A novel artificial muscle material and miniature valves and micropumps made therefrom are provided. The artificial muscle material bends reversibly when electroactuated by applying low voltage, in a wide pH range, even at that of physiological pH, and works without contact with electrodes. Miniature valves made from the artificial material are successfully triggered for the fluid release in a wide pH range, even at that of physiological pH. Novel fluid release devices were manufactured using this artificial muscle, and methods using the same were provided, including an implantable device optimized for trans-scleral drug delivery.

Description of the Invention

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided an electroactive artificial muscle, comprising a hydrogel comprising acrylamide; an unsaturated aliphatic acid having the formula R.dbd.CH--COOH, wherein R is selected from the group consisting of --CH.sub.2, --CH--COOH, and --CH--(CH.sub.2).sub.n--COOH, where n is an integer; a composite of a conductive polymer such as polypyrrole-carbon black, and at least one cross-linking agent, wherein the hydrogel is electroactive at a wide pH range, even at that of physiological pH, and in the absence of contact with the electrodes. In a preferred embodiment the unsaturated aliphatic acid is acrylic acid, maleic acid or glutaconic acid, or combinations of the above. In another preferred embodiment the acrylic acid, maleic acid, glutaconic acid, or their combination is present in the hydrogel precursor solution in an amount of about 65 wt %.

In another aspect of the invention, there is provided an actuating device or drug delivery device for controlled release of a therapeutic, prophylactic or diagnostic agent to an animal, comprising an electroactive artificial muscle, comprising a hydrogel comprising acrylamide; an unsaturated aliphatic acid having the formula R.dbd.CH--COOH, wherein R is selected from the group consisting of --CH.sub.2, --CH--COOH, and --CH--(CH.sub.2).sub.n--COOH with n being an integer; a composite of a conductive polymer such as polypyrrole-carbon black; and at least one cross-linking agent; wherein the hydrogel is electroactive at physiological pH and in the absence of contact with electrodes under the application of an electric field, preferably 1-4.5 V, with a current intensity preferably of 0.01-1 A, and wherein the artificial muscle electroactuation opens an enclosure (normally closed by the non actuated hydrogel), thus releasing the therapeutic, prophylactic or diagnostic agent from the drug delivery device.

In yet another aspect of the invention, there is provided an actuating or drug delivery device for the controlled release of a therapeutic, prophylactic or diagnostic agent to an animal, comprising an electroactive artificial muscle comprising acrylamide; an unsaturated aliphatic acid having the formula R.dbd.CH--COOH, wherein R is selected from the group consisting of --CH.sub.2, --CH--COOH, and --CH--(CH.sub.2).sub.n--COOH with n being an integer; a composite of a conductive polymer such as polypyrrole-carbon black; and at least one cross-linking agent, wherein the hydrogel is electroactive at physiological pH and in the absence of contact with electrodes under the application of an electric field, preferably 1-4.5 V, with a current intensity preferably of 0.01-1A, and wherein the electroactuated artificial muscle applies controlled mechanical force onto the wall of a flexible reservoir, releasing the therapeutic, prophylactic or diagnostic agent from the drug delivery device. In another preferred embodiment, the wall of the flexible reservoir comprises at least one portion of the artificial muscle.

In yet another aspect of the invention, there is provided an actuating or drug delivery device for the controlled release of a therapeutic, prophylactic or diagnostic agent to an animal, comprising an electroactive artificial muscle comprising acrylamide; an unsaturated aliphatic acid having the formula R.dbd.CH--COOH, wherein R is selected from the group consisting of --CH.sub.2, --CH--COOH, and --CH--(CH.sub.2).sub.n--COOH with n being an integer; a composite of a conductive polymer such as polypyrrole-carbon black; and at least one cross-linking agent. Such a hydrogel is electroactive in a wide pH range, even at that of physiological pH and in the absence of contact with electrodes under the application of an electric field, preferably of 1-4.5 V, with a current intensity preferably of 0.01-1 A, wherein an artificial muscle-based super-flexible bladder equipped with a one-way minivalve is optimized for implantable drug release.

