Degree Type

Dissertation

Date of Award

2017

Degree Name

Doctor of Philosophy

Department

Chemical and Biological Engineering

Major

Chemical Engineering

First Advisor

Kaitlin Bratlie

Abstract

Anti-inflammatory drugs can suppress or prevent chronic inflammation. However, uncontrolled application of anti-inflammatory drugs often impair the wound healing process. This can be overcome by combining hydrogel wound dressings with drug delivery systems to achieve stage-dependent drug release.

The pH of cutaneous wounds is dynamic and correlates with the stage of the wound healing process, with inflammation being acidic, granulation being progressively alkali, and remodeling returning skin to its pre-injury pH. By taking the advantage of this pH difference, stage-specific wound treatments can be developed to respond to these environmental cues using a pH sensitive hydrogel. In the first part of this study, pH sensitive methacrylated chitosan (MAC) hydrogels were synthesized and characterized through 1H NMR. Chitosan was first methacrylated and then crosslinked through three polymerization methods: step growth by thiol-ene photoclick reaction, chain growth by UV polymerization, and mixed model in which both step growth and chain growth mechanism were used. The resulting hydrogels exhibited adjustable mechanical properties, swelling ratios, and pH sensitivities without affecting degradation behavior and in vitro cell response. Cytocompatibility studies were performed using NIH/3T3 fibroblasts. Cell proliferation was suppressed when seeding on the hydrogel surfaces comparing to tissue culture plastic (TCP), yet no measurable cell death was observed.

With appropriate drug delivery systems, the responsivity of these gels to different pH environments may prove useful as stage-responsive wound dressings. However, the therapeutic effects of many modern drugs are limited owing to their low solubility and low half-life in circulation. Furthermore, there is a lack of design principles which adds the difficulty in synthesize efficacious drug carriers. The purpose of the second part of this study is to examine the relationship between drug delivery to cells and the chemical properties of the polymer micelle drug carriers.

Polyethylene glycol (PEG) based alternating copolymer poly[(polyoxyethylene)-oxy-5-hydroxyisophthalic] (Ppeg) with PEG molecular weights of 600 and 1000 were synthesized and modified with different alkanes to study the effects of altering the hydrophobic and hydrophilic chain lengths. NMR, critical micelle concentration (CMC), micelle size, and micelle zeta potential of the synthesized polymers were measured. The resulting polymer particles were able to form micelles in aqueous solution with CMCs lower than 0.04 wt%. Drug delivery studies were performed with a model hydrophobic drug, pyrene. Drug loading data showed the polymer particles were able to encapsulate pyrene and has a loading capacity up to 8 wt%. The sustain release ability was measured and the pyrene release was extended over 5 days. Both loading capacity and sustain release ability were found to be highly dependent on CMC. The micelles were exposed to RAW 264.7 cells to determine their cytocompatibility, Most Ppeg polymer micelles showed more than 85% cell viability with and without pyrene loading. Cell internalization of the micelles encapsulated drug was measured both quantitatively and qualitatively and was enhanced compared to unencapsulated drug. Predictive equations of drug loading, releasing, and internalization were obtained by factorial analysis as a function of PEG and alkane chain length. The results indicated that the internalization enhancement of polymer micelle was mainly affected by hydrophilic chain length; neither hydrophobic chain length nor loading capacity has significant influence on internalization.

Copyright Owner

Lida Zhu

Language

en

File Format

application/pdf

File Size

132 pages

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