Patent Application
20090131590
The present invention provides methods for forming a hydrogel material during processing using reactive compounding.
Hydrogels are water-swellable or water-swollen materials whose structure is typically defined by a crosslinked or interpenetrating network of hydrophilic homopolymers or copolymers. The hydrophilic homopolymers or copolymers can be water-soluble in free form, but in a hydrogel they may be rendered insoluble generally due to the presence of covalent, ionic, or physical crosslinks. In the case of physical crosslinking, the linkages can take the form of entanglements, crystallites, or hydrogen-bonded structures. The crosslinks in a hydrogel provide structure and physical integrity to the polymeric network.
Hydrogels can be classified as amorphous, semicrystalline, hydrogen-bonded structures, supermolecular structures, or hydrocolloidal aggregates. Numerous parameters affect the physical properties of a hydrogel, including porosity, pore size, nature of gel polymer, molecular weight of gel polymer, and crosslinking density. The crosslinking density influences the hydrogel's macroscopic properties, such as volumetric equilibrium swelling ratio, compressive modulus, or mesh size. Pore size and shape, pore density, and other factors can impact the surface properties, optical properties, and mechanical properties of a hydrogel.
Hydrogels have shown promise in biomedical and pharmaceutical applications, mainly due to their high water content and rubbery or pliable nature, which can mimic natural tissue and can facilitate the release of bioactive substances at a desired physiological site. For example, hydrogels have been used and/or proposed in a variety of tissue treatment applications, including as implants, tissue adhesives, bone grafts for spinal and orthopedic treatments such as meniscus and articular cartilage replacement, and intervertebral disc nucleoplasty. One drawback to the use of conventional hydrogels in certain tissue treatment applications, and in particular bone tissue treatments, is that such hydrogels are typically weak materials that fracture easily and do not have desired levels of durability and wear resistance. Devices made from polyvinyl alcohol (PVA) hydrogels have been observed to fail due to wear, such as by tearing, abrasion, or shredding.
Mixing two or more polymers together to produce blends or alloys is a strategy for achieving a specific combination of physical properties. Mixing, as used herein, means the break-up of droplets of one polymer to obtain a dispersed phase with a very small size in another polymer. Normally, blending, also referred to as compounding, is used to combine the properties of two or more polymers and is performed in extruders. However, it is often found that the material properties are not as good as expected due to a poor interfacial adhesion between the minor and the major component.
Thus, there is a need for an efficient and cost-effective means of preparing hydrogels having desired physical properties.
The present invention provides a method of forming a modified hydrogel material by reactive compounding. To that end, a hydrogel material is mixed with a plasticizer in the presence of heat and pressure in a compounding apparatus. During mixing of the hydrogel material and the plasticizer, a reactive chemical compound is added to the compounding apparatus. Suitable reactive chemical compounds contain reactive functional groups such as carboxylic acid, alkoxide, silane, epoxide, organometallic, aldehyde, amine, amide, carbonate, carbamate, sulfonic acid, sulfonimide, urea, or cyano functional groups. The reactive functional groups of the reactive chemical compound react with the hydrogel material to form a modified hydrogel material.
The present invention provides for methods of forming a modified hydrogel material by reactive compounding. Reactive compounding, also termed reactive processing or reactive extrusion, refers to the occurrence of chemical reactions during processing of polymers. In reactive compounding, chemical bonds are created across the interface between the minor and the major polymer components. This chemical bonding is generally done by functionalizing one of the components with reactive groups, such as carboxylic acid groups. The component may be functionalized with reactive groups by graft reactions. These groups then react with existing reactive sites of the other component. As an alternative, both components can be functionalized with mutually reactive sites. Additionally, reactive compounding allows bulk quantities of the product to be formed.
A primary distinguishing characteristic of reactive compounding is that chemical reactions are deliberately carried out during continuous melt extrusion to achieve desired product properties. In this case, a compounding or extrusion apparatus is used as a chemical reactor instead of only as a processing aid. A compounding apparatus, used herein, includes compounding reactor, compounding device, extrusion reactor, extrusion device, etc., as known to one skilled in the art. The chemical reaction may take place in the polymer melt phase or in the liquid phase, for instance, when bulk polymerization of monomers is performed in a compounding apparatus. In one embodiment, the chemical reaction is the formation of an ester. Additionally, the chemical reaction may take place in the solid phase when the polymer is conveyed through the compounding apparatus prior to the addition of a solvent slurry. Also, in the case of a bulk polymer, the chemical reaction may take place in the melting stage.
Reactive compounding can occur in conventional single-screw or twin-screw extruders. Because of their versatility, most extrusion devices are twin-screw extruders, which possess a segmented barrel, each segment of which can be individually cooled or heated externally. In addition to external heating, a molten material may be shear heated by the resistance of viscous material to the conveying motion of the screw; these processes can provide energy for chemical reaction.