In another aspect of the invention, there is provided a method for delivering a therapeutic, prophylactic or diagnostic agent to a patient comprising implanting in the body of the patient or applying to the body of a patient an actuating or drug delivery device comprising an electroactive artificial muscle comprising a hydrogel comprising acrylamide; an unsaturated aliphatic acid having the formula R.dbd.CH--COOH, wherein R is selected from the group consisting of --CH.sub.2, --CH--COOH, and --CH--(CH.sub.2).sub.n--COOH with n being an integer; a composite of a conductive polymer; and at least one cross-linking agent, wherein the hydrogel is electroactive at physiological. pH and in the absence of contact with electrodes under the application of an electric field, and wherein the electroactive artificial muscle applies controlled mechanical force onto the wall of a flexible reservoir of the device, releasing the therapeutic, prophylactic or diagnostic agent from the device.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a novel hydrogel composite for use as an artificial muscle. The artificial muscle contains an unsaturated aliphatic acid of the general formula R.dbd.CH--COOH, where R is selected from --CH.sub.2, --CH--COOH, or --CH--(CH.sub.2).sub.n--COOH, where n is an integer, such as for example, acrylic acid (H.sub.2C.dbd.CH--COOH), maleic acid (HOOC--CH.dbd.CH--COOH) or glutaconic acid (HOOC--CH.sub.2--CH.dbd.CH--COOH), or a combination thereof; acrylamide; and a composite of a conductive polymer, such as, for example, polypyrrole-carbon black (PPy/CB) (defined herein as a mixture of polypyrrole doped with carbon black, preferably having a ratio of polypyrrole to carbon black of 5:1), polythiophene-carbon black, polyaniline-carbon black, polypyrrole-carbon fibers, polythiophene-carbon fibers or polyaniline-carbon fibers. The artificial muscle of the invention provides rapid, reversible bending under the application of low voltage in solutions of wide pH range, e.g., from about pH 3 to about pH 10, including physiological pH. By low voltage is meant about 1 to about 5 V, preferably about 1 to about 2 V. The artificial muscle of the invention is particularly suited for microfabrication of electro-sensitive soft microvalves and micropumps for use in biomedical and other applications, such as, for example, the manufacture of artificial muscle valves that may be used externally or as implantable devices.

The ability of the artificial muscle of the invention to bend and the obtained response in terms of bending angle, depend on the chemical composition of the hydrogel precursor solution used for the polymerization of the artificial muscle. In general, the higher is the aliphatic acid content of the hydrogel, the higher is the bending angle of the material that can be achieved. Therefore, increase of the aliphatic acid content in the hydrogel precursor solution results in the increase of the artificial muscle response (for example, the increase in the acrylic acid content of a hydrogel from 45 wt. % to 57 wt. % and then to 65 wt. % results in the increase of the bending angle of the resulting hydrogel to 6.9.degree., 11.4.degree. and 15.0.degree., respectively under electroactuation at 3 V with a response time of 2 min). Further increase in the aliphatic acid content generally increases the hydrogel response at the expense of mechanical stability of the artificial muscle. Therefore, it is preferable that the hydrogel contains about 65 wt. % aliphatic acid as defined herein, although the amount can vary depending on the intended use of the artificial muscle, in terms of response, response time and lifetime of the material.

The response of the hydrogel is also affected by the number of COOH groups of the unsaturated aliphatic acid monomer used in the hydrogel precursor solution. In this regard, the selected unsaturated aliphatic acid may be a single unsaturated aliphatic acid with one carboxylic group, such as acrylic acid, or more carboxylic acids, like maleic acid or glutaconic acid, or even a mixture of unsaturated aliphatic acids may be used to provide the desired amount of COOH groups and hence elasticity and response of the artificial muscle. It was seen that the response of a hydrogel based on a 65 wt. % aliphatic acid content increases when using maleic acid (which. incorporates two carboxylic groups per molecule of monomer with molecular weight 116.07), to glutaconic acid (with two carboxylic groups per monomer molecule of molecular weight 130.10) to finally acrylic acid (with one carboxylic group per monomer molecule of molecular weight 72.06).

