In preferred embodiments, the present invention provides methods of controllably making a vinyl polymer hydrogel having desired physical properties without chemical cross links or radiation. The gelation process is modulated by controlling, for example, the temperature of a resultant vinyl polymer mixture having a gellant or using active ingredients provided in an inactive gellant complex. In accordance with a preferred embodiment, the method of manufacturing a vinyl polymer hyrodgel includes the steps of providing a vinyl polymer solution comprising a vinyl polymer dissolved in a first solvent; heating the vinyl polymer solution to a temperature elevated above the melting point of the physical associations of the vinyl polymer, mixing the vinyl polymer solution with a gellant, wherein the resulting mixture has a higher Flory interaction parameter than the vinyl polymer solution; inducing gelation of the mixture of vinyl polymer solution and gellant; and controlling the gelation rate to form a viscoelastic solution, wherein workability is maintained for a predetermined period, thereby making a vinyl polymer hydrogel having the desired physical property. In further preferred embodiments, the present invention provides physically crosslinked hydrogels produced by controlled gellation of viscoelastic solution wherein workability is maintained for a predetermined period. In another aspect, the present invention provides kits for use in repairing intervertebral disks or articulated joints including components that form the vinyl polymer hydrogel and a dispenser.

Description of the Invention

SUMMARY OF THE INVENTION

In preferred embodiments, the present invention provides methods of controlling the gelation kinetics of vinyl polymers. These methods include, in preferred embodiments, controllably making a vinyl polymer hydrogel having desired physical properties without chemical cross links or radiation. The gelation process is modulated by controlling, for example, the temperature of a resultant vinyl polymer mixture having a gellant (also spelled as gelant) or using active ingredients provided in an inactive gellant complex.

Preferred embodiments include an injectable hydrogel such as, for example, for nucleus pulposus augmentation using minimally-invasive surgical implantation of prosthetics fabricated in situ. The hydrogel in accordance with preferred embodiments of the present invention conform to the region of interest, for example, vertebral surfaces in a joint space. The load bearing hydrogels formed by in situ gellation methods of the present invention minimizes damage to, for example, the annulus fibrosus. In accordance with a preferred embodiment, the method of manufacturing a vinyl polymer hyrodgel includes the steps of providing a vinyl polymer solution comprising a vinyl polymer dissolved in a first solvent; heating the vinyl polymer solution to a temperature elevated above the melting point of the physical associations of the vinyl polymer, mixing the vinyl polymer solution with a gellant, wherein the resulting mixture has a higher Flory interaction parameter than the vinyl polymer solution; inducing gelation of the mixture of vinyl polymer solution and gellant; and controlling the gelation rate to form a viscoelastic solution, wherein workability is maintained for a predetermined period, thereby making a vinyl polymer hydrogel having the desired physical property. In further preferred embodiments, the present invention provides physically crosslinked hydrogels produced by controlled gelation of viscoelastic solution wherein workability is maintained for a predetermined period. In another aspect, the present invention provides kits for use in repairing intervertebral disks or articulated joints including components that form the vinyl polymer hydrogel and a dispenser.

In certain preferred embodiments, the step of providing a vinyl polymer solution typically includes the step of dissolving the vinyl polymer in the first solvent. The step of mixing the vinyl polymer solution with a gellant may precede or follow the step of heating the vinyl polymer solution to a temperature elevated above the melting point of physical associations of the vinyl polymer.

The desired physical property typically includes at least one of light transmission gravimetric swell ratio, shear modulus, load modulus, loss modulus, storage modulus, dynamic modulus, compressive modulus, cross-linking and pore size. In preferred embodiments, the desired physical property is physical cross-linking.

In preferred embodiments, the vinyl polymer is selected from the group consisting of polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone and mixtures thereof. Preferably the vinyl polymer is highly hydrolyzed polyvinyl alcohol of about 50 kg/mol to about 300 kg/mol molecular weight. In preferred embodiments, the vinyl polymer is highly hydrolyzed polyvinyl alcohol of about 100 kg/mol molecular weight. Typically the vinyl polymer solution is about 1 weight percent to about 50 weight percent solution of polyvinyl alcohol based on the weight of the solution. In preferred embodiments, the vinyl polymer solution is about 10 weight percent to about 20 weight percent solution of polyvinyl alcohol based on the weight of the solution.

