Source: http://www.google.com/patents/US7909867?dq=6,704,032
Timestamp: 2014-03-14 07:03:33
Document Index: 334595160

Matched Legal Cases: ['Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 60', 'Application No. 05807352']

Patent US7909867 - Interpenetrating polymer network hydrogel corneal prosthesis - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsThe present invention provides materials that have high glucose and oxygen permeability, strength, water content, and resistance to protein adsorption. The materials include an interpenetrating polymer network (IPN) hydrogel that is coated with biomolecules. The IPN hydrogels include two interpenetrating...http://www.google.com/patents/US7909867?utm_source=gb-gplus-sharePatent US7909867 - Interpenetrating polymer network hydrogel corneal prosthesisAdvanced Patent SearchPublication numberUS7909867 B2Publication typeGrantApplication numberUS 11/639,049Publication dateMar 22, 2011Filing dateDec 13, 2006Priority dateOct 5, 2004Also published asUS20070179605, WO2007133266A2, WO2007133266A3Publication number11639049, 639049, US 7909867 B2, US 7909867B2, US-B2-7909867, US7909867 B2, US7909867B2InventorsDavid Myung, Christopher Ta, Curtis W. Frank, Won-Gun Koh, Jaan NoolandiOriginal AssigneeThe Board Of Trustees Of The Leland Stanford Junior UniversityExport CitationBiBTeX, EndNote, RefManPatent Citations (45), Non-Patent Citations (15), Referenced by (3), Classifications (26), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetInterpenetrating polymer network hydrogel corneal prosthesisUS 7909867 B2Abstract The present invention provides materials that have high glucose and oxygen permeability, strength, water content, and resistance to protein adsorption. The materials include an interpenetrating polymer network (IPN) hydrogel that is coated with biomolecules. The IPN hydrogels include two interpenetrating polymer networks. The first polymer network is based on a hydrophilic telechelic macromonomer. The second polymer network is based on a hydrophilic monomer. The hydrophilic monomer is polymerized and cross-linked to form the second polymer network in the presence of the first polymer network. In a preferred embodiment, the hydrophilic telechelic macromonomer is PEG-diacrylate or PEG-dimethacrylate and the hydrophilic monomer is an acrylic-based monomer. Any biomolecules may be linked to the IPN hydrogels, but are preferably biomolecules that support the growth of cornea-derived cells. The material is designed to serve as a corneal prosthesis.
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Patent Application No. 60/843,942, filed Sep. 11, 2006, which is incorporated herein by reference. This application is a continuation-in part of U.S. patent application Ser. No. 11/243,952, filed Oct. 4, 2005, which claims priority from U.S. Provisional Patent Application No. 60/616,262, filed Oct. 5, 2004, and from U.S. Provisional Patent Application No. 60/673,172, filed Apr. 20, 2005, all of which are incorporated by reference herein. This application is also a continuation-in-part of U.S. Application Ser. No. 11/409,218, filed Apr. 20, 2006, now abandoned, which claims priority from U.S. Provisional Patent Application No. 60/673,600, filed Apr. 21, 2005, and which is a continuation-in-part of U.S. patent application Ser. No. 11/243,952, filed Oct. 4, 2005, which claims priority from U.S. Provisional Patent Application No. 60/616,262, filed Oct. 5, 2004, and from U.S. Provisional Patent Application No. 60/673,172, filed Apr. 20, 2005, all of which are incorporated by reference herein.
FIELD OF THE INVENTION The present invention relates generally to corneal implants. More particularly, the present invention relates to an interpenetrating network hydrogel material useful as a corneal prosthesis.
BACKGROUND It is estimated that there are 10 million people worldwide who are blind due to corneal diseases (See e.g. Carlsson et al. (2003) in a paper entitled �Bioengineered corneas: how close are we?� and published in �Curr. Opin. Ophthalmol. 14(4):192-197�). Most of these will remain blind due to limitations of human corneal transplantation. The major barriers for treating these patients are corneal tissue availability and resources, particularly for people in developing countries. To have corneas available for transplantation, a system of harvesting and preserving them must be in place. This requires locating potential donors, harvesting the tissue within several hours of death, preserving the tissue, and shipping it to the appropriate facility within one week. Patients who have had refractive surgery may not be used as donors. Therefore, a shortage of corneas may occur in the future, even in developed countries, as the number of patients undergoing refractive surgery increases. Even among patients who are fortunate enough to receive a corneal transplant, a significant number will develop complications that will result in the loss of vision. The most common complications are graft rejection and failure and irregular or severe astigmatism. In successful cases, the improvement in vision may take many months following the surgery due to graft edema and astigmatism.
