WO1998028364A1 - Nouvelle composition de gel polymere et leurs utilisations - Google Patents

Nouvelle composition de gel polymere et leurs utilisations Download PDF

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Publication number
WO1998028364A1
WO1998028364A1 PCT/CN1997/000150 CN9700150W WO9828364A1 WO 1998028364 A1 WO1998028364 A1 WO 1998028364A1 CN 9700150 W CN9700150 W CN 9700150W WO 9828364 A1 WO9828364 A1 WO 9828364A1
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Prior art keywords
temperature
composition
gel composition
tube
polymer gel
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PCT/CN1997/000150
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English (en)
Inventor
Chi Wu
Suhong Jiang
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The Chinese University Of Hong Kong
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Publication of WO1998028364A1 publication Critical patent/WO1998028364A1/fr
Priority to HK00104248A priority Critical patent/HK1025585A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
    • C08J5/18—Manufacture of films or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L101/00—Compositions of unspecified macromolecular compounds
    • C08L101/12—Compositions of unspecified macromolecular compounds characterised by physical features, e.g. anisotropy, viscosity or electrical conductivity
    • C08L101/14—Compositions of unspecified macromolecular compounds characterised by physical features, e.g. anisotropy, viscosity or electrical conductivity the macromolecular compounds being water soluble or water swellable, e.g. aqueous gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • C08L33/24—Homopolymers or copolymers of amides or imides
    • C08L33/26—Homopolymers or copolymers of acrylamide or methacrylamide
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/1128—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of nerves
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2333/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
    • C08J2333/24—Homopolymers or copolymers of amides or imides
    • C08J2333/26—Homopolymers or copolymers of acrylamide or methacrylamide
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2205/00—Polymer mixtures characterised by other features
    • C08L2205/04—Polymer mixtures characterised by other features containing interpenetrating networks
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof

Definitions

  • Patent Application Serial No. 60/033,897 entitled “Novel Polymer Gel Composition and
  • a gel is a three- dimensional cross-linked polymer network swollen by a large quantity of solvent, whose properties fall between those of a liquid and those of a solid. For this reason, polymer gels are sometimes classified as wetware in order to distinguish them from software and hardware.
  • the present invention generally relates to polymer compositions that have enhanced temperature-dependent shrinking rates, increased strength, and improved pliability over previously known polymer compositions.
  • the present invention provides thermally responsive polymer gel compositions comprising a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within the hydrophobic polymer matrix, wherein the polymer gel composition has enhanced thermal responsiveness as compared to the hydrophobic polymer matrix alone.
  • This combination results in polymer gel compositions having improved properties, including increase shrinking rates, increased gel breaking strength, and other advantageous properties, such as described above.
  • compositions of the invention find particular use in surgical applications for the repair and reinforcement of damaged tissues, such as, for example, blood vessels, neurons, nerves, and the like, especially in warm-blooded animals.
  • compositions of the invention are particularly useful in in vivo and ex vivo surgical applications for sealing leaking or ruptured blood vessels and for joining two blood vessel segments or two nerve segments, and the like, especially in warm-blooded animals.
  • the hydrophobic polymer matrix comprises poly(n-isopropylacrylamide) (PNIPAAM) and the interpenetrating hydrophilic polymer network comprises an amount of protein, typically gelatin, disposed within the PNIPAAM.
  • the invention provides a composition of matter which comprises a polymer gel comprising a thermally sensitive polymer matrix and a hydrophilic polymer network interpenetrating said the thermally sensitive polymer matrix.
  • the polymer gel is capable of shrinking at a greater rate in response to a change in temperature as compared to the thermally sensitive polymer matrix alone.
  • the invention also provides a thermally responsive biocompatible polymer gel composition, comprising a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within said hydrophobic polymer matrix, wherein the polymer gel composition has a shrinking rate that is greater than a shrinking rate of the hydrophobic polymer matrix.
  • the invention provides an interpenetrating polymer network gel composition
  • a thermosensitive polymer and a hydrophilic polymer interpenetrating the thermosensitive polymer.
  • the thermosensitive polymer and the hydrophilic polymer are arranged with respect to each other so that at least one type of interaction develops between the thermosensitive polymer and the hydrophilic polymer. Such interaction is sufficient to cause the composition to shrink at a greater rate than the thermosensitive polymer alone at a temperature above a shrinking temperature of the composition.
  • the invention also provides thermally responsive polymer gel compositions formed into sheets or tubes. Such sheets and tubes find useful in various applications of the invention, including in methods for sealing severed or ruptured blood vessels and as prosthetic blood vessels for medical and surgical applications.
  • the invention provides a thermally responsive polymer gel composition comprising PNIPAAM and gelatin, and further comprising a chemical incorporated into the gel composition, said chemical capable of being released from the composition in response to an increase in the temperature of the gel composition to a temperature above a shrinking temperature of the composition.
  • a thermally responsive polymer gel composition comprising PNIPAAM and gelatin, and further comprising a chemical incorporated into the gel composition, said chemical capable of being released from the composition in response to an increase in the temperature of the gel composition to a temperature above a shrinking temperature of the composition.
  • Such methods comprise providing a tube comprising a thermally responsive biocompatible polymer gel composition of the present invention, the tube having a first end and a second end, and an internal lumen therebetween, and the tube being maintained at a temperature of no more ' than about 32°C, and providing a severed blood vessel comprising a first end and a second end, the vessel being within a warm-blooded animal having a minimal internal ambient temperature of from about 25°C to about 40°C, and more preferably, at least about 35°C.
  • the first severed end of the blood vessel is inserted into the first end of the tube, and the second severed end of the blood vessel is inserted into the second end of the tube.
  • a preferred thermally responsive biocompatiable polymer gel composition comprises PNIPAAM and gelatin in relative amounts described herein below.
  • the invention provides an in vivo method for repairing a blood vessel system in a warm-blooded animal.
  • the method comprises the steps of providing a tube comprising a thermally responsive polymer gel composition of the present invention, said tube having a first end, a second end, and an internal lumen therebetween, said tube being maintained at a temperature lower than a shrinking temperature of the polymer gel composition; providing a blood vessel system comprising a first blood vessel segment having an internal lumen and an end and a second blood vessel segment having an internal lumen and an end, said first and second blood vessel segments contained within the animal, said animal having a minimal internal ambient temperature greater than the shrinking temperature of the polymer gel composition; inserting the end of the first blood vessel segment into the first end of the tube; inserting the end of the second blood vessel segment into the second end of the tube such that tube is positioned over the first and second ends of the blood vessel segments; and maintaining the tube in position until the temperature of the tube achieves the internal ambient temperature of the animal and shrinks onto the blood vessel segments
  • a preferred thermally responsive polymer gel composition comprises PNIPAAM and gelatin in relative amounts as described below.
  • methods for sealing a blood vessel system in vivo in a warm-blooded animal comprise the steps of providing a tube comprising a thermally responsive polymer gel composition according to the present invention, the tube having a first end and a second end, and an internal lumen therebetween, said tube being maintained at a temperature lower than a shrinking temperature of the polymer gel composition; providing a blood vessel system comprising a first blood vessel segment having an internal lumen and an end and a second blood vessel segment having an internal lumen and an end, said system being within a warm-blooded animal having a minimal internal ambient temperature that is greater than the shrinking temperature of the polymer gel composition; inserting the end of the first blood vessel segment into the first end of the tube and all the way through the tube such that the end of the first blood vessel segment emerges from the second end of the tube; connecting the end of the first blood vessel segment with the end of the second blood vessel
  • the invention provides methods for joining a first nerve segment and a second nerve segment of a nerve system in vivo in a warm-blooded animal comprising the steps of providing a tube comprising a thermally responsive polymer gel composition of the present invention, the tube having a first end and a second end, and an internal lumen therebetween, and the tube being maintained at a temperature lower than a shrinking temperature of the polymer gel composition; providing a nerve system comprising a first nerve segment having an end and a second nerve segment having an end, said first and second nerve segments being within a warm-blooded animal having a minimal internal ambient temperature that is greater than the shrinking temperature of the polymer gel composition; inserting the end of the first nerve segment into the first end of the tube and through the tube such that the end of the first nerve segment emerges from the second end of the tube; connecting the end of the first nerve segment with the end of the second nerve segment with at least one surgical stitch; positioning the tube over the ends of the first and second nerve segments; and maintaining the tube in position until the
  • a preferred thermally responsive biocompatible polymer gel composition comprises PNIPAAM and gelatin in amounts as described below.