In certain preferred embodiments, the method includes the step of further contacting the viscoelastic solution with a gellant, typically to modify the physical or chemical properties of the resulting gel. This method is suitable for producing a local modification in the physical properties of the gel, such as to maintain the gel in place within a body cavity, such as a space within an intervertebral disk.

In preferred embodiments, the first solvent is selected from the group consisting of deionized water, dimethyl sulfoxide, an aqueous solution of a C.sub.1 to C.sub.6 alcohol and mixtures thereof. Preferably the gellant is more soluble than the vinyl polymer. In certain preferred embodiments, the vinyl polymer is introduced into an aqueous solution of a gellant.

Typically, the Flory interaction parameter of the mixture of vinyl polymer solution and gellant ranges from 0.25 to 1.0. In preferred embodiments, the Flory interaction parameter of the mixture is at least 0.5.degree., more preferably about 0.25 to about 0.5.

Typically the gellant is selected from the group consisting of salts, alcohols, polyols, amino acids, sugars, proteins, polysaccharides, aqueous solutions thereof, and mixtures thereof. In preferred embodiments, the gellant is selected from the group consisting of chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin sulfate and mixtures thereof. In other preferred embodiments, the gellant is selected from the group consisting of biglycan, syndecan, keratocan, decorin, aggrecan and mixtures thereof. In further preferred embodiments, the gellant is an alkali metal salt, most preferably sodium chloride.

The gellant may be added as a dry solid or in solution. For example, solid NaCl can be added to an aqueous solution of vinyl polymer, or added as an aqueous solution of sodium chloride from about 1.5 molar to about 6.0 molar, more preferably about 2.0 molar to about 6.0 molar. In further preferred embodiments, the gellant is an aqueous solution of an alcohol chosen from the groups consisting of methanol, ethanol, i-propanol, t-propanol, t-butanol and mixtures thereof.

The gellant may be in an active form or an inactive form when it is mixed with the vinyl polymer solution. In preferred embodiments, the step of inducing gelation of the viscoelastic solution includes the step of activating the gellant. Preferably, the inactive gellant is activated by a controllable trigger event.

In certain preferred embodiments, the inactive gellant is a macromolecule and the active gellant comprises fragments of a macromolecule that are released by cleavage of the macromolecule. In some embodiments, the cleavage of the macromolecule is enzymatic cleavage; a preferred macromolecule is a physiological substrate of the selected enzyme. In preferred embodiments, the macromolecule is selected from the group consisting of chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, heparin, heparin sulfate and mixtures thereof and the enzyme is selected from the group consisting of chondroitinase ABC, chondroitinase AC, chondroitinase B, testicular hyaluronidase, hyaluron lyase, heparinase I/III and mixtures thereof. In other preferred embodiments, the macromolecule is selected from the group consisting of biglycan, syndecan, keratocan, decorin, aggrecan, perlecan, fibromodulin, versican, neurocan, brevican and mixtures thereof and the enzyme is selected from the group including, for example, without limitation, aggrecanase and mixtures thereof.

In other embodiments, macromolecule can be thermally denaturable; in such embodiments, a referred macromolecule is collagen. Alternatively, cleavage of the macromolecule is by irradiation with electromagnetic radiation or particulate radiation.

In further preferred embodiments, the inactive gellant is a bad solvent sequestered in a vesicle, a liposome, a micelle or a gel particle. In some preferred embodiments, the liposome is a phototriggerable diplasmalogen liposome. In alternate preferred embodiments, the liposome undergoes a phase transition at about the body temperature of a mammal. Preferably, the liposome includes, without limitation, a mixture of dipalmitoylphosphatidylcholine and dimyristoylphosphatidylcholine. In further preferred embodiments, the inactive gellant is associated with a gel particle that is in an active form upon undergoing a phase transition at about the body temperature of a mammal. In such embodiments, the get particle suitably comprises a polymer selected from the group consisting of poly(N-isopropyl acrylamide-co-acrylic acid), N-isopropylacrylamide, hyaluronic acid, pluronic and mixtures thereof. In other preferred embodiments, the gel particle releases its contents upon undergoing degradation.

