Development of orthogonally crosslinked thiol-ene hydrogels for encapsulation of pancreatic β-cells
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 in vitro. 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 in situ 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.
Lin, Purdue University.
Off-Campus Purdue Users:
To access this dissertation, please log in to our