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Title

SYNTHESIS AND EVALUATION OF STABILIZED ALGINATE MICROBEADS

Creator

Soma, Sami Isaac

Date

2018, 2018-05

Description

Alginate hydrogels have been investigated for a broad variety of medical applications. The ability to assemble hydrogels at neutral pH and...
Show moreAlginate hydrogels have been investigated for a broad variety of medical applications. The ability to assemble hydrogels at neutral pH and mild temperatures makes alginate a popular choice for the encapsulation and delivery of cells and proteins. Alginate has been studied extensively for the delivery of islets as a treatment for type 1 diabetes. However, stability of the encapsulation systems after implantation remains a challenge. The broad goal of this proposal was to develop and investigate methods for enhancing the stability of alginate-based encapsulation systems. First, a method was developed to create dual crosslinked alginate microbeads. Alginate was modified with 2-aminoethyl methacrylate hydrochloride (AEMA) to introduce groups that can be photoactivated to generate covalent bonds. This enabled formation of dual crosslinked structure upon exposure to ultraviolet light following initial ionic crosslinking into bead structures. The degree of methacrylation was varied and in vitro stability, long term swelling, and cell viability examined. At low levels of methacrylation, the beads could be formed by first ionic crosslinking followed by exposure to ultraviolet light to generate covalent bonds. The methacrylated alginate resulted in more stable beads and cells were viable following encapsulation. Alginate microbeads, ionic (unmodified) and dual crosslinked, were implanted into a rat omentum pouch model. Implantation was performed with a local injection of Lipopolysaccharide (LPS) to stimulate a robust in inflammatory challenge in vivo. Implants were retrieved at 1 and 3 weeks for analysis. The unmodified alginate microbeads had all failed by week 1, whereas the dual-crosslinked alginate microbeads remained stable up through 3 weeks. The modified alginate microbeads may provide a more stable alternative to current alginate-based systems for cell encapsulation. In the next set of studies, multilayered alginate microbeads (Alginate-Poly-l-ornithine-Alginate (APA)) were investigated for cell encapsulation. The APA microbeads were generated with a thick outer alginate layer that is present in order to reduce inflammation post implantation. The dual crosslinking approach was applied to the outer layer APA microbeads. Dual crosslinked outer layer multilayered alginate microbeads remained intact in presence of chelating agents. APA alginate microbeads, ionic (unmodified) and dual crosslinked were tested using omentum pouch model with local injection of LPS. Dual crosslinked microbeads remained intact up to three weeks without significant change in outer layer size. In conclusion, alginate was modified with methacrylate groups to enhance stability when subjected to an inflammatory challenge. APA microbeads with methacrylated outer layer hold a great potential for cell encapsulation therapies.
Ph.D. in Biomedical Engineering, May 2018
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