Typically, the rate of gelation is controlled to provided an ad equate period of workability needed for further processing of the viscoelastic solution, including injecting, molding or calendaring. In preferred embodiments, the viscoelastic solution is injected into an actual or potential space in the body of a mammal. In particularly preferred embodiments, the viscoelastic solution is injected into an intervertebral disk or an articulated joint, such as a hip or knee. The hydrogel can be retained within the body space by virtue of general physical properties or by its local physical properties at the injection site. In preferred embodiments, desired local physical properties can be adjusted by a further addition of gellant near the injection site. In other preferred embodiments, the hydrogel can be retained within the body space by the use of known medical devices to seal, reinforce or close the injection site or other defect of the body cavity. Suitable such devices are disclosed in published International Patent Applications WO 01/12107 and WO 02/054978, which are hereby incorporated by reference in their entirety.

In other preferred embodiments, the step of processing includes covering a burn or a wound.

The preferred embodiments of the present invention provide methods of making a gel and controlling a property of the gel. In accordance with a preferred embodiment of the present invention, a method for making a gel includes comprising dissolving a vinyl polymer in a first solvent to form a vinyl polymer solution and introducing the vinyl polymer solution in a volume of a second solvent to cause gelation, the second solvent having a higher Flory interaction parameter at a process temperature than the first solvent. The Flory interaction parameter (.chi.) is dimensionless and depends on, for example, temperature, concentration and pressure. Solvents can be characterized as having a low .chi. value or solvents having a higher .chi. value wherein .chi.=0 corresponds to a solvent which is similar to a monomer. A solvent having a higher .chi. value is characterized as a solvent that causes a gelation process at a temperature. A thetagel, in accordance with the present invention, is formed by using a second solvent having a Flory interaction parameter that is sufficient to cause gelation.

Preferably the second solvent used in the preferred embodiment has a Flory interaction parameter in the range of 0.25 to 1.0. Typically, first and second solvent characteristics are chosen to allow use of the method of the preferred embodiment at room temperature or at body temperature of a mammal. The gel produced by the method of the invention has physical cross-linking, and is substantially tree of chemical crosslinking agents. In a preferred embodiment, the vinyl polymer is polyvinyl alcohol.

In some embodiments, a plurality of cycles of contacting the vinyl in an immersion solvent (second solvent) and contacting with the first solvent are performed. Alternatively, the method may include subjecting the gel to at least one freeze-thaw cycle. The polyvinyl alcohol (PVA) hydrogels thus may be both a thetagel and a cycle. Partial gelling can be accomplished with either method and then completed using the other, or even alternating between the two methods.

While the examples and discussion herein are directed towards vinyl polymers and in particular PVA hydrogels, thetagels can be made in a similar manner using any polymer that possesses the appropriate kind of phase diagram as described hereinafter with respect to the Flory interaction parameter. A mechanical force can be applied to the gel during the gelling process, changing the manner in which it gels and alternatively producing oriented gelation.

In several embodiments, the vinyl polymer is highly hydrolyzed polyvinyl alcohol of about 50 kg/mol to about 300 kg/mol molecular weight. In other embodiments, the vinyl polymer is highly hydrolyzed polyvinyl alcohol of about 100 kg/mol molecular weight. The vinyl polymer solution is about 1 weight percent to about 50 weight percent solution of polyvinyl alcohol based on the weight of the solution. Preferably, the vinyl polymer solution is about 10 weight percent to about 20 weight percent solution of polyvinyl, alcohol based on the weight of the solution.

The first solvent is selected from the group of solvents having a low .chi. value that is not sufficient to enable gelation, i.e., solvents in which the energy of interaction between a polymer element and a solvent molecule adjacent to it exceeds the mean of the energies of interaction between the polymer-polymer and the solvent-solvent pairs, as discussed below. In several embodiments, the first solvent is selected, without limitations from the group consisting of deionized water, dimethyl sulfoxide, an aqueous solution of a C.sub.1 to C.sub.6 alcohol and mixtures thereof.

