University of California, Berkeley
Grant: $224,240 - National Institutes of Health - Jul. 22, 2009
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Award Description: Background: Myopia (shortsightedness) This project explores a novel approach to the prevention and treatment of myopia (near-sightedness), which involves excessive elongation of the eye due to remodelling in the sclera, the outer supporting wall of the eye. Recent years have witnessed a rapid rise in the prevalence of myopia, especially within Asian communities where it has reached epidemic (>90%) levels in some young adult student populations. Trends show a decreasing age of onset, and higher average amounts of myopia. High myopia (>-6D), once considered rare, is increasingly common, and so represents a serious public health concern due to potentially blinding retinal complications. Topical ophthalmic atropine is currently the only drug treatment for myopia although its use is mostly limited to 'high-risk' Asian communities, because of associated significant ocular side-effects and compliance problems. Scope of Project: This project will apply modern tissue engineering principles to develop novel treatment for myopia that target the sclera. Specifically, we propose to investigate biomimetic hydrogels as: (1) a method for reinforcing/reversing the changes in the myopic sclera, and (2) a sustained drug delivery device that will allow delivery of therapeutically active agents directly to the sclera. Our drug of choice is atropine, for which the sclear represents one of 2 possible sites for its antimyopia action, the other being the retina, which is also accessible via this scleral route. Our treatment goals for these products are to stabilize the weakened sclears of high myopes and to slow elongation in eyes showing myopia progression, with minimal side-effects. We have shown already using the chick as an animal model for myopia, that biomimetic hydrogels formulated as semi-interpenetrating polymer networks (sIPN) can be used to manipulate scleral growth. Chick studies of eye growth regulation have been generally predictive of the behavior of mammals and primates. However, because the sclerea largely determines eye size, differences in its structure in avian compared to mammalian and human eyes require a switch to a mammalian model for our project. Specifically the mammalian sclera comprises fibrous connective tissue while the avian sclera is bilayered, with an additional inner cartilaginous layer, and there are clear differences in both the viscoelastic properties of these tissues and the biomechanical mechanisms underlying eye enlargement. Thus we will extend our preliminary studies in chick to the guinea pig as a critical translational step. Planned experiments in this pilot project will involve the synthesis, characterization and biocompatibility testing of a set of synthetic and environmentally responsive biomimetic hydrogels formulated as semi-interpenetrating polymer networks (sIPNs) that can regulate the behavior of scleral fibrablasts, the resident cells in ocular sclera, and be used as a slow release drug delivery device. A nanoparticle formulation of atropine will aslo be made for use with sIPNs. These products will undergo limited in vivo testing.
Project Description: Summary of recent results: 1) Characterization the behavior of scleral fibroblasts on the sIPNs on the basis of attachment, proliferation, phenotype, and migration: Recent experiments have focused on cellular attachment assays using both chick and guinea pig scleral fibroblasts. Preliminary results suggest that at appropriate cell concentrations the sIPNs enable cells to have attachment rates similar to those observed in tissue culture polystyrene. 2) Synthesis & characterization of polylactide-b-methoxypolyethylene glycol (pLL-mPEG) for delivery of atropine: A pLL-mPEG diblock copolymer product has been synthesized and its characterization begun using the fluorescent red dye, Eosin Y in a Critical Micelle Concentration technique. The CMC value of pure pLL-mPEG is 14.29 mM and of pLL-mPEG with atropine, 15.25 mM. The slightly higher CMC of the copolymer with atropine compared to the CMC of the copolymer, is probably due to the presence of atropine (MW 289.4), which is much smaller than the diblock copolymer (~7500). Given this result, the release kinetics of encapsulated atropine from the micelles are currenty behing tested with 20mM of diblock copolymer, a concentration at which micelles are sure to form. Nanoparticle aggregation has also been demonstrated by electron microscopy. 3) In vivo biocompatability studies involving guinea pigs: Preliminary data suggest good biocompatibility with minimal inflammatory response. 4) Development of bioreactor for in vitro testing of sIPNs implanted on scleral tissue: A pressurized bioreactor for culturing scleral under pseudo-in vivo conditons has been designed and is currently undergoing validation. Assays for assessing the functional state of cultured scleral tissue, including TEM, collagen and GAG synthesis and content, are being development concurrently.
Jobs Summary: ARRA funds used to support 1 Graduate Student Research, 1 Post-Doc Employee (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 22, 2009. Help expand these official descriptions using the wiki below.
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