  • the invention provides methods for repairing a blood vessel system.
  • Such methods comprise the steps of providing a tube comprising a thermally responsive polymer gel composition according to the present invention as described, the tube having a first end, a second end, and an internal lumen therebetween, said tube being maintained at a temperature below the shrinking temperature of the polymer gel composition; providing a blood vessel system comprising a first blood vessel segment having an internal lumen and an end and a second blood vessel segment having an internal lumen and an end, said system being maintained at a temperature below the shrinking temperature of the polymer gel composition; inserting the end of the first blood vessel segment into the first end of the tube; inserting the end of the second blood vessel segment into the second end of the tube such that tube is positioned over the first and second ends of the blood vessel segments; and increasing the temperature of the tube to a temperature equal to or greater than the shrinking temperature of the polymer gel composition so as to cause the tube to shrink and to contact the blood vessel segments to provide contiguous blood flow through the two blood vessel segments, thereby
  • the invention provides temperature-dependent implantable medical devices comprising a thermally responsive polymer gel composition of the present invention as described herein.
  • Such devices may be in the form of a sheet for use in joining separated tissues or repairing damaged tissues.
  • the invention also provides temperature-dependent drug delivery systems and devices comprising a thermally responsive polymer gel composition of the present invention, as described herein, into which a biologically or physiologically active compound is incorporated.
  • a thermally responsive polymer gel composition of the present invention as described herein, into which a biologically or physiologically active compound is incorporated.
  • the compound is released from the composition in response to an increase in temperature of the composition.
  • Also provided are methods for releasing a biologically or physiologically active compound into a surrounding environment which comprise the steps of providing an implantable medical device, said device comprising a thermally responsive polymer gel composition of the present invention, as described herein, and a therapeutically effective amount of the biologically or physiologically active compound, said device being maintained at a temperature less than a shrinking temperature of the composition, said compound being released from the composition when a temperature of the composition is increased to a temperature equal to or greater than the shrinking temperature of the composition; implanting said device in a body of a warm-blooded animal having a minimal internal ambient temperature greater than the shrinking temperature of the composition; and allowing the temperature of the device to achieve the minimal internal ambient temperature of the animal such that the composition shrinks and the compound is released from the composition.
  • the invention provides methods for site-specific or systemic drug delivery into a warm-blooded animal in need thereof.
  • Such methods comprise implanting an implantable medical device comprising the thermally responsive polymer gel composition of the present invention, as described herein, and a therapeutically effective amount of the biologically or physiologically active compound into an animal having a minimal internal ambient temperature that is greater than the shrinking temperature ' of the composition, such that the device shrinks when its temperature achieves the internal ambient temperature of the animal, thereby releasing and delivering the compound into the animal.
  • the invention also includes methods of releasing a chemical into an environment.
  • Such methods comprise providing a thermally responsive polymer gel composition of the present invention, wherein said composition further comprises a chemical, and increasing a temperature of the composition to a temperature greater than the shrinking temperature of the composition such that the chemical is released from the composition into the environment.
  • the invention provides thermally responsive actuators comprising a polymer gel layer comprising the thermally responsive biocompatible polymer gel composition of the present invention, as described herein, disposed over a flexible planar element, wherein said flexible plana element is not substantially thermally responsive.
  • methods of producing a thermally responsive polymer gel composition comprising at least one hydrophobic polymer matrix and at least one interpenetrating hydrophilic polymer network disposed within the hydrophilic polymer network.
  • Such methods comprise the steps of: (a) combining the hydrophobic polymer matrix and the interpenetrating hydrophilic polymer network; (b) agitating the product obtained from step (a) to form a mixture; and
  • step (c) placing the product step (b) into a vessel adapted to store or deliver the composition.
  • Fig. 1 is a schematic illustration of the effects of temperature on a double-layer gel strip comprising a layer of poly(n-isopropylacrylamide) (PNIPAAM) gel and a layer of PNIPAAM gel having gelatin disposed therein constructed in accordance with the principles of the present invention at temperatures 20°C and 37°C, respectively.
  • PNIPAAM poly(n-isopropylacrylamide)
  • Fig. 2 is a graphic illustration of the relative swelling of thermally responsive polymer gel compositions of the present invention at a temperature of 37°C.
  • Fig. 3 is a graphical illustration of the shrinking ratios (Wt/Wd), as a function of temperature, of pure PNIPAAM gel and a polymer gel composition of the present invention comprising PNIPAAM and gelatin in a ratio of 0.33 gelatin to 1 PNIPAAM.
  • Fig. 4A is a schematic illustration of a tube comprising a thermally responsive polymer gel of the present invention at 20°C that is suitable for use in methods and applications according to the present invention.
  • Fig. 4B is a schematic illustration of a tube comprising a thermally responsive polymer gel of the present invention at 37°C that is suitable for use in methods and applications according to the present invention.
  • Fig. 4C is a schematic illustration of a tube comprising a composition of the invention maintained at a temperature of about 20°C and into which two ends of a severed blood vessel have been inserted.
  • Fig. 4D is a schematic illustration of the tube depicted in Fig. 4C after heating the tube depicted in Fig. 4C to about 37°C.
  • Fig. 5 is a schematic illustration showing the implantation of thermally responsive polymer gel piece constructed according to principles of the invention inserted between the peritoneum and rectus abdominis of an animal.
  • Fig. 6 is a schematic illustration depicting the implantation of a thermally responsive polymer gel piece constructed according to principles of the invention inserted between the femoral artery, femoral nerve, and femoral veins of the groin of an animal.
  • Fig. 7 shows a schematic illustration showing the subdermal implantation in the gluteus maximus muscle of an animal of a thermally responsive polymer gel piece constructed according to principles of the invention and suitable uses of such a gel piece to connect and/or repair a severed sciatic nerve of the animal.
  • biocompatibility refers to the manner and degree in which a material, such as a gel composition of the present invention, interacts with body tissues or fluids of an animal.
  • a completely biocompatible material shows no effect or interaction with the body, a satisfactory biocompatible material shows only slight effect or interaction with the body, and an incompatible material elicits a severe reaction from the body that it contacts. See, e.g., KIRK-OTHMER, ENCYLOPEDIA OF CHEMICAL TECHNOLOGY, Vol. 19 (3d ed. 1982).
  • enhanced thermal responsiveness means having an increased response to a change in temperature or an increased reaction due to a change in temperature.
  • thermally responsive as used herein means affected by or responding to a change in temperature.
  • thermosensitive means sensitive to a change in temperature.
  • subject as used herein includes animals and humans.
  • animal as used herein includes mammals and humans. II. Compositions of the Invention and Uses Thereof
  • the present invention is directed to novel polymer gel compositions and uses for these compositions.
  • the present invention provides non-toxic polymer gel compositions comprising a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within the hydrophobic polymer matrix that results in improved properties, including gel breaking strength, pliability, and a faster shrinking rate.
  • the introduction of the interpenetrating polymer network in the hydrophobic polymer matrix provides additional function groups which can be further utilized to bind the compounds, such as drugs and catalysts.
