WO1992002005A2

WO1992002005A2 - Gel phase transition controlled by interaction with a stimulus

Info

Publication number: WO1992002005A2
Application number: PCT/US1991/005312
Authority: WO
Inventors: Toyoichi Tanaka; Etsuo Kokufuta; Yong-Quing Zhang; Atsushi Suzuki; Akira Mamada; Yoshitsugu Hirokawa; Masayuki Tokita
Original assignee: Massachusetts Institute Of Technology
Priority date: 1990-07-26
Filing date: 1991-07-26
Publication date: 1992-02-06
Also published as: WO1992002005A3

Abstract

A phase-transition gel and a method of forming a phase-transition gel which undergoes a significant discontinuous volume change at a desired phase-transition condition in response to a stimulus is disclosed. The phase transition gel includes a liquid medium gelled with a polymer network which has a phase transition condition different from that desired and a phase-transition-modifying agent sufficient to cause, in response to the stimulus, the discontinuous volume change of the gel at the desired phase-transition condition.

Description

GEL PHASE TRANSITION CONTROLLED BY INTERACTION WITH A STIMULUS

Background of the Invention

Gels can exhibit phase transitions, or discontinuous volume change, in response to var-iation of the surrounding conditions. For example, the fluid supporting a gel can be modified to effect a discontinuous contraction or expansion of a gel such as by changing the pH, solvent composition, relative concentration of solvents or the ion concentration of the fluid.

The phase transition of gels, however, typically has been a function of conditions of surrounding fluids which are unaffected by the gels, per se. Discontinuous rates of expansion and contraction of gels have generally been limited, therefore, to variation of conditions unrelated to the conditions which are to be modified by the presence of the gels. Further, the conditions under which gels exhibit phase transitions have been limited to conditions which directly affect the polymer network of the gel. Summary of the Invention

The present invention relates to phase-transition gels and to methods of forming phase-transition gels which undergo a significant discontinuous volume change at a desired phase-transition condition in response to a stimulus.

A phase-transition gel which undergoes a significant discontinuous volume change at a desired phase-transition condition in response to a stimulus includes a liquid medium gelled with a polymer network which has a phase transition condition different from that desired. A phase-tranεition- modifying agent is incorporated into the phase-transition gel in an amount sufficient to cause, in response to the stimulus, the discontinuous volume change of said gel at the desired phase-transition condition in response to the stimulus.

A method of forming a phase-transition gel which undergoes a significant discontinuous volume change at a desired phase-transition condition in response to a stimulus includes gelling a liquid medium with a polymer network to form a phase-transition gel which has a phase-transition condition different from that desired. A phase-transition-modifying agent is incorporated in the phase-transition gel in an amount sufficient to cause, in response to the stimulus, the discontinuous volume change of said gel at the desired phase-transition condition.

-3-

Thiε inventions has many advantages and uses. Importantly, it provides the capabalility to engineer gels having a phase-transition at any desired condition. These engineered gels have many uses. For example, they can be used as sensors of the stimulus. For example, the ratio of substrate to product can be sensed by rapid expansion of the gels when the ratio of substrate to product exceeds a maximum limit. Gels of the present invention can also be used to model biological activities by triggering a phase transition of the gels in the presence of a stimulus. Also, biological function can be simulated by the gels. Examples of such functions are muscular contraction and nerve excitation. Also, actuators, transducers, memories, controlled release systems and selective pumps can be formed using gels of the present invention.

Brief Description of the Drawings

Figure 1 is a schematic representation of a memory device of the present invention.

Figure 2 is a schematic representation of a sensor device of the present invention.

Figure 3 is a schematic representation of an actuator device of the present invention. Figure 4 is a schematic representation of a transducer of the present invention.

Figure 5 is a schematic representation of a light pump of the present invention. Figure 6 is a schematic representation of a chemical release system of the present invention.

Figure 7 is a plot of the volume of an enzyme- free gel relative to the volume of the gel in a contracted phase over a temperature range during phase transition between an expanded phase and a contracted phase.

Figure 8 is a plot of the volume of a gel containing active enzyme and of a gel containing an inactivated enzyme relative to volumes of the gels in a contracted phase over a temperature range during phase transition between an expanded phase and a contracted phase.

Figure 9 is a plot of phase transition over time of a gel containing active enzyme and of an enzyme- free gel. Both gels are immersed in a solution containing a sufficient concentration of substrate to thereby cause the gels to exhibit a phase transition.

Figure 10 is a plot of phase transition of a gel containing a chlorophyllin during a change of temperature at various intensities of light.

Figure 11 is a plot of phase transition of a gel containing a chlorophyllin at constant temperature during exposure of the gel to a change of light intensity.

Detailed Description of the Invention

The features and other details of the phase-transition gel and method of forming the phase-transition gel of the invention will now be ore particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.

"Phase-transition" of gels, as that term is used herein, means a discontinuous volume change of gels between an expanded phase and a contracted phase.

"Phase-transition gels," as that term is used herein, are gels which exhibit a phase transition at a phase transition condition. The difference in volume between the expanded phase of phase-transition gels and the contracted phase of the phase-transition gels can be hundreds of orders of magnitude. Examples of phase-transition gels are disclosed in Tanaka, et al. , U.S. Patent No. 4,732,930 and in U.S. Patent Applications 07/425,788 and 07/470,977, the teachings of which are incorporated by reference.

