Browsing by Author "Kim, Boram"

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    Immunomodulatory biomaterials to enable long-term delivery of cell-based therapeutics
    (2023-04-05) Kim, Boram; Veiseh, Omid
    Type 1 diabetes (T1D) is a chronic autoimmune disease that involves the destruction of pancreatic beta-cells. Islet transplantation, a promising treatment for T1D, is restricted by the requirement for lifelong systemic immunosuppression to prevent graft rejection. Encapsulation of transplanted therapeutic cells using selectively permeable physical barriers offers a possible solution, but preventing fibrosis triggered by inflammatory responses upon biomaterial implantation remains a crucial unmet need. The aim of this thesis is to devise innovative immuno-engineering approaches to modulate immune responses against encapsulated cells within alginate hydrogels. The first strategy involves the chemical modification of encapsulation materials. Novel alginates with triazole modification were synthesized based on a prior library of small molecule-conjugated alginate analogs. Cellular barcoding was used to screen these new biomaterials by encoding the identity of the material with a unique single-nucleotide polymorphism (SNP) profile designed from 20 different human umbilical vein endothelial cell (HUVEC) donors. The lead alginate displayed mitigated anti-fibrotic responses after xeno-transplantation. Human islets implanted in STZ-induced immunocompetent T1D mice were protected by encapsulating with the lead alginate and inhibiting immune cell recognitions, successfully reversing T1D levels to normal glycemia, maintained up to 80 days post-implantation. The second strategy involves the use of engineered cell lines that can serve as sentinels. These sentinel cells detect immune cells and regulate their responses, leading to efficient immunomodulation. Therapeutic efficacy and long-term survival were assessed by performing diabetic reversal studies with T1D mice. Local delivery of immunomodulating cytokine-releasing capsules combined with encapsulated human islets allowed efficient immunomodulation, prevented fibrosis around islets-capsules, and showed long-term glycemic control in the diabetic mouse model. Lastly, we developed a reliable in vivo screening method using live fluorescence imaging to assess the vascularization within biomaterials, which is critical for the long-term survival and function of transplanted cells. By leveraging the IVIS fluorescence probe, we could test various materials in parallel with longitudinal resolutions and cost-effective ways. Taken together, these novel approaches to modulating immune responses have substantial potential for clinical translation in improving the performance of encapsulated cell-based therapeutics, particularly for the treatment of T1D patients. The proposed strategies may overcome the limitations of islet transplantation by providing a long-term solution for glycemic control without the need for systemic immunosuppression.