SUMMARY OF THE INVENTION The present invention provides a material having high oxygen and nutrient permeability, strength, water content, and resistance to protein adsorption. The material includes an interpenetrating polymer network (IPN) hydrogel, as well as biomolecules covalently linked to the hydrogel. The IPN contains a first polymer network, which is based on a hydrophilic telechelic macromonomer, and a second polymer network, which is based on a hydrophilic monomer. The hydrophilic monomer is polymerized and cross-linked to form the second polymer network in the presence of the first polymer network. Preferably, the first polymer contains at least about 50% by dry weight of telechelic macromonomer, more preferably at least about 75% by dry weight of telechelic macromonomer, and most preferably at least about 95% by dry weight of telechelic macromonomer. The telechelic macromonomer preferably has a molecular weight of between about 575 Da and about 20,000 Da. Mixtures of molecular weights may also be used.
DETAILED DESCRIPTION OF THE INVENTION Synthesis of Interpenetrating Polymer Network Hydrogels
Any hydrophilic telechelic macromonomer may be used to form the first polymer network. In a preferred embodiment, polyethylene glycol (PEG) macromonomers are used as the basis of the first network. PEG is known to be biocompatible, soluble in aqueous solution, and can be synthesized to give a wide range of molecular weights and chemical structures. The hydroxyl end-groups of the bifunctional glycol can be modified into photo-crosslinkable acrylate or methacrylate end-groups, converting the PEG macromonomers to PEG-diacrylate (PEG-DA) or PEG-dimethacrylate (PEG-DMA) macromonomers. Adding a photoinitiator to a solution of PEG-diacrylate or PEG-dimethacrylate macromonomers in water and exposing the solution to UV light results in the crosslinking of the PEG-DA or PEG-DMA macromonomers, giving rise to a PEG-DA or PEG-DMA hydrogel. Polymerizing and crosslinking a second network inside the first network will give rise to the IPN structure. Preparing IPN hydrogels through free-radical polymerization has the additional advantage that it will enable the use of molds to form corneal prostheses of desired shape. The free-radical polymerization can be initiated through UV irradiation�in which case transparent molds can be used�or through other means such as thermal-initiation in which non-transparent molds can be used. Preferably, the first polymer network contains at least 50%, more preferably at least 75%, most preferably at least 95% of the telechelic macromonomer by dry weight.
In one embodiment of the present invention, UV light-absorbing monomers can be incorporated into the synthetic process by co-polymerization. In particular, a benzotriazole monomer (2-(2′methacryloxy-5′-methylphenyl)-benzotriazole (Polysciences, Inc., Warrigton, Pa.) and a benzophenone monomer (2-hydroxy-4-acrylyloxyethoxy)-benzophenone (Cyasorb UV-2098, Cytec Industries, Inc., West Patterson, N.J.) can be used. These have been incorporated into (vinyl alcohol) hydrogels by Tsuk and coworkers (Tsuk et al. (1997) in a paper entitled �Advances in polyvinyl alcohol hydrogel keratoprostheses: protection against ultraviolet light and fabrication by a molding process� and published in �J. Biomed. Mat. Res. 34(3):299-304�). Once the UV-absorbing monomers have been incorporated into the materials, the light-absorbing capacity can be tested using a spectrophotometer. Finally, the refractive index of all candidate materials can be measured using an automated refractometer (CLR 12-70, Index Instruments, Cambridge, UK) or manually using an Abbe refractometer.