A phase-transition gel of the present invention undergoes a significant discontinuous volume change at a desired phase-transition condition in response to a stimulus. The phase transition gel includes a liquid medium gelled with a polymer network which has a phase transition condition different from that desired.

The liquid medium is suitable if it can be gelled with a polymer network to thereby form a phase-transition gel. Examples of suitable liquids include water, aqueous solutions, organic and inorganic liquids. The liquid medium also can be a solution or a mixture of liquids. An example of a suitable aqueous solution is a dioxane solution. The polymer networks can comprise natural polymers, synthetic polymers, copolymers of natural and synthetic polymers or cross-linked synthetic and natural polymers. Examples of synthetic polymer networks include N-isopropylacrylamide, N-isopropylacrylamide-acrylic acid copolymer gels, etc. Examples of natural polymers include deoxyribonucleic acid, ribonucleic acid, etc.

Phase-transition conditions at which the phase- transition gels exhibit a discontinuous volume change include physical conditions, chemical conditions or combinations of physical and chemical conditions. Examples of physical phase-transition conditions include: temperature; electromagnetic radiation, such as infrared energy, visible light and ultraviolet light; etc. Examples of chemical phase-transition conditions include: concentration of ionic species, such as hydrogen and water, i.e. pH; crosslinking agents, i.e. cross-linking agents which crosslink the polymer network of the phase-transition gel; inorganic and organic solvents; etc.

Phase-transition conditions at which the phase-transition gels exhibit a discontinuous volume change can include combinations of physical conditions, combinations of chemical conditions, or combinations of physical and chemical conditions. A phase-transition-modifying agent is disposed in the phase-transition gel which, in response to a suitable stimulus, is sufficient to cause a discontinuous volume change of said gel at the desired discontinuous volume change. A wide variety of phase-transition-modifying agents can be employed in the phase-transition gels of the present invention. These phase-transition-modifying agents can be, for example, small chemical molecules, such as chromophores, cross-linking agents, surfactants, etc. Alternatively, the phase-transition-modifying agents can be macromolecules, such as lectins (e.g., Concanavalin A) or polymers which do not comprise the main polymer network of the gel. Examples of natural polymers include proteins, such as enzymes, DNA, RNA, etc. The agents can also include combinations of small chemical molecules and/or polymers.

The phase-transition-modifying agent can be chemically attached to the polymer network, such as by covalent bonding to the polymer network, or it can be entrapped by a suitable method, such as forming the polymer network in the presence of the phase-transition agent.

The phase-transition-modifying agent can comprise chemical which exhibits properties in response to a suitable stimulus sufficient to cause the discontinuous volume change of the gel at the desired phase-transition condition. Examples of properties which the phase-transition agent can exhibit include enzymatic, catalytic, chelating, hydrophilic, hydrophobic and electromagnetic properties, etc.

Stimulus to which the phase-transition-modifying agents respond include a physical and/or chemical conditions. The phaεe-transition-modifying agent causes a discontinuous phase transition of the gel at a desired phase-transition condition in response to exposure of the stimulus to the phase-transition- modifying agent. Examples of suitable stimuli include: a subεtrate, when the phaεe-transition- modifying agent comprises an enzyme; an antigen, when the phase-tranεition-modifying agent comprises an antibody; reactants, when the phase-transition- modifying agent compriseε a catalyst; etc. The response of the gel to a stimulus causeε a phase transition of the phase-transition gel at a desired phase-transition condition by affecting either the interaction between polymers of the polymer network of the phase-transition gel, the interaction within the polymer network, and/or the interaction between the polymer network and the liquid medium within the gel. The effect on the polymer/copolymer, polymer/polymer or polymer/solvent interaction modifies the phase-transition gel sufficient to cause, in responεe to the εtimulus, a discontinuous volume change of the phase-transition gel at the desired phase transition condition.

The phase-transition gels of this invention can be engineered to have at a desired condition by including within the gel a suitable phase-transition-modifying agent in an amount sufficient to respond to a stimulus, whereby response of the phase-transition-modifying agent causes a discontinuous volume change of said gel at the desired condition. For example, the amount of phase-transition-modifying agent within the phase-transition gel can be selected to cause a discontinuous volume change of the gel at a temperature about 10^CC higher than the phase-transition gel would exhibit the discontinuous volume change in the absence of the phase-tranεition- modifying agent.

When the phaεe-transition-modifying agent comprises an enzyme, a discontinuous phase transition is caused by responεe of t. enzyme to the presence of a suitable substrate at a desired phase-transition condition. Substrate in a liquid medium surrounding the phase-transition gel migrates to within the gel, such aε by diffusion, convection or by selective attraction of the substrate by the enzyme. Responεe of the enzyme to the presence of the substrate, such as enzymatic reaction of the substrate, causes formation of substrate reaction products. The enzymatic reεponεe causes a discontinuous volume change of the phase-tranεition gel at the desired phase-transition condition.