  • the gel compositions of the present invention have applications in a variety of fields, including use as a prosthetic device for, e.g., repairing, joining, and/or sealing ruptured or severed blood vessels, neurons, nerves, or other tissues in vivo or ex vivo, or for reinforcing or augmenting structurally deficient blood vessels, neurons, nerves, or other tissues in vivo or ex vivo.
  • These gel compositions also have a variety of other uses that will become apparent from the following disclosure, including uses as thermal actuators, thermally responsive membranes, resistance thermometers, and drug delivery devices.
  • Such compositions of the invention are useful in methods for site-specific delivery of drugs, or systemic delivery of drugs, into warm-blooded animals in need thereof.
  • such compositions are useful in applications requiring the release of a specific chemical into an environment, including a particular tissue environment of a warm-blooded animal.
  • phase transition can be caused by, for example, hydrophobic interaction, van der Waals forces, hydrogen bonding, or ionic interaction within the polymer gel.
  • low-molecular compounds e.g., a solvent, such as water
  • precipitation may occur, which results in an increase in the density of the polymer gel.
  • phase transition refers to a change in volume of the gel composition between an expanded phase and a contracted (i. e. , collapsed or shrunken) phase or vice versa.
  • the phase transition has been identified with the increase in entropy of the solvent (i.e., water) in the polymer network with increasing temperature.
  • the solvent i.e., water
  • the relatively hydrophobic polymer network undergoes a decrease in entropy with increasing temperature as the network collapses near the lower critical solution temperature.
  • the overall contribution to the free energy of the gel system is negative, which leads to the spontaneous and reversible behavior at this critical temperature.
  • the thermal shrinking or swelling property of the polymer gel is a phase transition property which depends on a variety of conditions, including the structure of the polymer gel, the structure of the polymer molecules constituting the gel, the pH of the solution, the concentration of salt in the solution surrounding the gel, and the like conditions.
  • the phase transition of the polymer gel occurs critically and reversibly over at a particular temperature (or over a narrow temperature range) corresponding to the set of fixed conditions.
  • the temperature at which a polymer gel reversibly swells and shrinks under such a set of fixed conditions is defined as the phase transition temperature.
  • the phase transition of a polymer gel of the present invention can be set within a range of, for example, 5°C and 95 °C by selecting the above-described conditions.
  • the reversible phase transition is usually quite rapid (e.g., 1 second or less) if the heat transfer is conducted sufficiently quickly.
  • the polymer gel interacts significantly with the solvent surrounding the gel (e.g., water) and absorbs a large amount of the solvent into the gel network.
  • the solvent surrounding the gel e.g., water
  • the polymer gel When the temperature of the polymer gel is equal to or greater than the phase transition temperature, the polymer gel typically undergoes a phase transition, thereby increasing the interactions between the chains of the polymer and causing the polymer gel to shrink and discharge solvent from the gel network. As the gel shrinks, its structure changes from a relatively hydrophilic form to a relatively hydrophobic form.
  • the temperature at which a polymer gel composition according to the present invention shrinks is termed the “shrinking temperature.”
  • the shrinking temperature depends on a variety of conditions, including the particular composition of the polymer gel, including the relative amounts of the hydrophobic polymer matrix and hydrophilic polymer network which interpenetrates the hydrophobic polymer matrix.
  • a polymer gel composition of the present invention may shrink over a narrow temperature range.
  • the invention provides thermally responsive polymer gel compositions comprising a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within or interpenetrating the hydrophobic polymer matrix.
  • the polymer gel composition has enhanced thermal responsiveness as compared to the hydrophobic polymer matrix alone.
  • the enhanced thermal responsiveness generally comprises and is manifested by a shrinking rate that is greater than the shrinking rate of the hydrophobic polymer matrix alone at a temperature equal to or greater than the shrinking temperature of the composition.
  • the shrinking rate is the rate at which the gel composition shrinks in response to a change in condition (e.g., increase in temperature). That is, the shrinking rate is determined by the time required for a gel to shrink from its fully swollen state to its fully collapsed state.
  • the shrinking rate of the polymer gel composition may be increased or decreased by varying a ratio of an amount of hydrophobic polymer matrix to an amount of interpenetrating hydrophilic polymer network in said polymer gel composition.
  • Such polymer gel compositions may further comprise an amount of a hydrophobic monomer or an amount of a hydrophilic monomer sufficient to cause a shrinking temperature of said polymer gel composition to increase or decrease.
  • the hydrophobic monomer or hydrophilic monomer copolymerizes with the hydrophobic polymer matrix of said composition.
  • the polymer gel compositions of the present invention comprise a temperature-sensitive hydrophobic matrix, such as PNIPAAM gel, that is modified with an interpenetrating polymer network ("IPN") which leads to a faster shrinking and stronger gel composition.
  • IPNs include, e.g. , protein, such as gelatin and collagen. Gelatin and collagen are among the preferred proteins for forming IPNs in polymer gel compositions of the present invention.
  • such compositions include gelatin in an amount of from about 0.1% to about 25% by weight based on the total weight of the gel composition, which includes PNIPAAM, gelatin, and water.
  • the composition comprises gelatin in an amount of from about 0.5% to about 5% by weight, or even more preferably, in an amount of from about 1% to about 3% by weight, based on the total weight of the gel composition (i. e., w/w).
  • compositions according to the present invention comprise PNIPAAM in an amount of from about 5% to about 30% by weight based on the total weight of the composition.
  • the shrinking temperature of the composition is typically about 35°C.
  • PNIPAAM is a water-soluble, relatively hydrophobic polymer network that undergoes phase transition at a temperature equal to or greater than its lower critical solution temperature.
  • the lower critical solution temperature of a PNIPAAM gel is typically between about 31°C and about 33°C. At temperatures below its lower critical solution temperature, the PNIPAAM gel is soluble in aqueous media.
  • R. Yoshida et al Nature 374:240 (1995). Above its lower critical solution temperature, the PNIPAAM gel undergoes a discontinuous phase transition, precipitating from solution suddenly and reversibly over a narrow temperature range. See R. Yoshida et al, Nature 374:240 (1995); E.S. Matsuo et al, J. Chem. Phys. 89(3): 1695 (1988).
  • PNIPAAM gels usually undergo a phase transition from a low-temperature, highly water-swollen polymer gel network to a high-temperature, collapsed dehydrated polymer network at a temperature at or above the lower critical solution temperature.
  • the phase transition of the PNIPAAM polymer network typically causes a large discontinuous volume change.
  • PNIPAAM gels are known to shrink as much as about 10 to about 100 times in volume when heated above about 32°C.
  • Fig. 1 shows a schematic illustration of a shrink-rate experiment using a strip (1) comprising a layer (2) of pure PNIPAAM gel and a layer (3) of a PNIPAAM gel incorporating 1% (w/w) gelatin by weight based on the total weight of the gel composition.
  • the strip was prepared by adding gelatin to pre- polymerized PNIPAAM composition and initially maintained at a temperature of less than about 35°C.
  • the cross-linking densities of the PNIPAAM gel networks were identical at both sides. It was anticipated that upon heating to a temperature greater than 35°C, the strip (1) would bend in the direction of the pure PNIPAAM gel layer (2) (/ ' . e.
  • Fig. 2 shows a comparison of shrinking kinetics as a function of time at 37°C for PNIPAAM gel compositions in which various amounts of gelatin have been incorporated.
  • gel compositions comprising various ratios of gelatin: PNIPAAM, including 0.06: 1 (solid circles), 0.11 : 1 (open squares), 0.16: 1 (solid squares), and 0.33: 1 (open triangles) were compared with pure PNIPAAM gel compositions (open circles) (Fig. 2).
