Date of Award

Spring 2021

Document Type

Open Access Dissertation

Department

Chemical Engineering

First Advisor

Robert Michael Gower

Abstract

Inflammatory diseases have a huge economic impact on the healthcare system. Incidence of obesity and muscle atrophy, two high profile inflammatory diseases, continues to increase. Anti-inflammatory agents are potential therapeutics for these diseases. Resveratrol is a polyphenol that has anti-inflammatory effects; however, resveratrol suffers from low bioavailability and hasn’t had impressive clinical results when delivered orally. Mannose is a monosaccharide that also has anti-inflammatory effects, however, effects are highest when mannose is presented on the surface of a support the size of a bacteria. Incorporation of resveratrol and mannose into biodegradable polymer microparticles could be a feasible approach to overcome these drawbacks for treating inflammatory diseases. The most commonly used polymer for FDA approved microparticle formulations is poly(lactide-co-glycolide) (PLG) and the most common fabrication technique is the oil in water (O/W) emulsion solvent extraction method. The objective of this work was to fabricate and optimize resveratrol-encapsulated and mannose-presenting PLG particles using the O/W emulsion solvent extraction method, and to study particle effects on cells involved in inflammation.

Here, we show resveratrol can be encapsulated in (PLG) microparticles to a high extent and particles decrease lipid load in adipocytes grown in culture. We found that incorporation of resveratrol in the particle formation process causes nonspherical morphology, which is notable because stable emulsions are known to form spheres. Nonspherical morphology was dependent primarily on resveratrol and cosolvent concentration and it was found that nonspherical morphology was unique to resveratrol among several stilbene small molecules. Nonspherical morphology of particles has been shown to have biological implications, and addition of resveratrol to oil in water emulsions could be a simple method for conveying nonspherical morphology to particles fabricated with an already FDA approved method.

Many bioactive agents, such as mannose, bind cell surface receptors, and PLG particles can act as a support for these agents to promote cell signaling. Mannose was attached to the surface of PLG microparticles using a novel process. We chemically modified poly(vinyl alcohol) (PVA) using isothiocyanate chemistry and used this PVA as the emulsifier in the fabrication system, which will spontaneously coat the surface of particles. Mannose presenting particles bound macrophages, colocalized with the mannose receptor and directed macrophages to secrete factors that led to increased myotube formation, a key step in muscle regeneration. This process can be used as a new method for achieving surface functionalization and for treating inflammatory diseases.

Taken together, this work demonstrates the versatility of PLG as an immune modifying material. This work also demonstrates a new method for tuning morphology of polymer particles using resveratrol in the O/W emulsions, and a new method for attaching surface ligands through modifying PVA. In addition to treating obesity and muscle atrophy, adding resveratrol to PLG particles for tuning morphology and using PVA for surface functionalization are innovations that could be easily implemented in already FDA approved formulations, and could have far-reaching applications in this growing sector of the pharmaceutical industry.

Rights

© 2021, Christopher Isely

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