for use in ophthalmic surgical procedures
US5061738A (en) 1988-04-18 1991-10-29 Becton, Dickinson And Company Blood compatible, lubricious article and composition and method therefor
IT1219587B (en) 1988-05-13 1990-05-18 Fidia Farmaceutici SELF-CROSS-LINKED CARBOXYLY POLYSACCHARIDES
US4874360A (en) 1988-07-01 1989-10-17 Medical Engineering Corporation Ureteral stent system
US5444113A (en) 1988-08-08 1995-08-22 Ecopol, Llc End use applications of biodegradable polymers
US5502158A (en) 1988-08-08 1996-03-26 Ecopol, Llc Degradable polymer composition
AU4191989A (en) 1988-08-24 1990-03-23 Marvin J. Slepian Biodegradable polymeric endoluminal sealing
US4938763B1 (en) 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
US5085629A (en) * 1988-10-06 1992-02-04 Medical Engineering Corporation Biodegradable stent
FI85223C (en) 1988-11-10 1992-03-25 Biocon Oy BIODEGRADERANDE SURGICAL IMPLANT OCH MEDEL.
US5057606A (en) 1989-01-24 1991-10-15 Minnesota Mining And Manufacturing Company Form-in-place polysaccharide gels
US5089606A (en) 1989-01-24 1992-02-18 Minnesota Mining And Manufacturing Company Water-insoluble polysaccharide hydrogel foam for medical applications
US4948575A (en) 1989-01-24 1990-08-14 Minnesota Mining And Manufacturing Company Alginate hydrogel foam wound dressing
US5554388A (en) 1989-02-25 1996-09-10 Danbiosyst Uk Limited Systemic drug delivery compositions comprising a polycationi substance
US5425739A (en) 1989-03-09 1995-06-20 Avatar Design And Development, Inc. Anastomosis stent and stent selection system
US5324519A (en) 1989-07-24 1994-06-28 Atrix Laboratories, Inc. Biodegradable polymer composition
US5141516A (en) 1989-07-26 1992-08-25 Detweiler Mark B Dissolvable anastomosis stent and method for using the same
US5049138A (en) 1989-11-13 1991-09-17 Boston Scientific Corporation Catheter with dissolvable tip
US4994074A (en) 1990-02-01 1991-02-19 Ethicon, Inc. Copolymers of ε-caprolactone, glycolide and glycolic acid for suture coatings
ATE120377T1 (en) 1990-02-08 1995-04-15 Howmedica INFLATABLE DILATATOR.
US5178234A (en) 1990-03-15 1993-01-12 Tokyo Electric Co., Ltd. Checkout apparatus
US5077352A (en) 1990-04-23 1991-12-31 C. R. Bard, Inc. Flexible lubricious organic coatings
EP0454373B1 (en) 1990-04-23 1995-08-23 Monsanto Company Gellan gum fibers
NO171069C (en) 1990-05-29 1993-01-20 Protan Biopolymer As COVALENT CIRCUIT, STRONGLY SWELLING ALKALIMETAL AND AMMONIUM ALGINATE GELS, AND PROCEDURES FOR PREPARING THEREOF
IT1248666B (en) 1990-05-30 1995-01-26 Fidia Spa GEL IN THE FORM OF HIGHLY HYDRATED SELF-SUPPORTING FILMS, PROCESS FOR THEIR PREPARATION AND USE IN THE THERAPY OF INJURIES AND / OR SKIN PATHOLOGIES
US5077033A (en) * 1990-08-07 1991-12-31 Mediventures Inc. Ophthalmic drug delivery with thermo-irreversible gels of polxoxyalkylene polymer and ionic polysaccharide
US5149543A (en) 1990-10-05 1992-09-22 Massachusetts Institute Of Technology Ionically cross-linked polymeric microcapsules
JP2777279B2 (en) 1990-10-08 1998-07-16 工業技術院長 Wound dressing and method for producing the same
US5160341A (en) 1990-11-08 1992-11-03 Advanced Surgical Intervention, Inc. Resorbable urethral stent and apparatus for its insertion
US5162110A (en) 1990-12-19 1992-11-10 Rhone-Poulenc Rorer Pharmaceuticals Inc. Binding theophylline to ion exchange resins
GR920100122A (en) * 1991-04-05 1993-03-16 Ethicon Inc Ionically crosslinked carboxyl-containing polysaccharides for adhension prevention.
