In this dissertation, we develop an injectable polymer system to enable localized and prolonged release of therapeutic biomolecules for... Show moreIn this dissertation, we develop an injectable polymer system to enable localized and prolonged release of therapeutic biomolecules for improved treatment of Age-Related Macular Degeneration (AMD). Thermo-responsive hydrogels derived from N-isopropylacrylamide (NIPAAm) and cross-linked with poly(ethylene glycol) (PEG) poly(L-Lactic acid) (PLLA) copolymer were synthesized via free-radical polymerization. These materials were investigated for (a) phase change behavior, (b) in-vitro degradation, (c) capacity for controlled drug delivery, and (d) biocompatibility. The volume-phase transition temperature (VPTT) of the PNIPAAm-co-PEG- b-PLLA hydrogels was adjusted using hydrophilic and hydrophobic moieties so that it is ca. 33 C. These hydrogels did not initially show evidence of degradation at 37 C due to physical cross-links of collapsed PNIPAAm. Only after addition of glutathione chain transfer agents (CTA)s to the precursor did the collapsed hydrogels become fully soluble at at 37 C. CTAs signi cantly a ected the release kinetics of biomolecules; addition of 1.0 mg/mL glutathione to 3 mM cross-linker accelerated hydrogel degradation, resulting in 100 % release in less than 2 days. This work also explored the e ect of PEGylation in order to tether biomolecules to the polymer matrix. It was demonstrated that non-site-speci c PEGylation can postpone the burst release of solutes (up to 10 days in hydrogels with 0.5 mg/mL glutathione). Cell viability assays showed that at least two 20-minute bu er extraction steps were needed to remove cytotoxic elements from the hydrogels. Clinically-used therapeutic biomolecules Lucentis® and Avastin® were demonstrated to be both stable and bioactive after release form PNIPAAm-co-PEG-b-PLLA hydrogels. The thermo-responsive hydrogels presented here o er a promising platform for the localized delivery of proteins such as recombinant antibodies. Ph.D. in Chemical and Biological Engineering, May 2011 Show less
