Brett Thomes

Graduation Semester and Year

2006

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering

Department

Bioengineering

First Advisor

Liping Tang

Abstract

Posterior capsule opacification (PCO) is a major complication associated with the implantation of intraocular lens (IOLs). Evidence suggests that PCO formation is caused by abnormal lens epithelial cell (LEC) migration/proliferation. We hypothesize that pharmacologic agents must target inflammatory cells in addition to LECs to inhibit PCO formation. To successfully target both inflammatory cells and LECs, a novel intraocular drug delivery system (DDS) was developed for implantation in the lens capsular bag. Such a system permits direct delivery of anti-inflammatory and anti-proliferative drugs in the lens capsule for extended periods of time resulting in reduced PCO formation. A lubricious polyurethane coating was selected as the drug delivery platform for this study based on a series of tests including lubricity, adhesion, leachable, stability, toxicity, and biocompatibility testing. In vitro studies were used to identify specific drugs that were capable of inhibiting inflammatory cell activation, LEC migration, and/or LEC proliferation at low concentrations (<0.01 mg/mL), including diclofenac (DI), colchicine (COL), mitomycin-C (MMC), 5-fluorouracil (5-FU), RGD-peptide, dexamethasone, and heparin (HEP). Results also demonstrated that these drugs were released from the coating at minimum effective levels past 10 days by varying coating properties. In vivo studies (New Zealand white rabbit) demonstrated that the intraocular DDS using single drug and drug combinations including DI, COL, and MMC reduced IOL-associated foreign body reactions. Histological analysis provided evidence that cell adhesion to the IOL was significantly reduced compared to the control IOL. Histology also showed the effects of various drugs on ocular tissue and verified that optimal concentrations for each drug exist. When concentrations were not optimal, cellular responses were uninhibited and other side effects occurred including chronic inflammation. Within the scope of this study, DI, COL, and MMC demonstrated the ability to inhibit inflammation and LEC migration/proliferation at low concentrations in vitro and in a rabbit model. The intraocular DDS demonstrated that it was capable of releasing drugs for prolonged periods of time and effectively reduced IOL-associated foreign body reactions and subsequent PCO formation processes.

Disciplines

Biomedical Engineering and Bioengineering | Engineering

Comments

Degree granted by The University of Texas at Arlington

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