In general, the immersion solution comprises a solvent having a high or sufficient .chi. value that enables gelation. In some preferred embodiments, the immersion solution is an aqueous solution of a salt of an alkali metal, typically sodium chloride. In other embodiments, the immersion solution is an aqueous solution of a C.sub.1 to C.sub.6 alcohol, typically an aqueous solution of an alcohol chosen from the groups consisting of methanol, ethanol, i-propanol, t-propanol, t-butanol and mixtures thereof. In certain embodiments, the immersion solution is an aqueous solution of methanol.

In general, the vinyl polymer gels of the present invention can be made in-situ for applications such as filters, microfluidic devices or drug release structures in situations in which freeze-thaw gelation may be difficult or impossible to execute.

In one embodiment, the vinyl polymer solution is placed in a chamber having at least two sides and a membrane. The membrane has properties that contain the vinyl polymer while providing access to small molecules and solvents.

In some embodiments, the vinyl polymer solution is separated by the membrane from at least two different immersion solvents, typically a first immersion solvent and a second immersion solvent. In some embodiments, the first immersion solvent is an aqueous solution of sodium chloride from about 1.5 molar to about 6.0 molar. In some embodiments, the second immersion solvent is an aqueous solution of sodium chloride from about 2.0 molar to about 6.0 molar. In other embodiments, the first immersion solvent is a 1.5 molar aqueous solution of sodium chloride and the second immersion solvent is an aqueous solution of sodium chloride from about 2.0 molar to about 6.0 molar. In such embodiments, a gradient in chemical potential is formed across the vinyl polymer solution between at least two different immersion solvents. In one embodiment, a gradient in chemical potential is formed across the vinyl polymer solution of about 4 molcm.sup.-1.

In general, a gradient of a property is formed across the vinyl polymer gel that corresponds to the gradient in chemical potential formed across the vinyl polymer solution. Typically, the property is at least one of light transmission, swell ratio, shear modulus, load modulus, loss modulus, storage modulus, dynamic modulus, compressive modulus, cross-linking and pore size.

In some embodiments, one or both immersion solvents are changed in a temporal pattern to modulate the spatial gradient of a physical property. Such temporal cycling is done on a time scale shorter than the diffusion time to make an inhomogeneous gel. In this way, gels can be produced with a similar set of properties on the edges or peripheral region and another set of properties in the central region, such as greater cross-linking in the peripheral region as compared with the central region. Temporal cycling of immersion solvents can also be used to modify the structure of the gel for example, pore size, for production of filters. In such filters, small, locally varying pore size may be useful for some forms of chromatography (through size exclusion) or any other filtering application that requires pore size control.

Additional compounds can be combined in the physically cross-linked gel, including but not limited tot ionic or non-ionic species such as hyaluronic acid, polyacrylic acid and therapeutic agents.

In one embodiment, the invention provides a physically cross-linked hydrogel comprising at least about 10 weight percent poly(vinyl alcohol) solution gelled by immersion in about 2 to about 3 molar sodium chloride wherein the hydrogel is about 14 percent to about 21 percent physically cross-linked. In such an embodiment the final gel comprises about 12 to about 29 percent poly(vinyl alcohol).

The preferred embodiments of the present invention also provide articles of manufacture comprising a vinyl polymer gel having at least one gradient of mechanical properties. PVA thetagels may be used as a biocompatible load bearing or non-load bearing material for replacement, repair or enhancement of tissue. In general, PVA thetagels can replace PVA cryogels in applications where PVA cryogels are used.

In one embodiment, a one-piece prosthetic intervertebral disk is made comprising a polyvinyl polymer hydrogel wherein the distribution of mechanical properties of the one-piece prosthetic intervertebral disk approximates the spatial distribution of the mechanical properties of the combination of the nucleus pulposus and the annulus fibrosis of the natural interverebral disk.

