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Immune checkpoint-presenting granular hydrogels for T cell immune modulation
Dissertation

Immune checkpoint-presenting granular hydrogels for T cell immune modulation

Kenneth Min Kim
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2026
DOI:
https://doi.org/10.17918/00011341
pdf
Kim_Kenneth_20264.16 MB
PDF Embargoed Access, Embargo ends: 31 May 2028

Abstract

Autoimmune diseases Biomaterials Hydrogels Immune checkpoints Immune engineering Immune modulation Microbiology
Autoimmunity arises from the breakdown of immune tolerance, precipitating chronic inflammation and tissue damage. Current therapies rely on systemic immunosuppression, which can alleviate symptoms but can result in severe adverse drug reactions (infection, cancer). There remains a need for strategies that restore immunoregulation while minimizing adverse systemic effects; local biomaterial-based approaches for sustained immunomodulation are a promising alternative. Many autoimmune diseases, including psoriasis, are characterized by reduced regulatory T cell (Treg) populations and increased pro-inflammatory T cell responses. While Treg-based therapies (adoptive transfer, in vivo induction) have shown potential, they are limited by phenotypic-instability, lack of targeted delivery, and off-target biodistribution. This dissertation investigates an alternative strategy to locally promote immunoregulation through sustained checkpoint ligand presentation using injectable hydrogels. Granular hydrogels were engineered to present the novel immune checkpoint ligand B7x. This platform exhibits shear-thinning and self-healing properties for local delivery, supports bio-orthogonal conjugation of azide-modified B7x (B7x-Az), provides a porous microstructure that enables immune cell infiltration, and enables potential co-delivery of disease-specific antigens. In vitro, B7x-Az retained Treg-inducing function. Intravital near-IR imaging demonstrated that B7x-conjugated hydrogel (Gel-B7x-Az) exhibited enhanced initial checkpoint retention and persistence compared with soluble B7x (>28 days). In a murine psoriasis model, Gel-B7x-Az elevated Treg populations, reduced [gamma][delta]T17/Th17 populations, and ameliorated clinical measures of disease severity. Collectively, this work demonstrates that checkpoint-functionalized biomaterials can locally modulate immune responses to suppress inflammation. This platform is amenable to diverse immune checkpoints and co-delivery of soluble factors, offering broad therapeutic potential for autoimmune diseases, organ rejection, and tissue repair.

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