MINIMALLY INVASIVE COPOLYMERS FOR POSTERIOR SEGMENT OCULAR THERAPEUTICS

Abstract

<p>Efficient delivery of therapeutic cell and pharmaceutical suspensions to the posterior segment of the eye remains an elusive goal. Delivery is made difficult by blood ocular barriers that separate the eye from systemic circulation, the compartmentalized structure of the eye that limits diffusion across the globe, and effective clearance mechanisms that result in short drug residence times. The work presented in this thesis focuses on the design, synthesis, evolution and refinement of novel biomaterial scaffolds ultimately intended to facilitate the minimally invasive delivery of therapeutic payloads into the posterior segment of the eye. The first generation materials presented in this work (Chapter 2) consist of linear chains of temperature-sensitive amine-terminated poly(N-isopropylacrylamide) (PNIPAAm) grafted onto the backbone of type I collagen. Second generation materials (Chapter 3) saw the inclusion of the lubricious polysaccharide, hyaluronic acid (HA), and replacement of the bulky collagen backbone, which was observed to impede scaffold gelation, with small cell adhesive RGD peptide sequences. The introduction of degradability was the emphasis of third generation copolymers (Chapter 4) and was achieved through copolymerization with dimethyl-γ-butyrolactone acrylate (DBA). The DBA lactone side group was found to undergo a hydrolysis dependent ring opening, which raises copolymer LCST above physiologic temperature, triggering the gelled scaffold to solubilize and be excreted from the body via renal filtration without the liberation of any degradation by-products. Degradation was found to occur slowly, which is favourable for long-term release scaffolds intended to decrease the frequency of injections required to maintain therapeutically relevant concentrations within the vitreous. Finally, the design of a fourth generation material is discussed (Chapter 5), in which optical transparency is achieved through copolymerization of third generation materials with polyethylene glycol (PEG) monomers of varying molecular weight. Synthesis, design and characterization of the various copolymers is described herein.</p>