Sustained release of immune modulating agents is a potential strategy to enhance the efficacy of immunotherapies compared to traditional bolus delivery strategies. However, methods for sustaining release often rely on implants composed of materials that remain in the body over an extended period, often permanently, and remain susceptible to a pathogenic foreign body response (FBR). This body of work focuses on the design and validation of immune responsive degradable biomaterials to sustain release of immune modulating agents to facilitate drug delivery while mitigating the risk of an adverse FBR. This thesis focuses on harnessing the innate immune cell response to biomaterials through systematic studies assessing degradation and release of encapsulated agents. To this end, the development of a cell-permissive macroporous hyaluronic acid (HA)-based scaffold, termed HA cryogel, is reported. HA cryogels were formed by rapidly freezing an aqueous solution containing crosslinkable polymers. The resulting scaffold comprised interconnected pores which permitted stress dissipation during a minimally invasive deployment via an injection. Immunophenotypic characterization of innate immune cells infiltrating HA cryogels post-injection revealed that degradation is primarily mediated by neutrophils, which are early participants in the foreign body response. In mice modeling transient or chronic immune deficiency HA cryogel degradation was significantly delayed or altogether absent. The cell-responsive behavior of HA cryogels was leveraged to enhance immune reconstitution in post-hematopoietic stem cell transplanted mice through sustained release of granulocyte colony stimulating factor. The utility of HA cryogels was further validated in sustaining the release of vaccine components to enhance immunity in mouse models of immune deficiency and cancer. In a melanoma mouse model, the HA cryogel-based vaccine enhanced the antigen-specific adaptive immunity compared to bolus vaccination and induced robust prophylactic and therapeutic protection. In sum, this body of work provides a path for the development and validation of biodegradable materials as a therapeutic delivery modality that mediates sustained release of immune modulating agents.

Chronic autoimmune disorders collectively affect 5-7% of the global population and are a major public health concern. The prevailing paradigm for autoimmune disease treatment relies on immunosuppression, which can be effective but leaves patients susceptible to opportunistic or serious infections and cancer. Moreover, these therapies are not designed to correct immune dysfunction that underlies autoimmunity. For those that continue to experience disease symptoms, there is an unmet need for therapies that operate via immunoregulation and avoid generalized immunosuppression. A key challenge is that unlike diseases with known etiology, the pathogenesis of autoimmune diseases can be complex. However, a common feature involves hyperactivated immune cells that, left unchecked, can lead to permanent damage of healthy tissue. To this end, a key defect arises from a loss in the number and function of autoimmune-protective cells called regulatory T cells (Treg) that normally prevent immune responses against one’s own cells and tissues. The premise of this dissertation is that enhancing Treg can be harnessed to promote disease-specific immunoregulation without causing generalized immunosuppression. To test the premise, the work reported herein describes the development and applications of biomaterial-based disease modifying agents. Three methods are described. The first method described used an immunomodulatory nanocomplex formulation that differentially modulated immune cell metabolism to enhance Treg over inflammatory T cells. A kinetic model describing Treg enhancement confirmed a strong dependence on the initial T cell population. The second and third methods described demonstrated that the epigenetic modulation of immune cells can strongly influenced the immunophenotypic trajectories of T cells that favor a Treg phenotype. Further, the formulation of a novel sustained biomaterial designed to locally enhance Treg via epigenetic modulation and its application in a model of inflammatory arthritis is reported. Overall, this work paves the way for the systematic design and validation of immunoregulatory biomaterials for the treatment of autoimmune disorders.

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