Further optimization of the artificial muscle composition of the invention is based on the use of a composite of a conductive polymer, such as the polypyrrole/carbon black composite (PPy/CB) as an additive. The high conductivity of this composite results in an increase in the conductivity of the composition, enhancing the hydrogel electroactuation. It was seen that the degree of bending of a hydrogel containing 4 wt. % PPy/CB (polypyrrole doped with 20% carbon black) is higher (23.5.degree. bending angle) than that of a hydrogel containing 1 wt. % PPy/CB, (15.0.degree. bending angle). In addition, a hydrogel containing 4 wt. % carbon black alone presents a significantly lower response (15.8.degree. bending angle) than the 4 wt. % PPy/CB counterpart. The response of a blank artificial muscle without any PPy/CB additive is significantly less, with a respective bending angle of 10.3.degree., verifying the positive effect of the PPy/CB composite on the hydrogel electroactuation of the artificial muscle of the invention.

The effect of the electric field on the electroactuation of the artificial muscle of the invention was also examined. For example, the bending angle of an artificial muscle, based on 65 wt. % acrylic acid and 4 wt. % polypyrrole/carbon-black, under the application of 3V at 1 cm distance from each Pt electrode is 23.5.degree. in about two minutes. Decreasing the distance of the artificial muscle from each electrode to 0.5 cm results in the decrease of the response time of the artificial muscle to 30 seconds and an increase of the bending angle to 28.degree.. Conversely, an increase of the distance of the artificial muscle from each electrode results in a decreased response (e.g., 2.degree. under the application of 3V under the same period of two minutes) of the material.

The supporting electrolyte concentration also has an effect on the artificial muscle response time. For example, an artificial muscle based on a hydrogel composition containing 65 wt. % acrylic acid and 4 wt. % polypyrrole/carbon black (5:1) does not respond to the application of 3V under a period of two minutes when the electrolyte concentration is decreased by four orders of magnitude from 0.15 M to 0.15.times.10.sup.-4 M NaCl (the same hydrogel presents a bending angle of 23.5.degree. degrees under electroactuation with the same conditions in a 0.15 M NaCl test solution). A decrease in the intensity of the electric field (from 3V to 1V) results in an increase of the response time of the material (from 2 to 15 minutes).

The mechanism of deformation of the artificial muscle of the invention can be explained by the theory of the osmotic pressure in polymer networks, introduced by Flory (P. J. Flory, Principles of Polymer Science, Cornell Univ. Press, Ithaca, N.Y., 1953) and updated by Tanaka (Tanaka et al., Science, 1982, 218, 467). When a DC electric field is applied, the electrophoretic movement of ions results in an ion concentration gradient at the interfaces of the hydrogel with the test solution, resulting in the bending of the hydrogel toward the cathode. The bending angle of the artificial muscle depends on the electric field intensity, the local pH change, the sample dimensions, its relative proximity to the electrodes and the electrolyte ionic strength.

The response time of the artificial muscle of the invention depends on several factors, including the elasticity of the material, the dimensions of the artificial muscle, and the intensity of the electric field applied. If a faster response time is desired, a more elastic material may be synthesized. This may be achieved, for example by using less cross-linker or by selecting the unsaturated aliphatic acid to provide more elasticity. However, an increase in elasticity is generally accompanied by a decrease in mechanical stability for long-term use of the artificial muscle.

The artificial muscle material of the invention exhibits fast and reversible bending under electroactuation with a low applied voltage, in the range of about 1 to about 5 V, preferably in the range of from about 1 to about 2 V, in solutions of a wide pH range, even at that of physiological pH. This artificial muscle composition is readily applicable for use as an electroactuated micropump or microvalve, for example, for in vivo responsive drug delivery.