IPN hydrogels composed of a PEG first network with MW 8000 and concentration of 50% w/v in dH2O in the preparation state, and a second network of polyacrylic acid with 50% v/v in dH2O in the preparation state were used to test oxygen permeability. The hydrogels were first rinsed in distilled water, then soaked in phosphate buffer solution for at least 24 hrs. The harmonic thickness of the hydrogel was then measured using Electronic thickness gauge Model ET-3 (Rehder Development company). The hydrogel was then soaked again in phosphate buffered saline solution for at least 24 hrs. Next, an electrode assembly (Rehder Development company) was attached to a polarographic cell and electrical cables were attached between the electrode assembly and a potentiostat (Gamry instruments). About 1.5 L of buffer solution was then saturated with air for at least 15 minutes and preheated to 35� C. Next, the hydrogel was carefully placed onto the electrode, the gel holder was placed over the hydrogel, and a few drops of buffer solution were placed on top of the hydrogel to keep the hydrogel saturated with buffer solution. The central part of the cell was then attached onto the cell bottom and the top part of the cell, containing the stirring rod, impeller, and coupling bushing, was attached to the top part of the cell. Air saturated buffer solution at 35� C. was then poured into the assembled cell and filled almost to the top. Next, heating coiled tubing was placed around the cell, the tubing was connected to the heating bath, insulation was wrapped around and on top of the cell, and the flow of heating fluid was turned on. The speed was then set at 400 rpm and current data was collected until the steady state was reached. The speed was then reset in 100 rpm increments up to 1200 rpm, and data was again collected. This data was then used to get the oxygen permeability by plotting the inverse of steady current versus the Reynolds number to the minus ⅔. An oxygen permeability of 95.9�28.5 Barrers was obtained. Materials according to the present invention, as well as corneal prostheses made from these materials, preferably have an oxygen permeability of more than about 15 Barrers, more preferably at least about 60 Barrers, most preferably at least about 90 Barrers.
WC = W S - W d W S � 100 where Ws and Wd are the weights of swollen and dry hydrogel, respectively.
Concentration of AA
in the preparation state
of PEG/PAA IPN
TABLE 2 Compositions of PEG(8.0k)/PAA IPNs with varying preparation concentration of AA monomer Concentration of AA in Dry Wt. % Dry Wt. % (Dry Wt.PEG)/ the preparation state PEG in IPN PAA in IPN (Dry Wt. PAA) 30% 23.5% 76.5% 0.30 40% 17.5% 82.5% 0.20 50% 13.0% 87.0% 0.15 Optical Clarity
The percentage (%) of light transmittance of IPN hydrogels composed of PEG (50% w/v in dH2O) in the preparation state of the first network and polyacrylic acid (50% v/v in dH2O) at 550 nm was also measured using a Varian Cary 1E/Cary 3E UV-Vis spectrophotometer following the method described by Saito et al (Saito et al, �Preparation and Properties of Transparent Cellulose Hydrogels�, Journal of Applied Polymer Science, Vol. 90, 3020-3025 (2003)). The refractive index of the PEG/PAA hydrogel (with PEG MW 8000) was measured using an Abbe Refractometer (Geneq, Inc., Montreal, Quebec). The percentage of light transmittance was found to be 90%, and the refractive index was found to be 1.35. Materials according to the present invention, as well as corneal prostheses made from these materials, are preferably at least about 70% transparent.
We studied the glucose permeability across PEG/PAA IPNs, PEG polymers of varying molecular weight, PAA polymers, and PHEMA polymers, as well as human, bovine, and pig corneas in vivo using a modified blind well chamber apparatus developed in our laboratory. In these experiments, non-porous mylar and dialysis membranes (MWCO 12 kD-14 kD) were used as negative and positive controls, respectively. Glucose diffusion coefficients for PEG/PAA (1.10 mm thick) and PHEMA hydrogels (0.250 mm thick) were calculated using Fick's law and taking into account the sample thicknesses. Similarly, glucose diffusion coefficients for human, bovine, and pig corneas were also calculated taking into account corneal thicknesses. Our results indicate that PEG/PAA IPNs (DPEG-DA/PAA=9.0�1.2�10−07 cm2/s) are more permeable than PHEMA (DPHEMA=2.7�0.7�10−08 cm2/s), with a p value of <0.05. This is consistent with the published values of the diffusion coefficient of pHEMA membranes (DPHEMA�10−08 cm2/sec), which is about two orders of magnitude less than that of the human, bovine, rabbit and pig corneas we have measured in vitro, which are all on the order of D�10−06 cm2/sec)). This difference is largely due to the lower water content of PHEMA (40%), for the hydration of a material is known to be an important indicator of its permeability. The results from this study indicate that the PEG-DA/PAA IPN is able to facilitate adequate passage of glucose to an overlying epithelial cell layer.
