Biomaterial technologies to train innate immunity

The National Institute of Allergy and Infectious Diseases (NIAID) awarded the Regents of the University of Michigan a $425,226 Project Grant under the Allergy and Infectious Diseases Research program (CFDA 93.855) on June 25, 2025, with a completion date of May 31, 2027. This research project investigates the engineering of trained innate immunity using biomaterial implants to establish feasibility and control systemic immune responses. The primary deliverables include the development and fabrication of macroporous scaffolds from poly(lactide-co-glycolide) with tunable degradation rates and pore sizes, implantation studies in mice models, and comprehensive immunological assessments. The research will produce data on how scaffold characteristics influence innate immune training and will establish the specific aspects of the foreign body response necessary for inducing desired immune phenotypes through bone marrow transplant studies, cell depletion analyses, and single-cell transcriptomic characterization.

The project addresses a significant gap in biomedical research by developing practical methodologies to engineer trained innate immunity toward desired therapeutic outcomes, with potential applications in controlling pathological inflammatory responses. Research outputs will include scientific publications, isolated immune cell profiles, and mechanistic insights into immune cell recruitment and lineage-specific contributions to scaffold-mediated immunity training. This research is conducted at the University of Michigan in Michigan, USA, leveraging the institution's extensive research infrastructure and expertise in biomaterials and immunological investigations.

Abstract

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.