Extruder screws often have specialized sections or configurations, e.g., high shear mixing sections. Twin-screw extruder screws may be equipped with interchangeable screw elements that provide different degrees of mixing and surface area exposure by varying the depth between screw flights, the individual flight thicknesses, and direction and degree of flight pitch. Kneading blocks may be included as screw elements to provide intensive mixing. In addition, the two screws may be co-rotating or counter-rotating, intermeshing or non-intermeshing. By varying the external heating, the screw element configuration, and the clearance between screw and barrel wall in individual barrel segments, the total energy and the degree of mixing of material in each barrel segment may be varied. In this way, an extruder can have controlled reaction zones made up of individual barrel segments. In each of these segments, sequential chemical processes can take place.
In accordance with the invention, to provide a modified hydrogel material by reactive compounding, a hydrogel material is mixed with a plasticizer in the presence of heat and pressure in an extrusion device. During mixing, a reactive chemical compound is added to the mixture. The reactive chemical compound contains functional groups that react with the hydrogel material to form a modified hydrogel material. The functional groups can be carboxylic acid, alkoxide, silane, epoxide, organometallic, aldehyde, amine, amide, carbonate, carbamate, sulfonic acid, sulfonimide, urea, or cyano groups. Additionally, the reactive mixture may contain a reactive hydrogel material and another chemical compound wherein the functional groups are placed on the hydrogel material and react with a chemical compound.
In various embodiments, a modifier may be added to the reactive mixture to induce chemical changes in, for example, the hydrogel material. In one embodiment, the modifier decomposes to form free radicals. Examples of free radical-generating modifiers include organic peroxides, hydroperoxide, azo compounds, or diazo compounds. In this case, the free radical modifier decomposes and the resultant free radical reacts with at least one of the components in the reactive mixture. In one embodiment, the free radical treated component then reacts with at least one other component in the reactive mixture, to create the modified hydrogel.
In one embodiment, the reactive chemical compound is selected from the group consisting of carboxyl-terminated poly-N-vinylpyrrolidone, carboxyl-terminated poly-2-vinyl pyridine, carboxyl-terminated poly-N-vinyl imidazole, alpha-methoxy-omega-succinic acid terminated polyethylene glycol, and glutaraldehyde and combinations thereof.
In one embodiment, the hydrogel material comprises at least one polymer that is a hydrophilic polymer. In an exemplary embodiment, the hydrophilic polymer is polyvinyl alcohol, polyvinyl pyrilidone, poly(ethylene-co-vinyl alcohol), or a derivative thereof. By way of illustration only, other hydrophilic polymers that may be suitable include poly(hydroxyethyl methacrylate), poly(acrylamide), poly(acrylic acid), hydrolyzed poly(acrylonitrile), poly(ethyleneimine), ethoxylated poly(ethyleneimine), poly(allylamine), or poly(glycol) as well as blends or mixtures of any of these hydrophilic polymers.
In some embodiments, the plasticizer is a solvent. In some embodiments, the plasticizer and/or solvent is an anhydrous compound such as anyhdrous dimethyl sulfoxide, tetrahydrofurane, methylene chloride, ether, toluene, or dimethylforamide.
In some embodiments and as described above, the compounding apparatus is an extrusion reactor. In a typical reactive compounding process, the reactants are fed into the extruder feed throat where the material is usually heated to initiate reaction or increase the reaction rate. The reactant mixture is conveyed through sequential barrel segments where degree of mixing and specific energy input bring the reaction to the desired degree of completion within the limits of residence time in the extruder. At this stage, the reaction may be quenched by cooling or addition of a catalyst quencher where applicable, and volatile by-products or excess reactants may be removed. The molten polymer may be forced from the extruder through a die with one or more openings. The geometry of the die openings is one factor determining the pressure against which the extruder has to pump by the conveying motion of the internal screw. In some cases, polymer melt emerging from the die is usually rapidly cooled by contact with a fluid medium, such as water. In one embodiment, the modified hydrogel material is pelletized as it is extruded from the extrusion reactor. In a further embodiment, the pelletized, modified hydrogel material is formed at a rate of at least about 2 kg/hr.
In some embodiments, additional components may be added to the reactive mixture comprising the hydrogel material and the reactive chemical compound during the reaction or to the resultant modified hydrogel polymer while still in a flowable state. Examples of such additives include additional polymers, peptides and proteins, such as collagen, or conventional additives such as components for inhibiting or reducing crack formation or propagation, components for inhibiting or reducing creep, or particulates or other additives for imparting radiopacity to the article. By way of example only, an additive for imparting radiopacity can include metal oxides, metal phosphates, or metal sulfates, such as barium sulfate, barium titanate, zirconium oxide, ytterbium fluoride, barium phosphate, and ytterbium oxide.
The present invention provides not only a means for cost-efficient, bulk production of the modified hydrogel material, but it also enables the formation of a modified hydrogel material having high concentrations of polymer. High concentrations of polymer in the modified hydrogel material can only be achieved in a compounding or mechanical mixing apparatus because of the high viscosity of the material. In some embodiments, the modified hydrogel material has a polymer concentration of greater than about 30% w/v. In one embodiment, the modified hydrogel material has a polymer concentration of about 50% w/v. Additionally, because of the ability of the compounding apparatus to work with viscous materials, high molecular weight hydrogel materials may be used. Such high molecular weight hydrogel materials can impart increased mechanical strength to the resultant modified hydrogel material.