Examples of suitable enzymes include rabbit liver esterase, ureaεe, amylaεe, lipase, galactosidase, catalase, protease, etc. Examples of substrates include sugarε, lipidε, proteinε, hydrogen peroxide, etc. It is to be understood that an enzyme inhibitor can be used to interact with the enzyme to thereby cause the discontinuouε phaεe tranεition. When urease, for example, is dispoεed in an N-iεoprpylacrylamide-acrylic acid copolymer network, a phaεe tranεition can be caused at a desired phase- tranεition condition by enzymatic reaction with urea to form carbon dioxide and ammonium ion. It iε believed that the ammonium ion ionizes the acrylic acid to thereby induce the phase transition of the gel.

When the phase-transition-modifying agent co priseε a chromophore, the phase-tranεition gel can exhibit a diεcontinuouε volume change at the desired phase-tranεition condition in by responεe to visible light as a suitable stimulus. It is believed that, in some caseε, heat generated by the chrompohore raises the temperature of the phase-transition gel and thereby increases the osmotic preεεure within the gel, thereby causing the phase tranεition. An example of a suitable chromophore iε triεodium salt of coppered chlorophyllin.

Alternatively, the phase-tranεition-modifying agent within the gel can co priεe a photoactive material which isomerizes during exposure to light. The stimulus is light. Although the mechanism is not completely understood, it is believed that isomerization of the photoactive material alterε the polymer/copolymer or interpolymer interaction and thereby changeε the phaεe-tranεition conditionε. An example of a photoactive material includes diazobenzene.

In another embodiment, a suitable hydrophobic gel is contacted with a suitable surface chemical, such as surfactant molecules comprising both hydrophobic groups and hydrophilic groups. It is believed that the surfactants form a coating on the polymer gel which acts to ionize the polymer, thereby causing it to become a hydrophilic gel, whereby the environmental conditions at which the gel exhibit a phase transition are changed. Examples of surfactants include sodium dodecyl sulfate ( (CH_ (CH.) ..SO ~)Na ) (anionic) and dodecyl trimethyl ammonium chloride ( (CH₃(CH₂)_1;LN)⁺(CH₃)C1)~) - (cationic) .

When the phase-transition-modifying agent compriseε a croεslinking agent, a stimulus present in a given amount in the surrounding solvent causes crosslinking of the polymer network. The phaεe tranεition can be markedly altered by εuch crosslinking. Examples of crosslinking agents include ethylene diamine, polyethylene diamine. It is believed that the catalytic reaction modifies the polymer/polymer interaction, intrapolymer interaction or polymer/fluid interaction to thereby cauεe a phase transition at environmental conditions at which phase transition of the gel would not otherwise occur. An example of a suitable polymer network is polyacrylamide and an example of a suitable catalyεt iε poly(4-vinylimidazole) . An example of a suitable reactant includes p-nitrophenylacetate.

Specific devices employing the phase-transition gels of this invention are illustrated in the Figures. Memory device 44, illustrated in Figures 1A and IB, includes phase-transition gel 46 disposed within cylinder 48. Cylinder 48 includes aperture 52 for exposing phase-tranεition gel 46 to environment 54. Panel 55 is slidably engaged with guides 56 0 wherein panel 55 is in non-interfering relation with migration of stimulus 58 from environment 54 to phase-transition gel 46 through aperture 52. Phase-transition gel 46 includes a phase-transition- modifying agent 59 which causes a phase transition of phase-transition gel 46 at a desired phase transition condition during exposure of gel body 46 to a sufficient concentration of stimulus 58. Piston 60 is disposed in cylinder 48 adjacent to gel body 46 for movement from a first position, shown in Figure o 1A, where phase-transition gel 46 iε in a contracted phaεe, to a εecond poεition, εhown in Figure IB, where gel 46 is in an expanded phase. Piston 60 iε connected by wire 62 to panel 5 . Upon sufficient expoεure to εtimulus 58 by migration of stimulus 58 5 through aperture 52 to gel 46, gel 46 exhibits a phase transition from the contracted phase to the expanded phase.

During expansion of gel 46 from the contracted phase to the expanded phase, gel 46 moves piston 60 ₀ from the first poεition to the εecond position. Movement of piston 60 from the first position to the second position causes piston 60 to pull panel 55 along guides 56 by wire 62 to thereby seal gel 46 from environment 54. Sealing of gel 46 from environment 54 prevents gel body 46 from exhibiting a phase transition from an expanded phase to a contracted phase during subsequent changes in the presence of stimulus 58 in environment 54, thereby causing memory device 44 to retain a memory of the occurrence of a change in the concentration of stimuluε 58 in environment 54.

