Development of orthogonally crosslinked thiol-ene hydrogels for encapsulation of pancreatic beta-cells

<p>Type I diabetes mellitus (T1DM) is an autoimmune disease caused by auto-reactive T-cell-mediated destruction of insulin-producing β-cells. Effective encapsulation strategies can protect the transplanted islets from direct attack by host immune cells while maintaining insulin secretion. To achieve this goal, I have developed a hydrogel conformal coating using a visible light-mediated interfacial thiol-ene photopolymerization. Unlike conventional chain-growth visible light polymerizations, no additional cytotoxic co-initiator or co-monomer was required in thiol-ene gelation scheme for rapid gelation. More importantly, islets coated with thiol-ene gel maintained their viability and function <em>in vitro</em>. In addition to microencapsulate β-cells, the second objective of my dissertation focuses on developing a macroencapsulation technique using thiol-ene hydrogel with bioactivity and anti-inflammatory property. While islet transplantation holds potential in permanently reversing T1DM, this procedure initiates a cascade of inflammatory processes. To address this issue, we have developed thiol-ene hydrogel crosslinked by thiolated β-cyclodextrin (βCD). The conjugation of amphiphilic βCD affords enhanced loading and prolonged release of curcumin, an anti-inflammatory drug candidate but with poor water solubility. In addition, bioactive peptide such laminin-derived peptide flanked with two cysteine residues could be readily incorporated through orthogonal crosslinking, thus mimicking extracellular microenvironment in the pancreatic islets. Finally, in order to provide coated β-cells with an ideal biomechanical microenvironment, it is essential to identify a suitable gel stiffness to support the viability and functions of β-cells. To this end, a thiol-allylether hydrogel with on-demand tunable matrix stiffness was developed. Specifically, host molecule βCD was immobilized in the hydrogel network to provide binding sites for soluble guest molecule poly(ethylene glycol)-adamantane. Gel stiffness was tuned through introducing reversible host-guest interactions. After <em>in situ</em> stiffening of the cell-laden hydrogel, the encapsulated β-cells showed increased in insulin mRNA expression, suggesting the profound impact of matrix stiffness on pancreatic β-cell fate.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Engineering

Year

2016

Author dc:creator

• Shih, Han

Contributors dc:contributor

• Chien-Chi Lin
• Raghu Mirmira
• Alyssa Panitch
• Dong Xie

• Applied sciences
• Hydrogel
• Islets
• Macroencapsulation
• Microencapsulation
• Photopolymerization
• Thiol-ene
• Biomedical Engineering and Bioengineering

Repository record dc:identifier

https://docs.lib.purdue.edu/open_access_dissertations/846

OAI identifier oai:identifier

oai:docs.lib.purdue.edu:open_access_dissertations-2038