  • t/t is defined as the reduced time, where t is the time at which a measurement is taken and t is the time required for a pure PNIPAAM gel to reach its fully collapsed or shrunken state.
  • the gel composition was formed into the shape of a disk having a diameter of about 15 mm and a thickness of about 2 mm and was stored in deionized water at 20°C prior to performing the experiment.
  • the shrinking process was conducted in deionized water having a temperature of about 37°C.
  • the gel was removed from the deionized water at specific time intervals (t), weighed and then put back into the deionized water.
  • the shrinking rate also known as the "deswelling rate”
  • the shrinking rate by approximately three orders of magnitude.
  • Fig. 3 shows a comparison of the "shrinking ratio" (W/Wd), as a function of temperature, for a pure PNIPAAM gel and a gel composition comprising a ratio of gelatin to PNIPAAM of 0.33 to 1.
  • the shrinking ratio is defined as W/Wd, where W is the weight of water inside the gel and Wd is the weight of the dry gel (i.e., fully collapsed gel).
  • incorporation of gelatin (about 1 to about 3% (w/w)) into a hydrophobic polymer matrix (e.g., PNIPAAM) was found to enhance or increase the gel breaking strength by three times at a temperature lower than a shrinking temperature of the polymer gel composition, thereby providing a fiirther advantage of composition of the invention.
  • the gel breaking strength refers to the relative amount of force or pressure needed to break, crack, or fracture the polymer gel composition.
  • incorporation into PNIPAAM of at least about 1% gelatin by weight based on the total weight of the composition was found to increase the gel breaking strength of the composition in its fully swollen state as compared to PNIPAAM alone.
  • the invention provides a composition of matter which comprises a polymer gel comprising at least one thermally sensitive hydrophobic polymer matrix and at least one hydrophilic polymer network interpenetrating said at least one thermally sensitive hydrophobic polymer matrix.
  • the polymer gel is capable of shrinking at a greater rate in response to a change in temperature as compared to the thermally sensitive polymer matrix alone.
  • Such compositions are especially useful in repairing, reinforcing, and/or sealing blood vessel tissues and segments and nerve tissues as described herein, and for use in drug delivery devices, systems and methods, and methods for releasing chemicals into particular environments.
  • the invention provides thermally responsive polymer gel composition that is especially suitable for applications and uses in animals and humans, as described herein.
  • a composition may comprise a thermally responsive biocompatible polymer gel composition.
  • Such compositions comprise a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within the hydrophobic polymer matrix, wherein the resulting composition has a shrinking rate that is greater than the shrinking rate of the hydrophobic polymer matrix alone.
  • the hydrophobic polymer matrix comprises poly(n- isopropylacrylamide) (PNIPAAM) and the hydrophilic polymer network comprises a protein, such as collagen or gelatin
  • the invention provides an interpenetrating polymer network gel composition
  • a thermosensitive polymer and a hydrophilic polymer interpenetrating the thermosensitive polymer are arranged with respect to each other in the composition so that at least one type of interaction develops between the thermosensitive polymer and the hydrophilic polymer. Such interaction is sufficient to cause the composition to shrink at a greater rate than the thermosensitive polymer alone at a temperature above a shrinking temperature of the composition.
  • Protein is a representative example of a hydrophilic polymer that may be employed in compositions of the invention.
  • Other hydrophilic polymers such as poly(acrylamide) and poly( vinyl alcohol), can also be used to promote the shrinking rate.
  • Gelatin is a type of protein that may be employed as an IPN in compositions of the invention.
  • Gelatin may be selected from the group consisting of gelatin A and gelatin B.
  • Gelatin A is gelatin extracted in an acidic medium and gelatin B is a gelatin extracted in a basic medium.
  • derivatized PNIPAAM gels can also be used in compositions of the invention, and such gels can have different shrinking temperatures.
  • Polymer gels comprising derivatized PNIPAAM modified with hydrophilic protein IPN(s) exhibit increased shrinking rates and increased strength over other polymer gel compositions (as well as particular properties pertaining to the derivatized PNIPAAM' gel itself).
  • the PNIPAAM gel can be modified or derivatized by copolymerizing another type of hydrophilic or hydrophobic monomer into the PNIPAAM backbone chains (i.
  • Suitable monomers that can be used for polymerization include acrylate (hydrophobic) and acrylic (hydrophilic) acids, such as, for example, acrylic acid, methacrylate, methacrylic acid, acrylamide, methacrylamide, vinyl acetate, styrene, and their derivatives.
  • polymer gel compositions according to the present invention can be prepared which can selectively capture or incorporate a chemical from a liquid medium that passes through the interpenetrating network of the gel composition.
  • a chemical can be included in the solvent in which the gel is prepared and thus incorporated or captured by the gel network when the gel composition is in its fully swollen state in the solvent. The chemical is effectively trapped inside the interpenetrating polymer gel network.
  • Such a chemical is capable of being released from the composition to the surrounding environment when in response to an increase in the temperature of gel composition to a temperature above the shrinking temperature (or phase transition temperature) of the composition. That is, as the gel network dehydrates and collapses during phase transition in response to the temperature change, the chemical is discharged and released from the network.
  • heavy metal ions such as copper (Cu +2 ) and lead (Pb +2 ) ions.
  • the shrinking temperature (and phase transition temperature) of a polymer gel composition of the present invention are typically dependent on the particular nature and components of the composition.
  • increasing the amount of comonomer in the gel by direct copolymerization increases the lower critical solution temperature of the system and broadens the temperature range of the phase transition.
  • the shrinking temperature of a polymer gel composition of the invention can be adjusted, changed, or varied (in the range of from about 20°C to about 50°C) by copolymerizing or incorporating a small amount of a hydrophobic or hydrophilic monomer into a hydrophobic polymer matrix (e.g., PNIPAAM) which has a hydrophobic polymer network disposed therein.
  • a hydrophobic polymer matrix e.g., PNIPAAM
  • a polymer gel composition of the invention comprising a hydrophobic polymer matrix and an interpenetrating polymer network disposed within the hydrophobic polymer matrix exhibits an enhanced thermal responsiveness as compared to the hydrophobic polymer matrix alone.
  • the enhanced thermal responsiveness of the composition may comprise an increased shrinking rate at an elevated temperature as compared to the hydrophobic polymer matrix alone.
  • the enhanced thermal responsiveness of the composition is observed in an increased shrinking rate at temperatures above about 35°C, and preferably above about 37°C.
  • the temperature range of the shrinking temperature can be shifted to higher or lower values (e.g., from about 5°C to about 95°C) by a copolymerization of either hydrophilic or hydrophobic monomers into the PNIPAAM network.
  • the enhanced thermal responsiveness of the composition may also comprise an increased gel breaking strength at temperatures above about 35°C, and preferably above about 37°C, as compared to the hydrophobic polymer matrix alone.
  • the shrinking rate and the shrinking temperature of polymer gel compositions of the present invention can be increased or decreased (i. e., adjusted) by varying a ratio of an amount of hydrophobic polymer matrix to an amount of interpenetrating hydrophilic polymer network disposed within or interpenetrating the hydrophobic polymer matrix.
  • the relative increase in the shrinking rate (alternatively, deswelling rate) of the composition is found to increase for ratios of PNIPAAM/gelation of 0.06/1, 0.11/1, 0.16/1, and 0.33/1, respectively.
  • the polymer gel compositions of the invention are capable of reversibly swelling and shrinking by changing the temperature of such compositions to a temperature below or above the lower critical solution temperature.
  • the polymer gel compositions of the invention may comprise at least a first polymer matrix and a second polymer network interpenetrating said first polymer matrix, wherein the gel is capable of undergoing a phase separation in response to a change in temperature so that the gel shrinks at a greater rate when temperature is increased and swells at a greater rate when temperature is decreased as compared to the first polymer matrix alone.