Senεor device 64, illuεtrated in Figureε 2A and 2B, includeε phase-transition gel 66. Phase-tranεition-modifying agent 68 and indicator 70 are diεposed in gel 66. Phaεe-transition-modifying agent 68 causes a phase transition of gel 66 from a contracted phase, shown in Figures 2A, to an expanded phase, shown in Figure 2B, upon exposure of sensor 64 to a sufficient concentration of stimulus 71 in environment 72. Upon exposure of sensor 64 to a sufficient concentration of stimuluε 71 in environment 72, gel 66 exhibits a phase transition from the contracted phase to an expanded phaεe. Phase transition of gel 66 releases indicator 70, such as a dye, to environment 72, thereby indicating the presence of stimulus 71. Subsequent reduction of the amount of stimulus 71 in environment 72 causeε gel 66 to exhibit a phase transition from the expanded phase to the contracted phase, thereby terminating release of indicator 70. Actuator device 74, illustrated in Figures 3A and 3B, includes cylinder 76 and phase-tranεition gel 78 disposed in cylinder 76. Piston 80 is dispoεed in cylinder 76 adjacent to gel 78. Piston 80 is moveable between a first position, shown in figure 3A, and a second piston, shown in Figure 3B. Push rod 82 extends from piston 80 and is fixed to switch 84 of electrical circuit 86. Phase-tranεition- odifying agent 88 is disposed in gel 78. Phase-transition-modifying agent 88 cauεeε gel 78 to exhibit a phaεe tranεition from a contracted phase to an expanded phaεe upon expoεure of gel 78 to a εufficient concentration of stimulus 90 in environment 92. Aperture 94 at cylinder 76 provides fluid communication between environment 92 and gel 78. Increasing concentration of stimulus 90 in environment 92 causes stimuluε 90 to migrate through aperture 94. Exposure of gel 78 to stimulus 90 causes gel 78 to exhibit a phase transition from a contracted phase, shown in Figure 3A, to an expanded phase, shown in Figure 3B. Phase transition of gel 78 within cylinder 76 causes gel 78 to move from the first position to the second position. Movement of piston 80 directs push rod 82 against εwitch 84, thereby moving εwitch 84 from an open position, shown in Figure 3A, to a close position, shown in Figure 3B. Moving switch 84 to the closed position closes electrical circuit 86, thereby actuating electrical circuit 86. Reduction of the amount of stimulus 90 in environment 92 causes gel 78 to exhibit a phase transition from the expanded phase to the contracted phase, thereby opening electrical circuit 86.

Transducer device 96, illustrated in Figures 4A and 4B, includes cylinder 98 and phase-transition gel 100 disposed within cylinder 98. Electrically conductive coil 102 extends around cylinder 98. Apertures 104 in cylinder 98 provide fluid communication between fluid 106 and gel body 100. Phaεe-tranεition-modifying agent 108 iε diεpoεed in gel 100. Phase-transition-modifying agent 108 comprises a suitable electromagnetic responsive material which, upon exposure to sufficient electromagnetic radiation, causeε gel 100 to exhibit a phaεe transition from a contracted phase, shown in Figure 4A, to an expanded phase, shown in Figure 4B. Piston 110 is disposed adjacent gel 100. Push rod 112 extends from piston 110. Electrical energy iε conducted through electrically conductive coil 102 from electrical power source 114. Electrically conductive coil 102 thereby generates electromagnetic radiation. Agent 108 thereby exposes gel 100 to sufficient electromagnetic radiation to cause gel 100 to exhibit a phase transition from the contracted phase to the expanded phase. Piston 110 and push rod 112 are thereby directed from a first position, shown in Figure 4A, to a second position, shown in Figure 4B. Electrical energy is thereby transduced to mechanical work. Electrical energy can be terminated in elecrically conductive coil 102 to thereby cause gel 100 to exhibit a phase transition from the expanded phase to the contracted phase, to thereby return piston 110 and push rod 112 from the second position to the first position.

A light pump based upon this invention is illustrated in Figures 5A and 5B. Light pump 114 includes cylinder 116 and phase-transition gel 118 disposed within cylinder 116. Phase-transition- modifying agent 120 is disposed in gel 118. Agent 120, upon exposure to sufficient visible light, causeε gel 118 to exhibit a phase transition from a contracted phase, shown in Figure 5A, to an expanded phase, shown in Figure 5B. Cylinder 116 is translucent. Aperture 121 in cylinder 116 provide fluid communication between fluid 122 and gel 118. Piston 124 is disposed within cylinder 116 and is adjacent gel 118. Push rod 126 extends from piston 124 to diaphragm pump 128. Push rod 126 is fixed to diaphragm 129 of diaphragm pump 128. Expoεure of gel to a sufficient intensity of visible light 130 from light source 131 causes gel 118 to exhibit a phase tranεition from a contracted phaεe to an expanded phaεe. Phase transition of gel 118 to the expanded phase moves piston 124 and push rod 126 from a first position, shown in Figure 5A, to a second position, shown in Figure 5B. The intenεity of visible light is then reduced by suitable means to below an amount sufficient to maintain gel 11.8 in an expanded phase, whereby gel 118 exhibits a phase transition from an expanded phase to a contracted phase, thereby causing piston 124 and push rod 126 to move from the second postion to the first position. Repeated increase and decreaεe of visible light intensity causeε repetitive expansion and contraction of gel body 126 and operation of diaphragm pump by consequent movement of piston 124 and push rod 126 between the first and second positions.

