Designing supramolecular delivery strategies to understand and exploit synergies in immunoregenerative medicine

ABSTRACT It remains unclear why some tissue injuries regenerate and heal while others fibrose and scar. It is evident, however, that the inflammatory response underlies these divergent outcomes. This immune system’s response to injury depends on a multitude of cell types and organ systems that remain in communication to evolve collectively, guiding tissue-level outcomes. My lab’s expertise is in the design of local drug delivery systems for immune modulation. We will leverage these delivery platforms to explore immune systems interactions after local therapeutic delivery, with applications toward tissue healing and arresting inflammatory disease progression. Theme 1: How does cell-targeted delivery of therapeutics alter monocyte & macrophage crosstalk? Macrophages are a primary component of the innate immune system, acting as first-responders to injury and initiating the activation of other cell types – including their replacement by monocyte precursors recruited from the bone marrow. Promoting a pro-regenerative macrophage phenotype is a promising therapeutic avenue under widespread investigation. However, little is known about how macrophage polarization alters monocyte recruitment and differentiation. This project area builds on my experience in therapeutic macrophage polarization to develop cell-targeted therapeutics that promote a pro-healing macrophage phenotype at the injury site, exploring the hypothesis that altered monocyte recruitment and differentiation, not the long-lasting generation of pro-healing macrophages, is the critical axis supporting an immunoregenerative response. Theme 2: How does the promotion of early post-injury inflammation alter adaptive immune response? The magnitude and temporal sequence of cell signals, including chemokines and cytokines, is a critical regulator of cell migration, differentiation, and polarization; these processes guide evolution of the injury immune microenvironment and resulting tissue-level outcomes. It has been recently observed that exogenous delivery of inflammatory signaling promotes tissue healing after ischemic injury. Here, we will explore the hypothesis that beneficial effects result from the recruitment and differentiation of regulatory T cells by macrophage-derived signals, which can be re- capitulated by sequential biomolecule release from injectable hydrogels. If successful, this project will elucidate new design principles for guiding the injury immune microenvironment toward a functional orientation that supports tissue healing. Theme 3: Can remote drug delivery systems modulate damaging systemic inflammation? A sequela of dysregulated systemic inflammation often results from significant tissue insults (heart attack, kidney injury) or chronic inflammatory disease (inflammatory bowel, rheumatoid arthritis). Such insults are associated with deleterious multi-organ effects, including renal and pulmonary fibrosis, atherosclerosis, and heart failure. This area of research explores the capacity to develop refillable drug reservoirs for delivering immunomodulatory drugs to distant immune organs, thereby modulating inflammation at the primary cell sources.