UCLA

The immune system serves as a vital defense mechanism, protecting the body against exogenous pathogens and endogenous aberrations through a complex network of cells and signaling pathways. Many diseases arise as a consequence of imbalanced or ineffective immune responses. However, altering the immune system systematically can lead to a range of complications and negative outcomes. Thus, targeted and controlled modulation of the local immune cells and their responses is highly desirable, which minimizes side effects throughout the body and provide precision medicine with the lowest effective dose at local tissues. My thesis harnesses principles of immunoengineering, drug delivery and regenerative medicine to achieve local immune modulation via engineered microneedle patches (MNP) that enables minimally invasive tissue penetration and local retention. To address the critical role of destructive immune cells in tissue loss and achieve periodontal tissue regeneration, I engineered a modular MNP that allows a multistage and controlled release of antibiotics and cytokines. My work demonstrated that the dual delivery of antibiotics and cytokines modulated immune cells, promoted pro-regenerative signals locally, and reversed the degeneration of soft tissue and bone. I further simplified the formulation by identifying a bifunctional antibiotic that not only suppresses bacterial growth but also modulates the macrophages to suppress inflammation, and utilized a fast-degrading MNP loaded with biodegradable PLGA microparticles. Significant therapeutic effects, including suppression of pro-inflammatory cytokine secretion, induction of pro-regenerative cytokines and promotion of tissue/bone regeneration markers were observed in rat periodontitis model. In another application, to suppress the immunogenicity of viral vectors during in vivo gene delivery and boost gene transduction efficiency, I optimized a dissolvable MNP that maintains the virus integrity and releases immunomodulatory agents slowly via microparticles that can be integrated into MNP, and showed that local and slow release of immunosuppressants (i.e. dexamethasone) enhances gene transfer efficiency. Our results in mouse ischemia-reperfusion model demonstrated a significant increase of gene transduction efficiency in the heart. Overall, this work uses MNP as a drug delivery strategy for its minimal invasiveness, local penetration, sustained release and controlled delivery. It reveals the feasibility and efficacy to locally modulate immune responses for more efficient tissue regeneration and gene therapy.