Chemical release system 132, illustrated in Figures 6A and 6B, includes phaεe-tranεition gel 134 diεpoεed within fluid 136. Phase-transition- modifying agent 138 and chemical 142 are disposed in gel 134. Agent 138 causes gel 134 to exhibit a phase transition from a contracted phase to an expanded phase upon exposure of gel 134 to a sufficient amount of a suitable stimulus 142. Chemical 140, upon release from gel body 134, inhibits the activity of stimulus 142. For example, chemical 140 can be insulin and stimulus 142 can be glucose. Upon exposure of gel 134 to a sufficient concentration of stimuluε 142, gel 134 exhibits a phase transition from a contracted phase, shown in Figure 6A, to an expanded phase, shown in Figure 6B. Chemical 140 is released from gel 134 while gel 134 is in the expanded phase until the stimuluε diminishes to below an amount sufficient to maintain gel 134 in an expanded phase. Gel 134 then exhibits a phase transition from the expanded phase to the contracted phase, whereby release of chemical 140 from gel 134 stops. Release of chemical 140 form gel 134 stops. Release of chemical 140 is thereby controlled by controlled chemical release system 132. It is to be understood that in all of the embodiments, the gels described can be designed to exhibit a phase transition from an expanded phase to a contracted phaεe upon exposure to a stimulus. The present invention has many other applications. For example, gels of the present invention can by used as desiccating agents or as sponges. Sponges employing the gels have many applications, such as for cleanup of oil spillε. The gelε can alεo be uεed for expelling fluid. Moisturizers can be formed using gels of the preεent invention to releaεe moiεture upon drying of a εurrounding layer. Exampleε of such moisturizers include gels which could be applied to leaves of plants, or moisturizers which also include sun block for application to human skin.

Chelating agents disposed in gels can form gelε which respond to the existance of metals as contaminants, thereby causing selective reaction of the chelating agents to concentrate and to purify liquids. Gels of the present invention can also absorb impurities and to neutralize fluids.

Biological materials, such as Salmonella, can be detected by causing the gelε of the present invention to release a dye upon phase transition. The gels can also be used for flavoring upon exposure to sufficient environmental conditions, such as heat. Also, fragrances can be disposed from a gel of the present invention during exposure of gel to noxious odors, such as for use with diapers. A finely tuned array of gels in micropores can by formed, whereby the gels are tuned to exhibit a phase transition upon exposure to infrared energy. The array can thereby act as a sensor of infrared energy by, for example, expanding to close a gap. Gels of the present invention can be used for laboratory testing, such as immunoasεay systems and ovulation testing. Actuators can be constructed using the gels, such aε an energy efficient window, wherein a blind iε controlled in response to light by a mechanical εyste operated by expansion of the gelε in response to light.

Fire retardant gels for use in clothing can also be formed, whereby the gels release fire retarding chemicals upon exposure to extreme heat. Physical barriers can be formed by expansion of gels in response to stimulus.

Reaction can also be triggered by phase transition of the gels, wherein gels expand to thereby allow chemicals to combine. Also, chemicals can be selectively combined, which chemicals would deteriorate rapidly if not otherwise kept separate. The gels can be employed to release insecticide upon exposure during periodε of daylight, when inεect activity typically iε highest.

Colorε can be selectively released in an emulsion upon exposure of the emulsion upon a subεtrate to variouε wavelengthε of light, thereby acting aε a photgraphic film. Carbonleεε copying can be performed by impregnating a gel, containing a dye, in paper, whereby εelective expoεure of the paper to light releaseε the dye to form an image on the paper. Gels which expand upon exposure to light can be employed for self repairing opaque containers. The gels of the present invention can also be used to concentrate chemicals, including some foodε, for transport. Osmotic pumps can be constructed with gels εuch as for desalinization of water. Detergents can employ the gels for controlled release of detergent in response to temperature, for example, during a wash cycle.

A gel can be designed to respond to certain stimuli, such as high glucose, that undergoes phase transition upon seeing this stimuli and releases a drug, such as insulin, that has been loaded into the gel. In another embodiment, the gel could mechanically push a drug, such as insulin, out of a reservoir upon encountering a stimuli, such as glucose, by undergoing a phase transition. A gel material could be designed that changes its mechanical properties upon encountering the proper stimuli. For instance, a gel valve can be created where the gel is designed to undergo phase transition (and close or open depending on how it is designed) when it sees a particular chemical εpecies. This valve might be uεed to shut down a process upon encountering a contaminant.

Custom polymer gels can be designed to undergo phase transition upon encountering a chemical at a certain stage of manufacturing. This might be useful in a process where it is important to remove a polymer intermediary. This intermediary could be removed by phase transition.

A light-triggered polymer gel containing ink could be used for instant photography. THe ink would be released upon encountering light.

A gel can be cuεtom-designed to undergo phase transition when encountering a contaminant or waste and thereby soak up the waste. Another version of this application would involve creating a gel that undergoes phase transition through chelating (which could remove contaminating metals (i.e. chromium 6) from a process.

A custom gel could be created to absorb certain chemicals, for example, blood in a gel tampon, by undergoing phase tranεition.

Gel pore size changes in the two phase states.

This can be used to selectively filter or separate chemical species by size. Because of the large osmotic pressure that the gel generates when it undergoes a phase transition, it could actually be used to withdraw water from the human body, for example, a diuretic that doesn't use the kidneys. It could be used for dialysis because it could absorb ions, like urea, in this way. The gel would be infused into the patient rectally or orally.