To incorporate peptides directly into IPN hydrogels, the peptides can be reacted with acryloyl-PEG-NHS to form acrylate-PEG-peptide monomers. (See Mann et al. (2001) in a paper entitled �Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering� and published in �Biomaterials 22:3045-3051�; Houseman et al. (2001) in a paper entitled �The microenvironment of immobilized Arg-Gly-Asp peptides is an important determinant of cell adhesion� and published in �Biomaterials 22(9):943-955�; and Hern et al. (1998) in a paper entitled �Incorporation of adhesion peptides into nonadhesive hydrogels useful for tissue resurfacing� and published in �J. Biomed. Mater. Res. 39(2):266-276�). These peptide-containing acrylate monomers can be copolymerized with other desired acrylates, including PEG-diacrylates, using standard photopolymerization conditions to form peptide-containing hydrogels. The major advantage of this approach is that the peptide is incorporated directly into the hydrogel, and no subsequent chemistry is needed.
Azidobenzamido groups react with light (250-320 nm, 5 min) to generate aromatic nitrenes, which insert into a variety of covalent bonds. In a preferred embodiment, biomolecules such as proteins and/or peptides are fixed to the artificial cornea photochemically. For the photochemical fixation of peptides/proteins to the hydrogel surfaces, an azide-active-ester chemical containing a photoreactive azide group on one end and an NHS end group (which can conjugate cell adhesion proteins and peptides) on the other end is used. With this method, shown schematically in FIG. 9, a solution of 5-azido-2-nitrobenzoic acid N-hydroxysuccinimide ester is spread over the hydrogel surface 910. This can be accomplished by dissolving 5 mg of 5-azido-2-nitrobenzoic acid N-hydroxysuccinimide ester in 1 mL of N,N-dimethylformamide (DMF) (See Matsuda et al. (1990) in a paper entitled �Development of micropatterning technology for cultured cells� and published in �ASAIO Transactions 36(3):M559-562�) and spreading the solution over hydrogel surfaces. After air drying the hydrogel, it is then exposed to UV irradiation 920, for example for 5 minutes. Upon UV irradiation, the phenyl azide group reacts to form covalent bonds with the hydrogel surface 910. The irradiated surfaces are then thoroughly rinsed with solvent to remove any unreacted chemicals from the surface. The hydrogels are then incubated for 24 hours in a solution containing the amine-containing biomolecule of interest 930 (e.g. collagen type I), which reacts 940 with the exposed NHS end groups. For the purpose of the present invention, biomolecules present in the cornea and/or aqueous humor, or derivatives thereof, would be candidates for attachment to hydrogels.
The skirt of the artificial cornea may be made of an IPN hydrogel, as described above, or a single network hydrogel. In one embodiment, both the core and skirt is made of PEG/PAA of the same or different relative composition (by dry weight and molecular weight) of PEG and PAA. In another embodiment, the skirt is made of PHEA, which is a hydrophilic, biocompatible, and rapidly photopolymerizing network that can be patterned with high fidelity. In addition, PHEA can interpenetrate into another network prior to polymerization to form a �seamless� core-skirt junction. With any skirt material, the central core and skirt of the artificial cornea may be joined together through an interdiffusion zone, in which the central core component interpenetrates the skirt component or vice versa.
FIG. 14 shows a schematic (A) and an actual (B, C) photolithographic mask that may be used to synthesize porous hydrogel skirts. Mask 1400 contains an unmasked central region 1410, for forming the central core, and a patterned, masked peripheral region 1420, for forming the peripheral skirt. Patterned peripheral region 1420 contains UV-blocking disks 1424, as shown in insert 1422. FIG. 14B shows an actual photolithographic mask 1430 that may be used according to the present invention. Discs may be made of any UV-blocking material, including but not limited to chrome, platinum, tungsten, copper, aluminum, gold, or ink, such as ink on a transparency using a high-resolution printer. This mask has a 2 cm unpatterned central region 1440, and a patterned peripheral region 1450 with 60 μm diameter discs 1452 spaced 10 μm apart along lines with 1� of separation. Discs 1452 can be clearly seen in the magnified view of mask 1430, shown in FIG. 14C. While the central region of this mask is 2 cm in diameter, other dimensions are possible. Similarly, other disc dimensions are possible, preferably ranging from about 20 μm to about 200 μm diameter. Any pattern of discs may be used, including but not limited to radial and grid patterns. For example, FIG. 15 shows a photomicrograph of a grid style chrome pattern (A), a representative resulting porous hydrogel after UV irradiation (B) and the porous hydrogel in cross section (C).