  • the invention provides gel compositions exhibiting a reversible temperature-dependent phase separation and a lower solution critical temperature.
  • Such compositions comprise a hydrophobic polymer matrix, and a hydrophilic polymer network which is typically in an amount of from about 0.1% to about 25% by weight based on the total weight of the composition, wherein the composition has an increased shrinking rate at a temperature above the lower solution critical temperature as compared to the hydrophobic polymer matrix alone.
  • the gel compositions of the invention may be used in potential biological and medical applications, including as special adsorbents, as actuators, in drug delivery devices, and for site-specific or systemic drug delivery methods.
  • the compositions of the present invention may be used for surgical applications, including those used for surgical treatment of animals and humans in need thereof.
  • the fast-shrinking and stronger polymer gels of the invention may be used to repair damaged blood vessels, e.g., connect severed vessels, reinforce weakened vessels, or patch ruptured vessels in vivo.
  • these compositions can be used to repair neurons or other tissues.
  • the polymer gel compositions will often be fabricated in a tubular format or in a planar sheet to facilitate their use in these applications.
  • the polymer gels may be formed into tubes or sheets which may be used to surround or encase ruptured or severed tissues or vessels, thereby assisting with connection and repair of such tissues or vessels.
  • the invention also provides in vivo or ex vivo methods for repairing a blood vessel system in a warm-blooded animal.
  • Such methods comprises the steps of: (a) providing a tube comprising a thermally responsive polymer gel composition of the invention, said tube having a first end, a second end, and an internal lumen therebetween, said tube being maintained at a temperature lower than a shrinking temperature of the polymer gel composition; (b) providing a blood vessel system comprising a first blood vessel segment having an internal lumen and an end and a second blood vessel segment having an internal lumen and an end, said first and second blood vessel segments contained within the animal, said animal having a minimal internal ambient temperature greater than the shrinking temperature of the polymer gel composition; (c) inserting the end of the first blood vessel segment into the first end of the tube; (d) inserting the end of the second blood vessel segment into the second end of the tube such that tube is positioned over the first and second ends of the blood vessel segments; and (e) maintaining the tube in position until the temperature of the
  • the hydrophobic polymer matrix comprises PNIPAAM and the interpenetrating polymer network comprises gelatin.
  • the shrinking temperature of the polymer gel composition employed in such methods is typically at least about 32°C, and the minimal internal ambient temperature of the animal is at least about 33°C.
  • Such methods comprise the steps of: (a) providing a tube comprising a thermally responsive polymer gel composition of the invention, the tube having a first end, a second end, and an internal lumen therebetween, said tube being maintained at a temperature below the shrinking temperature of the polymer gel composition; (b) providing a blood vessel system comprising a first blood vessel segment having an internal lumen and an end and a second blood vessel segment having an internal lumen and an end, said system being maintained at a temperature below the shrinking temperature of the polymer gel composition; (c) inserting the end of the first blood vessel segment into the first end of the tube; (d) inserting the end of the second blood vessel segment into the second end of the tube such that tube is positioned over the first and second ends of the blood vessel segments; and (e) increasing the temperature of the tube to a temperature equal to or greater than the shrinking temperature of the polymer gel composition so as to cause the tube to shrink and to contact the blood vessel segments to provide con
  • the invention provides methods for sealing a blood vessel system in vivo in a warm-blooded animals.
  • Such methods comprise the steps of: (a) providing a tube comprising a thermally responsive polymer gel composition of the present invention, the tube having a first end and a second end, and an internal lumen therebetween, said tube being maintained at a temperature lower than a shrinking temperature of the polymer gel composition; (b) providing a blood vessel system comprising a first blood vessel segment having an internal lumen and an end and a second blood vessel segment having an internal lumen and an end, said system being within a warm-blooded animal having a minimal internal ambient temperature that is greater than the shrinking temperature of the polymer gel composition; (c) inserting the end of the first blood vessel segment into the first end of the tube and all the way through the tube such that the end of the first blood vessel segment emerges from the second end of the tube; (d) connecting the end of the first blood vessel segment with the end of the second blood vessel segment with at least one surgical stitch;
  • Such a method may also be used ex vivo.
  • the blood vessel segments are maintained outside the animal body at a temperature lower than the shrinking temperature.
  • the temperature of the tube is warmed to a temperature equal to or greater than the internal ambient temperature of the animal into which the segments and tube are to be reinserted, thus permitting the tube to shrink around the segments and to hold them tightly.
  • the segments and tube may then be reinserted into the animal body.
  • the polymer gel composition may comprise, for example, a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within said hydrophobic polymer matrix, wherein said polymer gel composition has an enhanced thermal responsiveness as compared to the hydrophobic polymer matrix alone.
  • PNIPAAM is a preferred hydrophobic polymer matrix
  • gelatin is a preferred interpenetrating hydrophilic polymer network for use in such methods.
  • the tube may maintained at a temperature of no more than about 32°C, and the warm-blooded animal may have a minimal internal ambient temperature of from about 25°C to about 40°C, and more preferably, at least about 35°C.
  • Also provided by this invention are methods for reinforcing a blood vessel segment or a nerve segment in vivo in a warm-blooded animal having a minimal internal ambient temperature of at least about 33°C.
  • Such methods comprise the steps of: providing a sheet comprising a thermally responsive polymer gel composition of the invention, said sheet being maintained at a temperature of no more than about 30°C; contacting said blood vessel segment or said nerve segment with the sheet, said blood vessel segment or said nerve segment being contained within the animal; using an applicator to form the sheet into a tube around said blood vessel segment or said nerve segment; and maintaining the tube in position until the temperature of the tube achieves the internal ambient temperature of the animal and contacts said blood vessel segment or said nerve segment, thereby reinforcing the blood vessel segment or nerve segment.
  • Fig. 4A illustrates another aspect of the present invention.
  • Fig. 4A shows a tube (4) comprising a thermally responsive polymer gel composition of the invention which comprises a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed within the hydrophobic polymer matrix at a temperature of about 20°C.
  • the tube (4) has a first end (17) and a second end (18), and an internal lumen (19) therebetween.
  • Fig. 4B shows the same tube (4) at a temperature of about 37°C.
  • the hydrophobic polymer matrix comprises PNIPAAM
  • the interpenetrating hydrophilic polymer network comprises a protein, such as collagen or gelatin.
  • the interpenetrating hydrophilic polymer network of the polymer gel composition comprises at least 1% gelatin by weight based on the total weight of the composition.
  • the tube (4) when the tube (4) is heated from 20°C to 37°C, the tube shrinks.
  • Fig. 4C which presents another embodiment of the present invention, is a schematic illustration of an in vitro (or in vivo) use of a tube (4), said tube having a first end (17) and a second end (18).
  • the tube comprises a polymer gel composition of the present invention to seal or connect a severed or ruptured blood vessel (5).
  • the non-shrunken polymer gel tube (4) is positioned around the rupture point of the blood vessel such that the two severed ends of the blood vessel are encompassed by the tube.
  • the first end (6) and second end (7) of the severed blood vessel (5) are inserted into the lumen of the tube (4) while the tube (4) is maintained at a temperature lower than the shrinking temperature of the polymer gel composition of which it is made (e.g., about 20°C).
  • the first end (6) and the second end (7) of the blood vessel are brought together and tube (4) is placed over these ends.
  • the tube (4) loosely holds the first and second ends of the blood vessel together, and blood (20) is observed to flow from the ends of the vessel out through the first end (17) and second end (18) of the tube.
  • Fig. 4D depicts the blood vessel (5) and tube (4) after heating to a temperature equal to or greater the shrinking temperature of the polymer gel composition (e.g., for PNIPAAM/gelatin, the shrinking temperature is about 37°C).