The gel could be used to absorb toxins from the gastrointestinal tract, such as toxins released by e_^ coli in Traveler's Diarrhea. This could be a non-antibiotic agent to relieve the diarrhea.

The gel could also be used in robotics for response by robotics to environmental conditions The above description of alternative uses of the present invention is not exhaustive and other applications of the present invention will be apparent to those skilled in the art.

The invention will now be further and specifically described by the following examples.

All parts and percentages are by weight unlesε otherwiεe stated.

Example I - Phase-Transition-Modifying Agent = Enzyme (Rabbit Liver Esterase)

Three different gelε were formed. The first two gels, Gel 1 and Gel 2, were formed in the presence of an enzyme, thereby entrapping the enzyme in the polymer network of the gel. Gel 2 was then exposed to a sufficient temperature to inactivate the enzyme entrapped within it. A third gel, Gel 3, was formed by the same method, but without the presence of enzyme. Gel 3 was, therefore, a control gel to measure the different environmental conditions at which gels exhibit phase transition between a gel which has an enzyme trapped within the polymer network and a gel which has no enzyme trapped within the polymer network. a) Gel 1 Formation: Activated Enzyme

7.8 gm of purified N-isopropylacrylamide mono¬ mer, commercially available from Kodak, 0.133 gm of N,N'-methylenebisacrylamide crosεlinking agent, commercially available from Bio-Rad Laboratorieε, and 240 icroliterε of tetramethylethylenediamine accelerator, commercially available from Bio-Rad Laboratories were dissolved in one hundred milliliters of water to from an aqueous solution. Three milligrams of rabbit liver este-ase, commercially available from Sigma Chemicals Company was dissolved in one milliliter of the aqueous solution. The aqueous solution containing the rabbit liver esteraεe was then exposed to vacuum for a period of time sufficient to degas the aqueous solution. Ten microliters of four percent aqueous ammonium persulfate solution initiator, commercially available from Mallinckropt was combined with the degassed aqueous solution to form a reaction solution. The reaction solution was transferred to a glasε capillary tube having a length of twenty centimeterε and an internal diameter of 0.1 millimeter. The reaction εolution gelled in the glaεε capillary tube, whereby the monomer and croεs- linking agent reacted to form a polymer network which entrapped a substantial portion of the rabbit liver esterase in the polymer network, thereby forming a Gel 1 of a polymer network and an active element comprising an entrapped enzyme. Following gelation, Gel 1 was removed from the capillary tube and washed with water. Washed Gel 1 was disposed in a glass micropipette having an internal diameter of one millimeter.

b) Control Gel Formation: Deactivated Enzyme Gel 2 was formed by the method described above and subεequently waε expoεed to a temperature of about 100°C for a εufficient period of time to inactivate the enzyme. A right cylinder having a diameter of about 0.1 millimeter and a length of about two millimeterε waε then formed from Gel 2. The right cylinder waε diεpoεed in a second glasε micropipette.

c) Control Gel Formation: No Enzyme

Gel 3 was formed by the same method described above but without disεolving an enzyme into the aqueouε solution. Gel 3 was cut to form a right cylinder having the same dimensions as the above gelε and waε then diεpoεed in a third glaεs micropipette.

d) Comparison of Phase Transition of the

Activated Enzyme and of the Control Gel l and Gel 2

Aqueous solutions were prepared of ethylbutylate as a substrate stimulus and/or butyric acid and ethanol, which were products of hydrolysis of ethylbutylate catalyzed by the rabbit liver esterase. The size and shape of the gels in the micropipettes were monitored at different temperatures using a Model C1966 AVEC image procesεor commercially available from Hamamatεu Photonics, Inc. The concentration of ethanol, butyric acid and ethylbutylate in the aqueous solution was determined by using a Model 588OA gas chromatograph, commercially available from Hewlett Packard Inc.

Figure 7 is a plot of the volume of Gel 3, containing no enzyme, relative to the volume of Gel 3 in a contracted phase over a temperature range during expansion and contraction Gel 3. Curves A and B represent the volume of Gel 3 during expansion and contraction, respectively, in an aqueous solution containing 47.3 mM of substrate, i.e. ethylbutylate, and no substrate reaction product, i.e. butyric acid or ethanol. As can be seen in curves A and B, the gel changes phase as the temperature of the aqueous solution is raised or lowered in a temperature range of from about 27.9'C to about 28.4*C. Curves C and D represent the volume of the same gel during phase transition of expansion and contrac¬ tion, respectively, in an aqueous solution containing 47.3 mM each of ethanol and butyric acid, but containing no stimulus, i.e., ethylbutylate. As can be seen from curves A, B, C and D, the temperatures of volume change are higher when the aqueous solution is relatively rich in product of hydrolyzed substrate than when the solution is relatively rich in sub¬ strate. Curves E and F represent the volume of the same gel during phase transition of expansion and contrac¬ tion, respectively, in an aqueouε solution containing neither substrate nor product of hydrolyzed sub- strate. As can be seen from curveε E and F, the te peratureε of phase transition are higher when the aqueous solution contains no subεtrate or product than when the aqueous solution contains either product or substrate. Figure 8 is a plot of the volume of Gel 1 (containing active enzyme) and Gel 2 (containing inactivated enzyme) in their expanded phases during gradual reduction and increase of temperature relative to the same gels in their contracted phases. Curves A and B represent plots of expansion and contraction, respectively, of Gel 2, containing inactivated enzyme. Curves C and D represent plots of expansion and contraction, reεpectively, of Gel 1, containing activated enzyme. Both gels were immersed in an aqueous solution saturated with subεtrate (47.3 milimoles per liter of solution) . As can be seen from Figure 8, Gel 1 exhibited a phaεe tranεition at higher temperatureε than did Gel 2. The activity of the enzyme trapped within the polymer network, therefor, increaεed the temperature at which the gel exhibited a phaεe transition. Also, by comparing Figure 7 and Figure 8, it can be seen that, whereas the presence of either substrate or product lowered the temperature at which the gel exhibited a phase tranεition, entrapment of an activated enzyme in the -27-