In general, the hydrogel precursor solution used for the preparation of the artificial muscles of the invention is prepared by mixing each of the components in the desired amount of water, preferably deionized water. The composite of the conductive polymer, most preferably a premix of polypyrrole and carbon black, preferably in a ratio of about 5 to 1, is dispersed in deionized water under sonication, for example. The desired amount of monomers of acrylamide, N,N'-methylenebisacrylamide and the desired combination of one or more unsaturated aliphatic acids are added to the premix of polypyrrole/carbon black solution and mixed to ensure thorough blending. The amount of unsaturated aliphatic acid(s) used is preferably in the range of about 25 to 75 wt. %, and most preferably about 65 wt. %; the content of acrylamide is preferably about 0.6 to about 20 wt. %, most preferably 6 wt. %; and the amount of N,N'-methylenebisacrylamide is preferably about 2 to 50 wt. %, most preferably 20 wt. %. Catalysts, such as potassium persulfate, sodium metabisulfite, and accelerators, such as TEMED (N,N,N,N-tetramethylethylenediamine), are added in the hydrogel precursor solution after the thorough mixing and degassing of the solution with nitrogen, for the removal of molecular oxygen.

When the hydrogel precursor solution is thoroughly mixed it is placed in an appropriate mold with the desired shape and dimensions and is cured by heating, for example at a temperature in the range of about 25.degree. to about 140.degree. C., preferably about 50.degree. to about 60.degree. C. The cured hydrogels may be stored in a saline solution, for example in a 0.15 M NaCl solution, for later use.

In one aspect of the invention, the hydrogel precursor solution may contain the desired amount of a therapeutic or prophylactic agent, such as for example, an antimicrobial agent, pharmaceutical agent, therapeutic protein, cells, nucleic acid, and the like. During the polymerization procedure of the hydrogel, the therapeutic agent is entrapped inside the hydrogel. Therefore, the hydrogel prepared by this manner can be used for the passive release of the therapeutic or prophylactic agent, based solely on the diffusion of the drug, or in the case of charged therapeutic or prophylactic agents, the release of the drug at higher rates can be aided by migration under the electroactuation of the hydrogel. The amount and type of therapeutic or prophylactic agent loaded into the artificial muscle depends on the intended use of the material and can be readily ascertained by the skilled practitioner.

In another aspect of the invention, the cured and shaped artificial muscle is operatively connected to a reservoir or multiple reservoirs containing the therapeutic agent(s) or prophylactic agent(s). The hydrogel, which is placed between the electrode plates, can rest on the top of a reservoir(s) filled with fluid. Under no electroactuation, the hydrogel seals the opening of the reservoir and inhibits the release of the therapeutic or prophylactic agent to the environment. When an electric field is applied, the hydrogel bends towards the cathode, uncovering the opening of the reservoir, and therefore allowing the therapeutic or prophylactic agent(s) to diffuse into the surrounding tissue or blood. Thus, electroactuation of the artificial muscle is used to open and close the reservoir(s), allowing the delivery of therapeutic or prophylactic agent(s). Preferably, an electric field of from about 1 to about 5 V is applied and preferably a current of 40 mA or less is generated. The electric field can be applied at a predetermined cycle of positive and negative voltage to effect an oscillating motion of the device of the artificial muscle.

The therapeutic agent used in combination with the artificial muscle can be for example, a local anaesthetic, e.g., lidocaine; antibiotic or anti-bacterial agent, e.g., penicillin or streptomycin; peptides or proteins, such as insulin; vasodilators; steroids; beta-blockers; a diagnostic agent, and the like. It is also possible to deliver more than one drug at a time, either as a mixture or from separate reservoirs, for example.

The artificial muscle of the invention can be formed in any desired configuration, dimensions and shape, such as for example, a flap valve. FIG. 1A (see Original Patent) illustrates an embodiment of the invention in which the artificial muscle is positioned in a flow channel. When immersed in a 150 mM NaCl aqueous solution and exposed to a DC electric field, for example +3 V, this flap valve bends toward the cathode, opening the channel and allowing the release and flow of the fluid within the channel (FIG. 1B (see Original Patent)). When the polarity of the electrodes is changed, the artificial muscle flips back to its original position, blocking the channel and stopping the release of the fluid in the channel.

FIG. 2A,B (see Original Patent) illustrates another configuration in which a cylindrical artificial muscle is connected to a flexible semi-spherical reservoir. When a voltage is applied, e.g., +3 V, the artificial muscle bends toward the cathode, and in the process pushes onto the semi-spherical flexible reservoir, thereby releasing some of the fluid contained within the reservoir (FIG. 2C (see Original Patent)).