High compression PVA thetagels can be made by placing PVA in a reverse osmosis membrane with NaCl and then making the outside concentration of NaCl quite high to compress PVA/NaCl. The NaCl concentration will climb as water leaves the reverse osmosis membrane gelling the PVA at high pressure. The concentration of PVA can be modified by the ratio of NaCl to PVA inside the reverse osmosis membrane.

In a preferred embodiment, gel microparticles can be made through gelation during agitation or by dropping blobs of fluid into a crosslinking solvent, such as the immersion solution.

In a preferred embodiment, gels can be embedded with particles that degrade (or do not adsorb) to "imprint" a pattern ("empty spaces") on the gel or as the drug release centers. Embedding neutrally charged polymers of varying molecular weights can be used to "space fill" the gel. These polymers are removable after the process, leaving a controlled pore structure. Materials that are sensitive to freeze-thaw cycles can be encapsulated. The gels can be embedded with particles or polymers that are electrostatically charged to provide extra repulsion at high compressions but are collapsed in high salt. Such embedded particles can be those that are active in some manner (e.g. for catalyses). Hydroxyapatite particles or other osteoinductive particles, agents, and similar moieties can be embedded to encourage bony in growth for possible cartilage replacement.

In a preferred embodiment, poly(vinyl alcohol) gels can be used to contain and release bioactive compounds such as growth factors, fibronectin, collagen, vinculin, chemokines and cartilage including therapeutic agents. The teachings with respect to incorporation of therapeutic agents of U.S. Pat. Nos. 5,260,066 and 5,288,503 are herein incorporated in their entirety. Contained compounds such as therapeutic agents or drugs can be released over time to modulate the local growth of normal tissues such as bone, blood vessels and nerves or tumors.

Temporal modulation of immersion solvents can produce thetagels in accordance with the preferred embodiment with appropriate structure and physical properties for containing and releasing drugs and other bioactive molecules. In one embodiment, an outer skin is formed that is highly crosslinked and an inner layer containing the drug/active agent is only weakly crosslinked. In such an embodiment, the outer skin is the rate limiting component and has a constant release rate. Thus, drug release in accordance with a preferred embodiment includes the release profile that is tunable by controlling the spatial gradient in PVA crosslinking.

In one embodiment, the present invention provides a method of controllably modulating the mechanical properties and structure of hydrogels. In a preferred embodiment, the present invention provides articles of manufacture with one or more gradients of mechanical properties that more closely match the existing gradients of such properties in natural structures. In one embodiment the invention provides prosthetic hydrogel articles of manufacture that mimic the mechanical behavior of natural structures. In a preferred embodiment, the invention provides polyvinyl alcohol prosthetic intervertebral disks that mimic gradients of mechanical properties found in the natural intervertebral disks. In another preferred embodiment, the invention provides a one-piece prosthetic intervertebral disk that mimics the spatial distribution of the mechanical properties of the nucleus pulposus plus annulus fibrosis of the natural intervertebral disk.

In a preferred embodiment, particulates may also be added to the gel. As described hereinbefore, particulates can be added to create a controlled pore structure. Further, in accordance with another preferred embodiment, particulates can be added to provide a particular nanostructured gel. The particles can be either charged or uncharged and allow PVA crystals to nucleate at the surface of the particles. Particles that can be added include, but are not limited to, inorganic or organic colloidal species such as, for example, silica, clay, hydroxyapatite, titanium dioxide or polyhedral oligomeric silsesquioxane (POSS).

In accordance with another preferred embodiment, particles are added to provide a charge effect to change the compressive modulus of the gel, and preferably increase the compressive modulus. This embodiment can use a thetagel having added particles. Upon compressing the gel in a salt solution, a structure having particles with close packing while shielding their charges results. Upon rehydrating with, for example, deionized (DI) water, the charge fields expand and results in a gel in tension. This allows the gel to approximate physical properties of cartilage, for example, at high charged particulate loads.

In accordance with another preferred embodiment, particulates are added to the gel structure to provide mechanical properties such as, for example, wear resistance. The addition of hardened glass (silica) or different clays can provide wear resistance to the gels.