  • the tube (4) shrinks, thereby contacting and gripping the first end (5) and second end (6) of the blood vessel (5) tightly, thereby permitting blood to flow from the first and second end of the blood vessel (/ ' . e. , through the blood vessel), but preventing blood from flowing out of the first end (17) and second end (18) of the tube (4).
  • the severed blood vessel (5) is effectively sealed and repaired, and leakage of blood into the environment surrounding the vessel is prevented.
  • a tube comprising a polymer gel composition of the present invention seals a severed blood vessel and prevents further leakage of blood from the vessel into the surrounding environment for a blood flow rate of more than 1 milliliter per second (mL/sec) or a flow speed of more than 5 meters per second (m sec).
  • mL/sec milliliter per second
  • m sec flow speed
  • the invention provides methods for joining a first nerve segment and a second nerve segment of a nerve system in vivo or ex vivo in a warm- blooded animal comprising the steps of: (a) providing a tube comprising a thermally responsive polymer gel composition of the invention, the tube having a first end and a second end, and an internal lumen therebetween, and the tube being maintained at a temperature lower than a shrinking temperature of the polymer gel composition; (b) providing a nerve system comprising a first nerve segment having an end and a second nerve segment having an end, said first and second nerve segments being within a warm-blooded animal having a minimal internal ambient temperature that is greater than the shrinking temperature of the polymer gel composition; (c) inserting the end of the first nerve segment into the first end of the tube and through the tube such that the end of the first nerve segment emerges from the second end of the tube; (d) connecting the end of the first nerve segment with the end of the second nerve segment with at least one surgical stitch; (e) positioning the
  • the polymer gel compositions of the invention may also be used in forming temperature-dependent implantable medical devices and drug delivery for use in a variety of applications, including surgical application described herein.
  • Such devices and systems are useful, for example, in the delivery of drugs or other biologically or physiologically active compounds in the body of subjects in need of such treatment, including humans and animals, and in joining separated tissues or repairing damaged tissues (e.g., blood vessels or nerves) or reinforcing or augmenting structurally deficient tissues, vessels or nerves.
  • the implantable medical devices and systems of the invention may be formed of various shapes and sizes, including sheets and tubes. Such devices, particularly when formed in sheets or tubes, are especially useful in various medical and surgical applications, including in vivo and ex vivo repair of damaged, ruptured, or severed blood vessels and neurons, repair of damaged or separated tissues, and reinforcement of weakened or structurally deficient tissues, vessels, and neurons.
  • implantable medical devices comprising polymer gel compositions of the invention are used as drug delivery systems or as components of such systems, they typically include one or more drugs, biologically or physiologically active compounds, or the like.
  • the compound is capable of being released from the gel composition when the gel composition shrinks in response to an increase in temperature.
  • the gel composition of the present invention which includes a hydrophilic IPN network releases the compound much more quickly at a particular site in the body of the subject in response to the change of temperature than does a gel composition that does not include a hydrophilic IPN network.
  • Each such biologically or physiologically active compound may be incorporated into the matrix network of the polymer gel composition by using various procedures that are well known in the art.
  • a drug or other biologically or physiologically active compound may be incorporated into a polymer gel composition of a temperature- dependent implantable medical device by a standard "loading" process.
  • a variety of methods well-known in the art can be employed to incorporate or "load” such drugs or other biologically or physiologically active compounds into the polymer gel composition, including those methods described below. See, e.g., Y.H. Kim et al, J. Controlled Release 28: 143 (1994), R. Yoshida et al, J. Biomat. Sci.-Polym. Ed. 6:585 (1994), and A.S. Hoffman, J. Controlled Release 6:297 (1987), which are incorporated herein in their entirety for all purposes.
  • the invention provides methods for releasing the biologically or physiologically active compound comprising the steps of: (a) providing an implantable medical device, said device comprising the thermally responsive polymer gel composition of the present invention and a therapeutically effective amount of the biologically or physiologically active compound, said device being maintained at a temperature less than a shrinking temperature of the composition, said compound being released from the composition when a temperature of the composition is increased to a temperature equal to or greater than the shrinking temperature of the composition; (b) implanting said device in a body of a warm-blooded animal having a minimal internal ambient temperature greater than the shrinking temperature of the composition; and (c) allowing the temperature of the device to achieve the minimal internal ambient temperature of the animal such that the composition shrinks and the compound is released from the composition.
  • a therapeutically effective amount is an amount adequate to effect a therapeutic result in more than 50% of subjects, including animals and humans so treated. The therapeutically effective amount will depend, among other things, on the body weight, physiology, and chosen method of administration.
  • the invention also provides methods for site-specific or systemic drug delivery which comprise implanting into the body of a subject in need thereof, including a wa ⁇ n-animal or a human having a minimal internal ambient temperature (e.g. , from about 25°C to about 40°C, and more preferably, at least about 35°C), a temperature- dependent implantable medical device comprising a thermally responsive polymer gel composition of the invention (including a biocompatible polymer gel composition) and a therapeutically effective amount of a biologically or physiologically active compound.
  • the animal has a minimal internal ambient temperature that is greater than the shrinking temperature of the composition.
  • the compound is capable of being released from the gel composition and delivered into the animal when the gel composition shrinks in response to an increase in temperature.
  • the device Prior to implantation, the device is maintained at a temperature of about 2°C to about 3°C lower than the shrinking temperature of the gel compositions (e.g. , typically no more than about 32°C). At the normal internal ambient temperature, the device will not release the compound, but when the temperature around the implanted gel rises about 2°C to about 3°C above the normal ambient temperature, the compound is released.
  • Such methods comprise implanting the device comprising polymer gel of the invention in the body of the animal and allowing the temperature of the gel composition of the device to increase and equilibrate with the body temperature of the animal. As the temperature of the gel composition increases and (rises above the critical solution temperature), the gel composition shrinks and releases the compound from the gel composition, thereby delivering the compound into the animal.
  • Drug delivery systems comprising polymer gel compositions of the invention may be prepared and employed as described herein and may be prepared and used by and in procedures well-known to those of ordinary skill in the art, including, e.g., the methods and applications described in: K.P. Rao, J. Biomater. Sci. Poly. Edn., 7(7):623-645 (1995); M. Mahoney et al, J.
  • the invention provides methods of releasing a chemical into an environment by using a thermally responsive polymer gel composition of the invention, such as PNIPAAM/gelatin polymer gel composition, into which a chemical is incorporated.
  • the chemical is capable of being released from the gel composition when the gel composition shrinks in response to an increase in temperature.
  • Such methods comprise providing a gel composition of the invention and increasing the temperature of the gel composition such that the gel composition shrinks and thereby releases the chemical from the gel composition.
  • a variety of well-known methods can be utilized to load or incorporate a desired chemical into the gel composition.
  • a desired chemical is placed into the pre-gel solution containing the monomers and hydrophilic polymers.
  • Polymerization of the monomers leads to a thermally sensitive gel network which includes the chemicals and the hydrophilic polymers.
  • the hydrophilic polymers can be further cross-linked to form an IPN.
  • the monomers react with each other to form the thermally sensitive gel network which is hydrophobic at higher temperatures.
  • NIPAAM n-isopropylacrylamide
  • the solution typically contains (by weight) about 10% monomers, about 0.5 to about 5% hydrophilic polymers, and some crosslinking agent and other chemicals.
  • all of the monomers and crosslinking agents interconnect with each other to form a three-dimensional network in which the hydrophilic polymers are trapped.
  • Such a network is termed a " semi-interpenetrating polymer network.
  • the hydrophilic polymers trapped inside the thermally sensitive gel network can be further cross-linked to form a interpenetrating gel network which contains two sets of polymer networks.
