United States Patent:  6,030,634

Assignee:  The Chinese University of Hong Kong (Shatin N.T., HK)

Filed:  December 15, 1997

The present invention general relates to thermally responsive polymer gel compositions that have enhanced temperature-dependent shrinking rates, increased strength, and improved pliability over previously known polymer compositions. In particular, the compositions are thermally responsive polymer gel compositions comprising a hydrophobic polymer matrix and an interpenetrating hydrophilic polymer network disposed therein, such that the resulting polymer gel composition has enhanced thermal responsiveness relative to the hydrophobic polymer matrix alone. This combination results in polymer gels having these improved properties. In a particular aspect, the hydrophobic polymer matrix is poly(n-isopropylacrylamide) ("PNIPAAM") and the interpenetrating polymer network is supplied by incorporation of an amount of protein, typically gelatin, within the PNIPAAM. The compositions of the invention find particular use in surgical applications for the repair of damaged tissues, e.g., blood vessels, neurons, and the like, and in temperature-dependent drug delivery systems.

SUMMARY OF THE INVENTION

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. In particular, 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. The 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. In addition, the 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. In a particular aspect, 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.

In another aspect, the invention provides a composition of matter which comprises a polymer gel comprising a thermally sensitive polymer matrix and a hydrophilic polymer network interpenetrating 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.

In still another aspect, the invention provides an interpenetrating polymer network gel composition comprising 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.

In another aspect, 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.

In yet another aspect of the invention, methods for sealing a blood vessel system in vivo are provided. 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^oC., 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^oC. to about 40^oC., and more preferably, at least about 35^oC. 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. The tube is allowed the tube to achieve the ambient temperature and to shrink around the first and second ends of the blood vessel, thereby sealing the blood vessel. For such methods, a preferred thermally responsive biocompatiable polymer gel composition comprises PNIPAAM and gelatin in relative amounts described herein below.

In yet another aspect, 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, thereby providing contiguous blood flow through the two blood vessel segments. For such methods, a preferred thermally responsive polymer gel composition comprises PNIPAAM and gelatin in relative amounts as described below.

Also provided are methods for sealing a blood vessel system in vivo in a warm-blooded animal which 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 segment with at least one surgical stitch; positioning the tube over the ends of the first and second 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, thereby providing contiguous blood flow through the two blood vessel segments and sealing the blood vessel system. For such methods, a preferred thermally responsive biocompatible polymer gel composition comprises PNIPAAM and gelatin in relative amounts as described below.

In another aspect, 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 temperature of the tube equilibrates with the internal ambient temperature of the animal and shrinks onto the nerve segments, thereby joining the first and second nerve segments. For such methods, a preferred thermally responsive biocompatible polymer gel composition comprises PNIPAAM and gelatin in relative amounts as described herein below.

Also included are methods for reinforcing a blood vessel segment or nerve segment in vivo in a warm-blooded animal having a minimal internal ambient temperature of at least about 33^oC. Such methods comprise the steps of providing a sheet comprising a thermally responsive polymer gel composition of according to the present invention, said sheet being maintained at a temperature of no more than about 30^oC.; contacting said blood vessel segment or said nerve segment with the sheer, said blood vessel segment or said nerve segment being contained within the animal; using an applicator to form the sheet into a tube around the blood vessel segment or nerve segment; and maintaining the tube in position until the temperature of the tube achieves the internal ambient temperature of the animal and contacts the blood vessel segment or nerve segment, thereby reinforcing the blood vessel segment or nerve segment. For such methods, a preferred thermally responsive biocompatible polymer gel composition comprises PNIPAAM and gelatin in amounts as described below.

In addition, 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 repairing the blood vessel system. Such a method can also be employed to repair or seal other tissues, including neuronal tissues.

In another aspect, 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. In such systems and devices, 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.

In yet another aspect, 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.

In yet another aspect, 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 planar element is not substantially thermally responsive.

In still another aspect of the invention, 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 are provided. 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 (c) placing the product step (b) into a vessel adapted to store or deliver the composition.

Claim 1 of 28 Claims

1. A thermally responsive polymer gel composition, comprising:

a thermosensitive polymer matrix comprising poly(n-isopropylacrylamide) (PNIPAAM) or a derivative thereof; and

an interpenetrating hydrophilic polymer network disposed within said thermosensitive polymer matrix, said hydrophilic polymer network comprising a protein,

wherein a shrinking rate of said polymer gel composition is increased by a factor of up to 1000 as compared to the thermosensitive polymer matrix alone at a temperature equal to or greater than a shrinking temperature of the polymer gel composition.

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