Date of Completion

3-8-2016

Embargo Period

3-8-2017

Keywords

PLGA, microsphere, polymer blends, coating, glucose sensor, DoE, long-term, foreign body reaction, degradation mechanism, pore formation, swelling

Major Advisor

Diane J. Burgess

Associate Advisor

Fotios Papadimitrakopoulos

Associate Advisor

Bodhisattwa Chaudhuri

Associate Advisor

Xiuling Lu

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

This work focuses on the development of poly (lactic-co-glycolic acid) (PLGA) microsphere/polyvinyl alcohol (PVA) hydrogel composite coatings to permit long-term glucose sensor functionality. Two aspects were addressed: 1) prevention of the foreign body reaction (FBR) for 6 months; and 2) investigation of the long-term effects of such coatings on glucose transport.

PLGA microspheres were prepared via blending low (RG503H, 25 kDa) and high (DLG7E, 113 kDa) molecular weight (MW) polymers. “Real-time” in vitro studies demonstrated that the dexamethasone release profiles were dependent on the polymer ratios. The duration of drug release lasted for approximately 2-6 months with varied burst release and lag phase. A discriminatory accelerated in vitro release method was developed to shorten drug release from 6 months to less than 2 weeks. One formulation exhibited continuous dexamethasone release in vitro as well as in vivo efficacy for 4.5 months.

A central composite design was applied to generate predictive mathematical models of drug loading and burst release to facilitate optimization of microsphere composition. The optimized composition for long-term drug release with suitable burst release and drug loading was DLG7E/RG503H/dexamethasone = 21/4/5 (w/w/w). The optimized microspheres showed continuous dexamethasone release in vitro and anti-FBR for 6 months. It was also determined that the released dexamethasone was stable for the entire 6-month period. Through analysis of an

in vitro drug release heat map together with the in vivo histological data, it was determined that the coatings should release approximately 0.1 µg dexamethasone per mg daily in order to counter chronic inflammation in rats.

To evaluate the effect of microsphere degradation in the coatings on glucose transport, two types of coatings were prepared incorporating different types of microspheres (i.e. microspheres with/without a lag phase). The patterns of pore formation and microsphere swelling were evaluated for both coatings. The coating thickness increased as a result of microsphere swelling and this was considered to contribute to a decrease in glucose transport.

In conclusion, the long-term dexamethasone releasing coatings developed here as well as the understanding of microsphere degradation within the coatings will facilitate the application of such coatings for implantable glucose sensors.

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