  • the polymer gel compositions of the invention are useful in a wide variety of applications where thermally sensitive materials are desired, such as, for example, for use as temperature-sensitive membranes or ba ⁇ iers.
  • the prefe ⁇ ed polymer gel compositions for use as temperature-sensitive membranes include gelatin in an amount of from about 0.1% to about 25% by weight, and preferably from about 0.5% to about 5% by weight, and PNIPAAM in an amount of from about 5% to about 30% by weight, based on the total weight of the gel composition.
  • an actuator comprises a polymer gel layer comprising a thermally responsive polymer gel composition disposed over a flexible planar element, such as a thin poly(styrene) film, that is not affected or at least not substantially affected by a change in temperature (i.e., thermally non-responsive or at least substantially thermally non-responsive).
  • a flexible planar element such as a thin poly(styrene) film
  • substantially thermally non-responsive is meant that a flexible planar element, for example does not shrink substantially in response to an increase in temperature.
  • the thermally responsive polymer gel composition comprises a hydrophobic polymer matrix and an interpenetrating polymer network disposed within the hydrophobic polymer matrix, wherein the polymer composition has enhanced thermal responsiveness as compared to the hydrophobic polymer matrix alone.
  • an actuator can be made in a bilayer format as follows.
  • a gel composition according to the present invention is prepared, formed into a strip or sheet (or other suitable shape or configuration), and stored in an aqueous solvent, such as water, such that it is in its swollen state.
  • a portion of the strip e.g., one -half of the strip
  • Such cross-linking may be accomplished, for example, by immersing a portion of the strip in a solution containing such a monomer.
  • the resulting strip or sheet will comprise a bilayer, with one layer having thermally responsive properties and the second layer having no or little thermally responsive properties.
  • the thickness and size of the strip or sheet for use an actuator will depend on the particular application (e.g., 1 mm to 1 cm).
  • the actuator may comprise a bilayer format in which the first layer includes a hydrophilic IPN, while the second layer includes a hydrophobic IPN.
  • the invention provides drug earners comprising the polymer gel compositions of the invention. Such earners are useful in delivering drugs to subjects in need of such treatment.
  • the drug ca ⁇ ier is designed to match the particular delivery application needed for the drug (e.g., oral delivery, delivery by implantation of device or material comprising polymer gel composition).
  • the ca ⁇ ier and polymer gel composition are designed and selected specifically for successful oral delivery, with attention being given to protecting against poor absorption across the gastrointestinal mucosa, protection against enzymatic degradation, and protection from the acidic environment of the stomach.
  • additional components such as enzyme inhibitors, permeation enhancers, and drug stabilizers, may be incorporated into the carrier comprising at least one polymer gel composition of the invention.
  • the invention sets forth methods of producing a thermally responsive polymer gel composition comprising at least one hydrophobic polymer matrix and at least one interpenetrating hydrophilic polymer network disposed within the hydrophilic polymer network.
  • Such methods typically comprise the steps of: (a) combining the hydrophobic polymer matrix and the interpenetrating hydrophilic polymer network; (b) agitating the product obtained from step (a) to form a mixture; and (c) placing the product step (b) into a vessel adapted to store or deliver the composition.
  • Methods for producing polymer gel compositions of the invention are also set forth below in the Examples.
  • NIPAAM N-isopropylacrylamide
  • B-type gelatin Bloom value 270, in solid form
  • a concentrated NIPAAM solution was prepared by dissolving 3.98 g NIPAAM, 0.068 g N,N_-methylenebis(acrylamide), and 0.122 mL of N,N,N_,N_-Tetramethylthylene diamine in sufficient deionized water to achieve a total volume of 25 mL.
  • An aqueous solution of 5.16% gelatin (w/w) in deionized water was prepared by dissolving the appropriate amount of gelatin in deionized water.
  • a potassium persulfate (KPS) solution was prepared by dissolving 0.12 g potassium persulfate in 5 mL deionized water. The solutions were stored at about 4 to 6°C until used.
  • NIPAAM Polymerization of NIPAAM: The gelation solution was heated to about 55°C while sti ⁇ ing until the gelatin melted completely. After the gelatin solution cooled to about 30 to about 35°C, 1.53 mL of the gelatin solution was mixed with 1.47 mL deionized water, and then 3.0 mL NIPAAM solution was added. The mixture was sti ⁇ ed for several minutes, and then 0.12 mL KPS was added to the mixture. The mixture was then immediately injected into a mold having the shape of the desired device (e.g., flat sheet or tube). The mold was placed in a sealed vessel. Oxygen was removed repeatedly by degassing the mixture using nitrogen at least three times. The mixture was allowed to polymerize for at least two hours at room temperature.
  • a mold having the shape of the desired device e.g., flat sheet or tube
  • the chemicals to be loaded into the gel can be added to the NIPAAM solution or gelatin solution before the polymerization process, or, alternatively, can be added to the aqueous gluctaric dialdehyde solution before the gelatin cross-linking process.
  • Such drug delivery systems or devices comprising thermally responsive polymer gel compositions of the invention are useful in a variety of applications, including those identified and described herein.
  • a variety of drugs may be included in such drug delivery systems and devices. The particular drag to be incorporated in such systems and devices will depend ' upon the particular application and the nature of the disease or condition to be treated.
  • this thermally responsive polymer gel composition can be used in surgery to facilitate tissue recovery and simplify the operation.
  • a series of primary in vivo experiments were conducted on rats to investigate tissue reactions to this
  • PNIP AAM/gelatin gel composition and uses of this composition in repairing tendon and sciatic nerves by direct application in surgical procedures.
  • PNIP AAM/gelatin is 1.0/0.16 (w/w)) polymer gel composition, flat square pieces
  • Fig. 5 shows a schematic illustration of the implantation of a flat square piece (8
  • PNIP AAM/gelatin polymer gel composition (6) prepared according to the present invention.
  • the gel piece (6) is inserted into between the peritoneum (7) and rectus abdominis (8) within the animal.
  • the ratio of the relative amount of gelatin to PNIPAAM in the gel piece is 0.16 to 1.0.
  • Fig. 6 shows a schematic illustration of the implantation of a flat square piece
  • PNIPAAM/gelatin polymer gel composition (9) preparing according to the present invention implanted into the groin of the animal.
  • This gel piece (9) is inserted between the femoral artery ( 10), femoral nerve (11), and femoral vein (12) of the groin.
  • the ratio of the relative amount of gelatin to PNIPAAM in this composition is 0.16 to 1.00.
  • Fig. 7 shows a schematic illustration of a subdermal implantation in the gluteus
  • PNIPAAM/gelatin polymer gel composition (13) prepared according to the present invention and inserted subdermally in the gluteus maximus (14) of the animal.
  • the ratio of the relative amount of gelatin to PNIPAAM in this gel piece is 0.16 to 1.00.
  • Fig. 7 also presents a schematic illustration of a subdermal implantation in the gluteus maximus muscle (14) of the animal of a tube (16) comprising a
  • PNIPAAM/gelatin polymer gel composition prepared according to the present invention that is positioned around and encases a raptured or severed point (21) of a sciatic nerve
  • Each operation site was opened and checked after 3 days, 1 week, and 2 weeks, respectively, to observe the tissue reactions and to obtain histological examinations.
  • PNIPAAM/gelatin 1.0/0.16 (w/w) tubes having an inside diameter of 2.1 mm, a thickness of 1 mm, and a length of about 6 mm were prepared and stored in deionized water.
  • the diameter of sciatic nerve of a mature rat ranges from about 1.5 to about 2.0 mm.