Typical operating conditions within the extrusion device are between about 70° C. to about 400° C. The extrusion temperature may be any temperature in a range in which the polymer material to be extruded is molten and flowed. Typical extruder residence times are between about 2 seconds and about 600 s. Residence time and, hence, the time available for chemical reaction is determined by extruder length, rate of introduction of reactants, and screw speed.
In some embodiments, the modified hydrogel material is thermoplastic in the form of a lyogel, which is a term generally used to describe the physical state of a hydrogel material before the solvent used to prepare the hydrogel material is replaced with water. The thermoplastic lyogel can be melted and re-solidified without losing its water-swellable properties. The thermoplastic quality of the modified hydrogel material as a lyogel allows for easy processability and end use. Upon melting, the lyogel becomes flowable and can therefore be extruded, injected, shaped, or molded.
The method of the present invention can be used to modify hydrogels to improve such properties as lubricity, creep, wear, shear resistance, mechanical strength, and compatibility. The modified hydrogel material of the present invention can be used in a variety of applications, including medical procedures, as known in the field. The modified hydrogel material can be employed as artificial meniscus or articular bearing components. The modified hydrogel material of the invention can also be used to replace or rehabilitate the nucleus pulposus of an intervertebral disc.
Various embodiments of modified hydrogel materials that may be formed in the present invention are set out in the following examples.
Table 1 shows the composition of modified hydrogel materials formed using the inventive method and compounds formed using traditional “bench-top” methods of forming hydrogels referred to as “Solution Rxn, Solution Casting”. The graft weight is the molecular weight of the polymer (or polymers) used to modify the hydrogel component. In this case, the graft weight is the polymer in the reactive chemical compound column used to modify polyvinyl alcohol.
In the first two examples in Table 1, a bench-top reaction occurred in a beaker equipped with a mechanical stirrer. Polyvinyl alcohol and dimethylsulfoxide (DMSO) were added to the beaker. The polyvinyl alcohol was 99+% hydrolyzed with a weight average molecular weight (Mw) of 146 kDa to 186 kDa and was used as received from Sigma-Aldrich (St. Louis, Mo.). The DMSO was used as received from Sigma-Aldrich and contained <0.4% water. The reactive chemical compound was carboxyl-terminated poly-N-vinylpyrrolidone. A mixture of two compounds, each having a different molecular weight, was used in the first example. The solution was heated to 90° C. for three hours. The solution was poured between two 8 in×8 in×0.05 in glass plates. The material was allowed to cool to room temperature. The dish was then placed into a freezer at −30° C. for twelve hours. The dish was removed from the freezer and the material was allowed to warm to room temperature. The resulting material was flexible and pliable. To extract the DMSO, 700 mL methanol was added to the resulting material. The resulting material remained translucent, flexible, and pliable. Because the process utilized a laboratory mixer, only a low polymer concentration in the hydrogel material was obtained, specifically 16.7% w/v.
In the third example in Table 1, a compounding apparatus was used, specifically a HAAKE Polylab® system equipped with a RheoMix, which was heated to 115° C. Polyvinyl alcohol and dimethylsulfoxide (DMSO) were added to the compounding apparatus. The polyvinyl alcohol was 99+% hydrolyzed with a weight average molecular weight (Mw) of 250 kDa and was used as received from Japan VAM & POVAL Co., Ltd. The DMSO was used as received from Sigma-Aldrich and contained <0.4% water. No reactive chemical compound was added. The blend was allowed to mix for 10 minutes. The blend was removed from the mixer, allowed to cool to room temperature, and chopped. The resultant material was translucent and pliable. The materials were molded utilizing a Morgan Press ram injection molder into 2½ in×2½ in×¼ in rectangular specimens. A high polymer concentration of 50.1% w/v was obtained by the non-reactive compounding method, but the hydrogel lacked the desired physical properties, such as durability and wear resistance.
In the last three examples in Table 1, modified hydrogel materials in accordance with the invention were made. A similar process was used as described for the third example, namely the polyvinyl alcohol was mixed with DMSO in a Haake Polylab® twin screw rheometer. However, during mixing, a reactive chemical compound was added, namely carboxyl-terminated poly-2-vinyl pyridine in the fourth example, alpha-methoxy-omega-succinic acid terminated polyethylene glycol in the fifth example, and carboxyl-terminated poly-N-vinyl imidazole in the sixth example. Blends were allowed to mix for 10 minutes. The blends were then removed from the mixer, allowed to cool to room temperature, and chopped. The resultant pliable materials were then post molded on a Morgan Press ram injection molder. A high polymer concentration of 50% w/v was obtained by the reactive compounding method as with the non-reactive compounding method in the third example, but the modified hydrogels prepared by reactive compounding are expected to exhibit improved physical properties.
The invention is further set forth in the claims listed below. This invention may take on various modifications and alterations without departing from the scope thereof. In describing embodiments of the invention, specific terminology is used for the sake of clarity. The invention, however, is not intended to be limited to the specific terms so selected, and it is to be understood that each term so selected includes all technical equivalents that operate similarly.
