(477d) Development of Improved Retinal Prosthesis, Using Local Release Polymer Coatings and Sustained Release Dendrimer-Drug Nanodevices
Human testing of electrical stimulation for retinal prosthesis has also revealed that patients with more advanced degeneration require greater amounts of electrical charge in order to experience visual percepts. Studies by our collaborators at the Kresge Eye Institute in RCS rats confirm the finding that charge thresholds for retinal stimulation increase as retinal degeneration progresses. By developing a model for chronic intravitreal drug infusion in these rats, we have discovered that neuroprotection via fluocinolone acetonide (FA) and ciliary-derived neurotrophic factor (CNTF) preserves retinal sensitivity to electrical stimulation relative to untreated controls in a dose-dependant manner. Thus, by pharmacologically enhancing the electrode/retinal tissue interface and preserving the health of the retina, we can improve the long-term efficacy of retinal stimulation for visual prosthesis. We are investigating polymer-based drug delivery systems for (1) sustained intravitreal delivery of fluocinolone acetonide, and (2) local release from the parylene-based retinal implant interface to address implant related inflammation. Dendrimer-FA conjugates are used for the former application, PLGA-FA coatings are being used for the latter. We hypothesize that local drug-release of neuroprotectants at the electrode-tissue interface could 1) improve the pharmacodynamic efficacy of drugs delivered to retina and retinal pigment epithelium and 2) reduce the ocular side-effects that can occur with some drugs via intravitreal drug-delivery.
Since the objective was to reduce device related neuroinflammation for a period of about 30-180 days, a PLGA-based sustained release coating was prepared. Even though the copolymer composition, and the drug content in the PLGA coating have to be optimized based on the in vivo results, an initial composition of PLA/PGA:80 /20 was chosen, with an overall molecular weight of ~110,000 g/mol. Initially, the stability of the parylene-PLGA interface was tested by depositing a PLGA coating on parylene, using methylene chloride as solvent. The PLGA-coated parylene device was immersed in deionized water for more than 30 days. The coating was very stable. Preliminary results retinal implants in rabbits (over a 30 day period) did not show any delamination of PLGA coating from Parylene. In vitro release studies suggested that the release profile was nearly linear, with a drug release of ~0.2 microg/day, as desired based on in vivo results. We hypothesized that drug-eluting polymer coating would allow the local release of neuroprotectants from the electrode would enhance the tissue interface and potentially improve the biocompatibility of a subretinal retinal prosthesis. To test this hypothesis, we developed a new model for the chronic subretinal implantation of polymer thin-film electrode arrays in rats. Using this model in albino Sprague-Dawley rats, we established four experimental groups. Group 1 received subretinal parylene thin-film electrodes, group 2 received PLGA-coated parylene devices, group 3 received parylene thin-film electrodes coated with PLGA-FA drug-eluting co-polymers, and group 4 served as an unoperated set of control animals. Subretinal devices remained in-situ for four weeks after implantation. At nine-weeks of age, the animals were euthanized for H&E retinal histology. Significant thinning of the outer and inner nuclear layers was observed in eyes that received uncoated subretinal parylene thin-films for four weeks. Fluocinolone-releasing PLGA coated parylene implants were associated with preserved numbers of outer and inner nuclear layer cells, demonstrating a neuroprotective effect and improved biocompatibility over uncoated parylene. Of note, inactive PLGA-coated parylene devices were not associated with more accelerated retinal cell-loss as compared to uncoated subretinal parylene devices, alone. Preliminary results show that FA-releasing PLGA enhanced the biocompatibility of the implants significantly. The composition and the thickness of the coating are being optimized based on the in vivo results.
For sustained intravitreal delivery of FA, PAMAM-G4-OH dendrimer-FA conjugates have been synthesized using protocols previously established in our group. Conjugates containing approximately four FA molecules/dendrimer have been synthesized. These will be delivered intravitreously for enhanced cellular uptake and sustained release.