The degree of bending and the response time of the artificial muscle under the application of an electric field can be tuned by altering the size dimensions of the muscle. FIG. 3 (see Original Patent) illustrates the fast and reversible bending of a micromuscle configuration under the application of various potentials. The artificial muscle is formed in a quasi-rectangular shape and is partially attached to a support so that half of its length was free to move under the application of the electric stimuli. The support with the attached artificial muscle is immersed in the electrochemical cell filled with 150 mM NaCl and placed between two gold electrode plates, under a microscope. Application of the cycled -1/+1 V voltage resulted in the bending of the artificial muscle in tune with the current wave presenting the response of 18.degree. bending angle. The increase in the magnitude of the applied potential to 2 and 3 V results in the increase of the bending angle muscle to 25.degree. and 32.degree., respectively. It should also be noted that the characteristics of the artificial micromuscle (bending angle and response time) are improved compared to an artificial macromuscle of the same composition and dimensions of 4.times.10 mm, with bending angle of 23.5.degree. degrees under the application of 3 V for 2 min.

The artificial muscle may also lie on the top of a reservoir filled with fluid and covered by a soft membrane, preferably biocompatible, such as a silicone rubber membrane (FIG. 4A (see Original Patent)). The end of the reservoir is connected to a calibrated microchannel. When the artificial muscle is electroactuated it gently presses against the membrane, resulting in the release of the fluid from the reservoir into the microchannel. In FIG. 4B (see Original Patent), the volume of the fluid released, which is in the order of microliters, by each electroactuation of the muscle is shown as a function of time. FIG. 4B demonstrates the ability of controlling the fluid release caused by each pulse of electroactuation by 4 V, while no fluid release is observed during the quiet time between the pulses when no potential is applied. The size and shape of the reservoir, and the material of the membrane may be varied depending on the desired application. The body of the reservoir can also be formed by any material, preferably biocompatible, such as silicone.

FIG. 5 (see Original Patent) illustrates another embodiment of the invention where the artificial muscle is covering the opening of a reservoir filled with fluid. When the artificial muscle is not electroactuated it blocks the opening of the reservoir, trapping the fluid inside the reservoir (FIG. 5A). The application of an electric field actuates the muscle, which is now bending exposing the opening of the reservoir and permitting the release of the fluid to the environment (FIG. 5B).

For transdermal therapy, the artificial muscle device, such as any of the devices containing a reservoir(s) described above, may also have an adhesive layer, which may be covered with tape or other suitable covering. After the covering tape is removed, the artificial muscle device is attached to the skin. The adhesive layer may contain one or more penetration enhancers to reduce the resistance of the skin.

The artificial muscle is preferably linked to an electric energy source such as a battery, for example, which provides a low voltage sufficient to actuate the muscle, e.g., preferably less than 4 V, more preferably between 1 and 3 V, and most preferably about 1.0 V. In a preferred embodiment of the invention, the battery cycles at a predetermined time to provide the controlled timed release of a drug or other agent.

The artificial muscle devices of the invention can be placed in suitable biocompatible housing for implantation at the desired site, such as for example, in close proximity to the coronary artery or the eye for trans-scleral drug delivery.

The artificial muscle material of the present invention may be tailored to be faster, or to bend more, and to require less voltage than any previously known artificial muscle polymer blend. The muscle material can be configured to any desired shape and dimensions, for use as an implantable device or for external use.
 

Claim 1 of 17 Claims

1. An electroactive hydrogel composition comprising acrylamide; unsaturated aliphatic acid having the formula R.dbd.CH--COOH, wherein R is selected from the group consisting of --CH.sub.2, --CH--COOH, and --CH--(CH.sub.2).sub.n--COOH, where n is an integer, or a combination of these aliphatic acids; a conductive polymer; and at least one cross-linking agent, wherein the hydrogel is electroactive in the absence of contact with electrodes and at a pH range of from about 3 to about 10.

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