EXAMPLES Photolithographically Patterned Artificial Cornea
Early passage rabbit corneal epithelial cells screened for epithelial differentiation were seeded on surface-modified PEG/PAA IPN hydrogels at a concentration of 1.0�105 cells/cm2. The epithelial cells exhibited excellent spreading (>75%) on collagen-bound PEG/PAA IPNs within 2 hours, achieved confluency within 48 hours, and had migrated over the remainder of the unseeded surface by day 5. A representative photomicrograph of the adherent cells is shown in FIG. 19A. As expected, the unmodified double network did not promote cell attachment or spreading (not shown). In addition, cell spreading was not observed when hydrogels were incubated with collagen type I without prior azide-active-ester functionalization, indicating that little or no physical adsorption of proteins to PEG/PAA had taken place (FIG. 19B). FIG. 19C shows cells seeded on an unmodified hydrogel without any prior exposure to collagen or cell-adhesion promoting biomolecules. The lack of cell spreading indicates that the unmodified hydrogel does not support cellular adhesion. We have also attached other biomolecules as well as combinations of biomolecules to the hydrogel surface through azide-active-ester linkage. FIG. 19D shows corneal epithelial cells growing on a hydrogel surface tethered with RGD peptides, which was prepared in the following way. RGD peptides were reacted with 5-azido-2-nitrobenzoic acid N-hydroxysuccinimide ester in mixture of phosphate buffered saline and dimethyl formamide solution overnight, drop-casted onto the hydrogel surface, air-dried, and then exposed to UV light. The cells were seeded on the surface in the way described above, and the photonicrograph was taken after 24 hours. FIG. 19E shows corneal epithelial cells growing on hydrogel surface tethered with a combination of collagen type I, RGD peptides, and fibronectin. This surface was created by preparing a hydrogel surface-functionalized with the azide-active-ester linker, and then reacting the active esters with a solution of collagen, RGD peptides, and fibronectin molecules in a 1:1:1 molar ratio overnight. The cells were seeded on the surface in the way described above, and the photomicrograph was taken after 24 hours.
Early passage corneal fibroblast cells were seeded on collagen type I-modified microperforated PHEA substrates at a concentration of 1.0�105 cells/cm2. Cells grew to confluence within 24 hours, as shown in FIG. 19F.
In preliminary studies, the implants were nearly indistinguishable from the surrounding stroma. During a two-week study, collagen type I surface modified PEG/PAA optics (�100 μm thick, 3.5 mm diameter) were implanted into 8 rabbits to assess the biocompatibility and nutrient permeability of the complete central optic prototype material. The implants were well-tolerated, with no signs of inflammation, epithelial ulceration, or opacification. In one of eight rabbits, the implant extruded due to mechanical factors associated with improper positioning of the optic. Clinical and histological evidence of epithelial and stromal health in these short-term studies demonstrates that the PEG/PAA IPN optics are biocompatible and can facilitate adequate nutrient transport to an overlying epithelium. FIG. 20A shows a histological section demonstrating healthy epithelial growth anterior to a PEG/PAA IPN hydrogel in a rabbit cornea after 14 days.
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Journal of Biomedical Materials Research, 1997. 34(3): p. 299-304.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS20100280147 *May 19, 2010Nov 4, 2010Laura HartmannHigh refractive index interpenetrating networks for ophthalmic applicationsUS20110166247 *Dec 20, 2010Jul 7, 2011David MyungInterpenetrating polymer network hydrogel contact lensesWO2008100617A1Feb 15, 2008Aug 21, 2008Curtis W FrankStrain-hardened interpenetrating polymer network hydrogel* Cited by examinerClassifications U.S. Classification623/5.16, 523/106, 424/427, 623/6.56, 351/159.33International ClassificationA61F2/14, C12N5/071Cooperative ClassificationA61F2/142, A61L27/26, A61L2300/252, A61F2/14, A61L2300/414, A61L27/54, C12N5/0621, A61L2300/258, C12N2533/54, A61L2300/214, A61L2300/23, A61L27/52, C12N2533/30European ClassificationA61F2/14, A61F2/14C, A61L27/54, C12N5/06B8C, A61L27/52, A61L27/26Legal EventsDateCodeEventDescriptionMar 29, 2007ASAssignmentOwner name: BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MYUNG, DAVID;TA, CHRISTOPHER;FRANK, CURTIS W.;AND OTHERS;REEL/FRAME:019124/0859Effective date: 20070321RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google