In accordance with another preferred embodiment of the present invention, a method for making a gel and controlling a property of the gel includes forming a thetagel as described hereinbefore by using a first solvent to form a vinyl polymer solution and subsequently introducing a volume of a second solvent to cause gelation, followed by promoting dehydration to controllably structure the gel. This method results in uniformly structuring the gel and homogenizing the physical crosslinking of the PVA thetagel. This structure can be achieved by immersing the contained PVA solution into a solvent which has a Flory interaction parameter that is higher than the theta point for the PVA solvent pair, and subsequently immersing the contained PVA in another solvent having a Flory interaction parameter lower than the theta point for the PVA solvent pair. The process can continue with successive decreases in the Flory interaction parameter until the desired interaction parameter value for the gel is reached.

In another method in accordance with a preferred embodiment of the present invention, the PVA solution can be subjected to a gradually changing solvent quality through a similar range of electrolyte concentrations by the gradual addition of a concentrated NaCl solution to deionized water such that the change of the salt concentration is slower, or equals to the diffusion process of the gel.

In accordance with another preferred embodiment of the present invention, the PVA solution may be subjected to at least one freeze-thaw cycle to fix the gel into a particular shape and then be immersed in a series of solutions with successively higher Flory interaction parameters until the final desired Flory parameter is reached. Alternatively, the PVA solution is subjected to the one or more freeze-thaw cycles after being immersed in a solution of 2 M NaCl.

In one preferred embodiment, nanoparticles are dispersed into solutions of PVA. The solvent may be water, dimethyl sulfoxide (DMSO), methanol or any other solution that exhibits a Flory interaction parameter that is lower than the theta point for the PVA solvent pair during solution preparation. The PVA/nanoparticle mixture is then subjected to at least one freeze-thaw cycle. Subsequent to the freeze-thaw cycling, the gelled PVA is immersed in a solvent that has a Flory interaction parameter near or higher than the theta point for the PVA/solvent pair to induce further physical crosslinking of the PVA/nanoparticle mixture.

Another aspect of the embodiments of the present invention further provide methods of controlling the rate of gelation of polymer gels by changing in the manner in which the polymer molecules interact. By controlling the rate of gelation, a "window" of time that allows the relatively slowly gelling PVA solution to be manipulated or worked, for example, by injection, molding or any other processing step that may be dependent on the flow of the gelling PVA solution. In preferred embodiments, the gelling PVA solution is injected into a region of interest such as a body cavity and gels in situ to form a PVA product. Preferred body cavities include the nucleus pulposus and a normal or pathological void within a joint.

In preferred embodiments, the rate of gelation can be controlled by holding the polymer, preferably PVA, above its crystallization temperatures, thus preventing gelation even if the solvent quality is poor. In other preferred embodiments, the rate of gelation can be controlled by using a second solvent that can be triggered to change from good to bad. In some preferred embodiments, the quality of the solvent can be changed by disruption of micelles. In other preferred embodiments, the quality of the solvent can be changed scission of high molecular weight molecules. In further preferred embodiments, a poor solvent is used in combination with process temperatures that accelerate the gelation process.

The foregoing and other features and advantages of the systems and methods for controlling and forming polymer gels will be apparent from the following more particular description of preferred embodiments of the system and method as illustrated in the accompanying drawings in which like references characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.
 

Claim 1 of 24 Claims

1. A method of making an injectable thetagel solution for injection into a region, wherein the method comprises the steps of: dissolving polyvinyl alcohol (PVA) molecules in a first solution to form a PVA solution, wherein the first solution has a Flory interaction parameter (chi value) that is not sufficient for gelation; contacting the PVA solution with a second solution in a controlled manner, wherein after the contacting the combination of both solutions has a Flory interaction parameter (chi value) that is sufficient for gelation, and thereby forms an injectable thetagel solution; and maintaining for a period of time the injectable thetagel solution at a temperature such that it is in a workable state, wherein the injectable thetagel solution can be injected into a region, and therein gel in situ after the injection to form in the region a polymer hydrogel that has physical crosslinks between PVA molecules, wherein the polymer hydrogel is formed without chemical crosslinkers, irradiation or thermal cycling.

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