polymer network of the gel increased the temperature at which the gel exhibited a phase transition in a solution saturated with the substrate.

Figure 9 is a plot of the phase transition of

5 Gel 1 and of Gel 3. Curve A is a plot of the time of phase transition of Gel 1, following immersion of the gel in a solution at 28.9*C. The concentration of substrate in the solution was 47.3 illimoles per liter of solution. Curve B is a plot of the phase

10 transition over time of Gel 3 in a solution including 47.3 millimoles per liter of solution and sixty milligrams of rabbit liver esterase. The shaded area of curve B indicateε that the phase transition occurred during a twenty minute interval within the

15 first two hours of immersion of the enzyme-free gel in the substrate-containing solution.

Gel 3 did not exhibit a phase transition until about 10% of the substrate in the subεtrate-containing solution had been hydrolyzed.

20 As can be seen from Figure 9, Gel 3 did not begin to exhibit a phase transition until the gel had been in the enzyme- and substrate-containing solution for about eighty minutes. Also, the rate of phase transition of the enzyme-free gel was not aε rapid aε

25 the enzyme-containing gel.

Leεε than about one percent of the substrate was hydrolyzed by the enzyme in Gel 1 during the first two hours that the gel was immersed in the substrate-containing solution. However, as can be

30 seen in Figure 9, Gel 1 exhibited a rapid phase transition immediately upon immersion of the gel in the substrate-containing solution. Therefore, the phase transition of Gel 1 was controlled by the concentration of the substrate and product within, or at the vicinity of the gel, but not by the concentration of substrate in the bulk solution.

Example II - Agent = Lectin (Concanavalin-A)

700 illimole of N-isopropylacrylamide/εodium acrylate, having a molar ratio of N-iεopropylacryla- mide:sodium acrylate of 20:1, was dissolved in 100 ml of water to form a solution. 0.133 gm of N,N-methylenebisacrylamide and 240 urn were then dissolved in the solution. Concanavalin-A (20 milligrams per gram of gel) and two grams of dextran sodium sulfonate were then added to the solution. Forty milligrams of ammonium persulfate were then added to the solution to initiate gellation. Without dextran sodium sulfonate, the gel undergoes a phaεe tranεition at below 34'C in water. In the presence of 0.1 percent of dextran sodium sulfonate in water, the transition temperature of the gel waε 40°C. When the concentration of dextran εodium εulfate waε below 0.1 percent, the gel waε in an expanded phase at 40"C. When the concentration of dextran sodium sulfate waε above 0.1 percent, the gel was in a contracted phase at 40"C. The dextran εodium sulfate was then replaced with an nonionized inhibitor, manno pyranose, to thereby cause the gel to exhibit a phase transition at below 34°C.

Example III - Agent = Enzyme (Urease)

An N-isopropylacrylamide gel prepared as in Example II but included 20 mg/ml of urease incorporated into the polymer network rather than dextran sodium sulfonate. Urea was used as a substrate, which was decomposed into carbon dioxide and ammonium ion. The latter ionized the acrylic acid and altered the phase transition temperature. For 10 -2M urea concentration the change in the transition temperature was approximately 20*C. The gel, when in a collapsed state at a temperature-of

50*C exhibited a phase transition to an expanded phase by adding 10 M urea.

Example IV - Visible Light Stimulus

In this example, 7.8 gm of purified N-isopropyl¬ acrylamide monomer, commercially available from Kodak, 0.67 gm of N,N'-methylenebisacrylamide croεεlinking agent, commercially available from

Bio-Rad Laboratories and 240 milliliters of tetra- methylethylenediamine accelerator, commercially available from Bio-Rad Laboratories were dissolved in one hundred milliliters of water to from an aqueous solution. 0.722 gm of trisodium salt of coppered chlorophyllin, commercially available from Aldrich, Inc. was diεεolved in one hundred milliliters of degased water at O'C The aqueous solution containing the rabbit liver esteraεe was then exposed to vacuum for a period of time sufficient to degas the aqueous solution. 0.2 gms of four percent aqueous ammonium persulfate solution initiator, commercially available from Mallinckrott, Inc. was combined with the degassed aqueous solution to form a reaction solution. The reaction solution was transferred to a glass capillary tube having a length of twenty centimeters and an internal diameter of one hundred millimeters. The reaction solution gelled in the glass capillary tube, whereby the monomer and cross¬ linking agent reacted to form a polymer network which entrapped a substantial portion of the chlorophyllin in the polymer network, thereby forming a gel of a polymer network and trapped enzyme. Following gelation, the gel was removed from the capillary tube and washed with deionized, distilled water. The washed gel was dispoεed in a glaεs micropipette having an internal diameter of one millimeter.