  • the operation procedure was conducted as follows: After cutting the sciatic nerve, one end of the nerve was threaded through the PNIPAAM/gelatin tube. Both ends of the nerve were then connected using one or two stitches. (At least 8 are typically required to connect two severed nerve ends if no tube is used; thus, the use of the tube (or similar device) according to the present invention reduces the number of stitches normally required to connect a severed nerve or the like (e.g., blood vessel). After this connection was made, the tube was moved to cover the connected nerve ends.
  • the temperature is typically higher than the gel shrinking temperature (e.g. , about 35°C) at which this particular PNIPAAM/gelating composition reaches its fully collapsed state, so that the shrinking gel tube collapsed about the two ends of the nerve, holding such ends tightly and pulling them together.
  • the nerve was checked after 3 days, 1 week, 2 weeks, and 3 weeks to observe the process of recovery. No effusion or infection was observed on the nerve or the su ⁇ ounding tissue. The nerve was swollen by a factor of approximately 2 at 2 weeks following the operation. After 3 weeks, this swelling was observed to decrease and fine blood cells were observed on the surface of the nerve.
  • the gel tube has two principal functions: (1) it serves to hold the two ends of the nerve tightly so that the number of the stitches required to hold the severed ends of the nerve in place and to connect them is decreased; alternatively, when the gel tube is employed, no stitches may be needed to hold the severed ends of the nerve in place and to connect them. Thus, with the use of the gel tube, the operation can be performed much more easily and quickly. In addition, the use of the tube in surgical procedures decreases the stitch-induced scar which may decrease the transmittance of the nerve. (2) The gel tube prevents against growth of adjacent or su ⁇ ounding tissue or other tissue between the severed ends of the nerve, which also decreases the transmittance of nerve.
  • the invention can also be used to make other types of fast-shrinking and stronger polymer gels provided the introduced interpenetrating polymer network is hydrophilic at a temperature higher than the shrinking temperature of the original polymer gel.
  • Such polymer gels can be used in a variety of applications, including those discussed above.

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Abstract

La présente invention concerne d'une manière générale des compositions de gels polymères réagissant thermiquement et présentant des rythmes améliorés de rétrécissement en fonction de la température, une résistance accrue et une souplesse meilleure par rapport à d'autres compositions de polymères connues à ce jour. Plus concrètement, les compositions sont des compositions de gel polymère réagissant à la chaleur comprenant une matrice polymère hydrophobe et un alliage IPN, de sorte que la composition de gel polymère résultante présente une réaction améliorée à la chaleur relative à la matrice polymère hydrophobe seule. Cette combinaison se présente sous forme de gel polymère dont les propriétés sont optimisées. Plus particulièrement, la matrice polymère hydrophobe est poly(n-isopropylacrylamide) ('PNIPAAM') et le réseau IPN est produit par l'incorporation d'une quantité de protéines, d'ordinaire la gélatine, au sein du PNIPAAM. Les compositions, faisant l'objet de l'invention, sont spécialement conçues pour être appliquées dans le domaine chirurgical en vue de la réparation de tissus abîmés, tels que les vaisseaux sanguins, les neurones et similaires et dans des systèmes de libération de médicaments sensibles à la température.
PCT/CN1997/000150 1996-12-20 1997-12-19 Nouvelle composition de gel polymere et leurs utilisations WO1998028364A1 (fr)

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HK00104248A HK1025585A1 (en) 1996-12-20 2000-07-11 Novel polymer gel composition and uses therefor

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US3389796P 1996-12-20 1996-12-20
US60/033,897 1996-12-20
CN97180823A CN1102614C (zh) 1996-12-20 1997-12-19 新型高分子凝胶体及其应用

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Cited By (4)

* Cited by examiner, † Cited by third party
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EP1159049A1 (fr) * 1999-03-17 2001-12-05 Foster-Miller Inc. Gels sensibles et leurs procedes d'utilisation
EP1423093A2 (fr) * 2001-04-23 2004-06-02 Wisconsin Alumni Research Foundation Hydrogels modifies bifonctionnels
DE102005054941A1 (de) * 2005-11-17 2007-05-31 Gelita Ag Nervenleitschiene
WO2007111736A1 (fr) * 2006-03-27 2007-10-04 Boston Scientific Scimed, Inc. dispositifs médicaux aux capacités d'administration locale de médicament

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NZ543288A (en) * 2003-04-30 2009-06-26 Univ Drexel Thermogelling polymer blends for biomaterial applications
SG10201807556TA (en) * 2005-09-09 2018-10-30 Ottawa Hospital Res Inst Interpenetrating Networks, and Related Methods and Compositions
CN101293963B (zh) * 2007-07-06 2011-06-22 东华大学 一种两性共连续聚合物网络及其制备方法和应用
CN101396569B (zh) * 2007-09-27 2013-04-10 北京师范大学 以生物体组织为支架的复合水凝胶、其制备方法及其用途
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CN103520777B (zh) * 2013-10-08 2014-12-10 天津工业大学 一种高韧性和孔洞可调的凝胶人造血管及其制备方法
CN103599565B (zh) * 2013-11-21 2015-04-22 无锡中科光远生物材料有限公司 一种抗菌组合物及使用其制备的温敏性抗菌膜和植入材料
CN103623468B (zh) * 2013-11-21 2015-04-22 无锡中科光远生物材料有限公司 一种使用抗菌组合物制备温敏性抗菌膜和植入材料的方法
CN105363063B (zh) * 2015-11-18 2018-12-14 武汉维斯第医用科技股份有限公司 具有温敏性能的胶原蛋白敷料及其制备方法
CN108342043A (zh) * 2017-12-29 2018-07-31 佛山市锦彤企业管理有限公司 一种抗菌温敏型高分子水凝胶
CN108456319A (zh) * 2017-12-29 2018-08-28 佛山市锦彤企业管理有限公司 一种高强度高分子水凝胶
CN108440771A (zh) * 2017-12-29 2018-08-24 佛山市锦彤企业管理有限公司 一种温度敏感型高分子水凝胶
CN108456318A (zh) * 2017-12-29 2018-08-28 佛山市锦彤企业管理有限公司 一种高延伸性抗菌高分子水凝胶
CN109513038A (zh) * 2018-12-14 2019-03-26 华南理工大学 负载铜金属有机骨架纳米粒子的温敏水凝胶及其制备方法

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EP0595226A2 (fr) * 1992-10-30 1994-05-04 Hoya Corporation Gel polymère contenant une substance active
JPH08134146A (ja) * 1994-11-09 1996-05-28 Res Dev Corp Of Japan 側鎖に核酸塩基を導入したポリマ−ゲル及びその製造方法

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1159049A1 (fr) * 1999-03-17 2001-12-05 Foster-Miller Inc. Gels sensibles et leurs procedes d'utilisation
EP1159049A4 (fr) * 1999-03-17 2002-01-16 Foster Miller Inc Gels sensibles et leurs procedes d'utilisation
EP1423093A2 (fr) * 2001-04-23 2004-06-02 Wisconsin Alumni Research Foundation Hydrogels modifies bifonctionnels
EP1423093A4 (fr) * 2001-04-23 2005-11-30 Wisconsin Alumni Res Found Hydrogels modifies bifonctionnels
US7615593B2 (en) 2001-04-23 2009-11-10 Wisconsin Alumni Research Foundation Bifunctional-modified hydrogels
US8025901B2 (en) 2001-04-23 2011-09-27 Wisconsin Alumni Research Foundation Bifunctional-modified hydrogels
DE102005054941A1 (de) * 2005-11-17 2007-05-31 Gelita Ag Nervenleitschiene
US8216602B2 (en) 2005-11-17 2012-07-10 Gelita Ag Nerve guide
WO2007111736A1 (fr) * 2006-03-27 2007-10-04 Boston Scientific Scimed, Inc. dispositifs médicaux aux capacités d'administration locale de médicament

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