JPH06506694A (en) 1991-04-10 1994-07-28 カペリ,クリストフアー・シー Antimicrobial composition useful for medical purposes
US5662913A (en) 1991-04-10 1997-09-02 Capelli; Christopher C. Antimicrobial compositions useful for medical applications
US5302393A (en) 1991-07-11 1994-04-12 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Method for inhibiting biological degradation of implantation polymeric material, inhibitor thereof and implantation polymeric material containing the inhibitor
WO1993009176A2 (en) * 1991-10-29 1993-05-13 Clover Consolidated, Limited Crosslinkable polysaccharides, polycations and lipids useful for encapsulation and drug release
US5200195A (en) * 1991-12-06 1993-04-06 Alza Corporation Process for improving dosage form delivery kinetics
ATE168040T1 (en) * 1991-12-20 1998-07-15 Allied Signal Inc LOW DENSITY, HIGH SPECIFIC SURFACE MATERIALS AND ARTICLES MOLDED THEREOF FOR USE IN METAL RECOVERY
US5489297A (en) 1992-01-27 1996-02-06 Duran; Carlos M. G. Bioprosthetic heart valve with absorbable stent
US5334640A (en) * 1992-04-08 1994-08-02 Clover Consolidated, Ltd. Ionically covalently crosslinked and crosslinkable biocompatible encapsulation compositions and methods
AU4033893A (en) * 1992-04-24 1993-11-29 Polymer Technology Group, Inc., The Copolymers and non-porous, semi-permeable membrane thereof and its use for permeating molecules of predetermined molecular weight range
US5306764A (en) 1992-09-03 1994-04-26 China Technical Consultants Inc. Water dispersible polyurethane and process for preparation thereof
US5292525A (en) 1992-10-14 1994-03-08 Merck & Co., Inc. Method and composition for removing an alginate from a cutaneous substrate
US5443458A (en) 1992-12-22 1995-08-22 Advanced Cardiovascular Systems, Inc. Multilayered biodegradable stent and method of manufacture
US5401257A (en) 1993-04-27 1995-03-28 Boston Scientific Corporation Ureteral stents, drainage tubes and the like
US5328939A (en) * 1993-04-27 1994-07-12 Alliedsignal Inc. Rigid materials having high surface area and low density
JPH08509511A (en) * 1993-05-03 1996-10-08 ヒェミッシェ ファブリーク シュトックハウセン ゲー.エム.ベー.ハー Polymer composition, process for producing polymer composition, in particular absorbent composition, and use thereof
CA2123647C (en) 1993-06-11 2007-04-17 Steven L. Bennett Bioabsorbable copolymer and coating composition containing same
US5425949A (en) 1993-06-11 1995-06-20 United States Surgical Corporation Bioabsorbable copolymer and coating composition containing same
JPH0733682A (en) 1993-07-26 1995-02-03 Shiseido Co Ltd Novel composite material and sustained-release preparation in which the same material is used as carrier
US5531716A (en) * 1993-09-29 1996-07-02 Hercules Incorporated Medical devices subject to triggered disintegration
US5514377A (en) 1994-03-08 1996-05-07 The Regents Of The University Of California In situ dissolution of alginate coatings of biological tissue transplants
US5541304A (en) * 1994-05-02 1996-07-30 Hercules Incorporated Crosslinked hydrogel compositions with improved mechanical performance
US5629077A (en) 1994-06-27 1997-05-13 Advanced Cardiovascular Systems, Inc. Biodegradable mesh and film stent
US5603955A (en) 1994-07-18 1997-02-18 University Of Cincinnati Enhanced loading of solutes into polymer gels
US5578662A (en) 1994-07-22 1996-11-26 United States Surgical Corporation Bioabsorbable branched polymers containing units derived from dioxanone and medical/surgical devices manufactured therefrom
US5527324A (en) 1994-09-07 1996-06-18 Krantz; Kermit E. Surgical stent
US5531735A (en) * 1994-09-27 1996-07-02 Hercules Incorporated Medical devices containing triggerable disintegration agents
US5690961A (en) 1994-12-22 1997-11-25 Hercules Incorporated Acidic polysaccharides crosslinked with polycarboxylic acids and their uses
CA2213403C (en) 1995-02-22 2007-01-16 Menlo Care, Inc. Covered expanding mesh stent
US5713852A (en) * 1995-06-07 1998-02-03 Alza Corporation Oral dosage and method for treating painful conditions of the oral cavity
US5702682A (en) 1995-12-01 1997-12-30 Hercules Incorporated Methods for preparing radiopaque medical devices
US5684051A (en) * 1996-04-24 1997-11-04 Hercules Incorporated Medical devices with improved elastic response
US5670161A (en) 1996-05-28 1997-09-23 Healy; Kevin E. Biodegradable stent
