Biomaterial technologies to train innate immunity

PROJECT SUMMARY Persistent inflammation can lead to trained innate immunity, or alterations in the innate immune response to future stimuli. Trained innate immunity has a wide variety of practical consequences both protective and deleterious. Despite the widely recognized impact on host immune response, very little effort has been put forth towards engineering trained innate immunity towards a desired phenotype. The goal of this study is to therefore establish the feasibility of engineering trained innate immunity using biomaterial implants. All implanted biomaterials elicit some degree of foreign body response that mimics the pathological conditions that lead to trained innate immunity and thus provides a potential avenue towards engineering this response. We have previously observed practical, long-lasting changes in the innate immune response to toll-like receptor stimulation using an implanted poly(ε-caprolactone) scaffold, thus supporting the hypothesis that this type of technology is a viable means of controlling the systemic innate immune response. We therefore plan to investigate two foundational aspects of scaffold-mediated trained innate immunity. Our first aim will focus on the effects of pore size and degradation time on innate immune training. We will fabricate macroporous scaffolds from poly(lactide-co-glycolide) with tunable degradation and pore size, implant these scaffolds into mice, and monitor innate immune phentoype through isolation of immune cells or induction of periodontitis. Our second aim will establish the aspects of the foreign body response necessary for innate immune training. Bone marrow transplants will determine the effects of immune cell recruitment to the scaffold on training, while cell type depletion and single cell transcriptomics will determine the impact of individual cell lineages on scaffold-mediated innate immune training.