The cylindrical gel was immersed in water, having a pH of 11.9 in a sealed rectangular glasε microcapillary, whoεe temperature was regulated within 0.1°C. An argon ion laser emitting light at a wavelength of 480 nm was used as a light source. The light intensity at the gel was adjusted using a polarizer and ranged from zero to 130mW. The inci¬ dent beam with a Gaussian width of approximately seven millimeters was focused with a lens of focal length nineteen centimeters, which produced a focuεed beam having a diameter of twenty,micrometerε and a focal depth of 0.8 micrometers. The size and shape of the gel were monitored and analyzed using the AVEC image processor (Model C1966, Hamamatsu Photonics) . The diameter of the gel was plotted as a func¬ tion of temperature in Figure 10 for three values of light intensity. At zero light intensity, the gel underwent a sharp, but continuous volume change at approximately 35*C. During exposure to light inten¬ sity of 60 mW, the volume change became sharper and the transition temperature waε lowered to 33^βC. During exposure to light intensity of 120 mW, the gel exhibited a discontinuous volume change, or phase transition, at 31.5*C.

The gel was then maintained at a constant temperature of 31.5'C and exposed to increasing light intensity which ranged from zero to 120 W. As can be seen in Figure 11, the gel exhibited a phase tranεition at a light intensity of 100 mW.

Example V - Hydrophobic Gel-Surfactant

7.8 grams of N-isopropyl acrylamide, 0.133 gms of N,N'-methylene bisacrylamide and 240 ml of tetra- methylethylenedia ine were added to 100 ml of water to form a solution. The solution was degassed and then one milliliter of the degassed solution was mixed with ten microliters of a four percent aqueous solution containing ammonium persulfate as an initiator. The solution containing the initiator was then quickly transferred to a capillary having a 0.1 mm internal diameter. The gelation was conducted at 0°C in a nitrogen atmosphere. The gel formed was removed from the capillary, washed with copious amounts of water and then cut to a length of one millimeter. The temperature at which the gel exhibits a phase transition in water was 34*C. The gel was then exposed to a 0.1 percent by weight solution of sodium dodecyl sulfate. The gel then exhibited a phase transition at a temperature of 60°C.

Claims

1. A phaεe-transition gel which undergoes a significant discontinuous volume change at a desired phase-tranεition condition in response to a stimulus, comprising: a) a liquid medium gelled with a polymer network and having a phase transition condition different from that desired; and b) a phase-transition-modifying agent in an amount sufficient to cause, in response to the stimulus, the discontinuouε volume change of εaid gel at the deεired phase-transition condition.

2. A phase-tranεition gel of Claim 1 wherein the phaεe-tranεition-modifying agent compriεes a small chemical molecule.

3. A phase-transition gel of Claim 2 wherein the phase-transition-modifying agent has electromagnetic-sensitive properties.

4. A phaεe-tranεition gel of Claim 2 wherein the phase-transition-modifying agent has catalytic properties.

5. A phase-tranεition gel of Claim 2 wherein the phase-tranεition-modifying agent has surfactant properties.

6. A phase-transition gel of Claim 2 wherein the phase-tranεition-modifying agent haε cross-linking properties.

7. A phase-transition gel of Claim 1 wherein the phase-transition-modifying agent comprises a polymer.

8. A phase-transition gel of Claim 7 wherein the phase-transition-modifying agent compriseε a εynthetic polymer.

9. A phase-transition gel of Claim 7 wherein the phase-transition-modifying agent comprises a natural polymer.

10. A phase-transition gel of Claim 9 wherein the phase-tranεition-modifying agent haε enzymatic propertieε.

11. A phase-tranεition gel of Claim 9 wherein the phaεe-tranεition-modifying agent compriεeε a deoxyribonucleic acid.

12. A phaεe-tranεition gel of Claim 9 wherein the phaεe-transition-modifying agent compriseε a ribonucleic acid.

13. A method of forming a phaεe-tranεition gel which undergoes a significant discontinuouε volume change at a desired phase-tranεition condition in response to a stimulus, comprising: a) gelling a liquid medium with a polymer network, whereby a phase-transition gel forms which has a phase transition condition different from that desired; and b) incorporating a phase-transition-modifying agent in the phase-transition gel in an amount sufficient to cause, in responεe to the εtimuluε, the discontinuous volume change of said gel at the desired phaεe-tranεition condition.

14. In a phaεe-tranεition gel formed of a liquid medium gelled with a polymer network: The improvement comprising a phase-transition-modifying agent in an amount sufficient to cause, in response to a stimulus, a discontinuous volume change of said gel at the desired phase-transition condition.