US5820918A (en) 1996-07-11 1998-10-13 Hercules Incorporated Medical devices containing in-situ generated medical compounds
US5830217A (en) 1996-08-09 1998-11-03 Thomas J. Fogarty Soluble fixation device and method for stent delivery catheters
US5718916A (en) 1997-02-03 1998-02-17 Scherr; George H. Alginate foam products

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030044408A1 (en) * 2001-06-15 2003-03-06 The Children's Hospital Of Philadelphia Surface modification for improving biocompatibility
US7589070B2 (en) * 2001-06-15 2009-09-15 The Children's Hospital Of Philadelphia Surface modification for improving biocompatibility
US20030046545A1 (en) * 2001-08-21 2003-03-06 Merkle James A. Systems and methods for media authentication
US8784354B2 (en) * 2001-08-27 2014-07-22 Boston Scientific Scimed, Inc. Positioning tools and methods for implanting medical devices
US9844453B2 (en) 2001-08-27 2017-12-19 Boston Scientific Scimed, Inc. Positioning tools and methods for implanting medical devices
US20110153030A1 (en) * 2001-08-27 2011-06-23 Synecor, Llc Positioning tools and methods for implanting medical devices
US9180036B2 (en) 2001-08-27 2015-11-10 Boston Scientific Scimed, Inc. Methods for implanting medical devices
US20080071384A1 (en) * 2006-09-19 2008-03-20 Travis Deal Ureteral stent having variable hardness
US9585989B2 (en) * 2006-09-19 2017-03-07 Boston Scientific Scimed, Inc. Ureteral stent having variable hardness
US20080132991A1 (en) * 2006-11-30 2008-06-05 Leonard Pinchuk Method for Ionically Cross-Linking Gellan Gum for Thin Film Applications and Medical Devices Produced Therefrom
US10086014B2 (en) * 2007-08-10 2018-10-02 Gelesis Llc Polymer hydrogels and methods of preparation thereof
US20160361350A1 (en) * 2007-08-10 2016-12-15 Gelesis Llc Polymer hydrogels and methods of preparation thereof
US20140296507A1 (en) * 2007-08-10 2014-10-02 Gelesis Llc Polymer Hydrogels and Methods of Preparation Thereof
US20100234233A1 (en) * 2007-08-10 2010-09-16 Alessandro Sannino Polymer hydrogels and methods of preparation thereof
US8658147B2 (en) * 2007-08-10 2014-02-25 Gelesis Llc Polymer hydrogels and methods of preparation thereof
US20120226194A1 (en) * 2009-11-24 2012-09-06 Malisa Sarntinoranont Apparatus and methods for blocking needle and cannula tracts
US9370626B2 (en) * 2009-11-24 2016-06-21 University Of Florida Research Foundation, Inc. Apparatus and methods for blocking needle and cannula tracts
US9629943B2 (en) 2009-11-24 2017-04-25 University Of Florida Research Foundation, Incorporated Apparatus and methods for blocking needle and cannula tracts
WO2011066340A1 (en) * 2009-11-24 2011-06-03 University Of Florida Research Foundation, Inc. Apparatus and methods for blocking needle and cannula tracts
US11130823B2 (en) 2011-06-07 2021-09-28 Gelesis Llc Method for producing hydrogels
WO2013159757A1 (en) 2012-04-25 2013-10-31 Contipro Biotech S.R.O. Crosslinked hyaluronan derivative, method of preparation thereof, hydrogel and microfibers based thereon
US11130824B2 (en) 2015-01-29 2021-09-28 Gelesis Llc Method for producing hydrogels coupling high elastic modulus and absorbance
JP2019503767A (en) * 2015-12-22 2019-02-14 アクセス・バスキュラー・インコーポレイテッドAccess Vascular, Inc. High strength biomaterial
US10471183B2 (en) 2015-12-22 2019-11-12 Access Vascular, Inc. High strength biomedical materials
US10485898B2 (en) 2015-12-22 2019-11-26 Access Vascular, Inc. High strength biomedical materials
CN108601865A (en) * 2015-12-22 2018-09-28 阿塞斯血管有限公司 High intensity biomedical material
WO2017112878A1 (en) * 2015-12-22 2017-06-29 Access Vascular, Inc. High strength biomedical materials
US11389570B2 (en) 2015-12-22 2022-07-19 Access Vascular, Inc. High strength biomedical materials
AU2021205003B2 (en) * 2015-12-22 2023-04-13 Access Vascular, Inc. High strength biomedical materials
US11577008B2 (en) 2017-06-21 2023-02-14 Access Vascular, Inc. High strength porous materials incorporating water soluble polymers
WO2020227705A1 (en) * 2019-05-09 2020-11-12 Soliman Sherif Hydrogel retinal tamponade agent

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CA2262523A1 (en) 1998-01-22
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CA2262523C (en) 2005-09-20
US6184266B1 (en) 2001-02-06
US6387978B2 (en) 2002-05-14
DE69725442D1 (en) 2003-11-13
US6060534A (en) 2000-05-09

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