Date of Completion

2-10-2015

Embargo Period

2-5-2015

Keywords

Biocompatibility; Biosensors; PLGA; Large Animal Models; Biomarkers

Major Advisor

Diane J. Burgess

Associate Advisor

Fotios Papadimitrakopoulos

Associate Advisor

Xiuling Lu

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

The present dissertation focuses and expands on the optimization and application of poly(lactic-co-glycolic acid) (PLGA)/polyvinyl alcohol (PVA) composite coatings and initiates metabolic studies in small animals to identify novel biomarkers to be utilized in exhaustion prediction. The composites are used to coat implantable biosensors and improve their biocompatibility. The objectives of the work are: i) investigate species differences related to the foreign body reaction (FBR) between small and large animals; ii) develop composite coatings to prevent the FBR in large animals; iii) develop composites loaded with combinations of dexamethasone, vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) to promote angiogenesis around implanted biosensors; and iv) apply multi-analyte monitoring to exhaustion prediction. The onset and severity of fibrosis was identified as a key difference between minipigs and rats, with minipigs demonstrating earlier onset and more severe chronic inflammation. In order to counter this, dexamethasone release must be continuous, with no lag phase. The effective dexamethasone dosing regime was 100 μg during the first day and 10 μg/day thereafter. A novel method for the preparation of microspheres containing insoluble drugs was developed to achieve homogeneous drug distribution, high loading and low burst release. Dexamethasone microspheres prepared by this method were utilized in microsphere/hydrogel composite coatings which successfully prevented FBR in a large animal model for a period of one month. Combinations of dexamethasone, VEGF and PDGF were investigated for the first time to prevent FBR and promote angiogenesis. It was determined that VEGF has to be delivered at higher doses than PDGF and an increase in dexamethasone must be accompanied by proportional increase in growth factors. An array of biomarkers that can be used in exhaustion prediction was successfully identified, with prediction times ranging from 10 to 20 minutes in normal as well as type 1 diabetic rats. It was discovered that multi-analyte biomarkers based on glucose and lactate are far more responsive in the subcutaneous tissue (an implantation-friendly compartment) than in the blood. In conclusion, the outcomes of this work contribute to the advancement biomaterials, as well as applications in exercise physiology.

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