Age and sex differences in the immune response to synthetic materials

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Project Summary The WHO estimates that 1 in 6 people will be 60 years or older by 2030. A hallmark of aging is the immunological changes that increase susceptibility of this population to inflammatory age-related diseases, hinder response to infections and vaccines, and lower regenerative capacity. Synthetic biomaterials are used in multiple ways including drug delivery, vaccines, prosthetics, and scaffolds in tissue engineering to promote tissue regeneration. The immune system is the first responder to any injury and implants, and it directs the foreign body reaction (FBR) to these materials—for synthetic materials it is often proinflammatory and leads to scarring. This immune response is not only dependent on the material itself but both the tissue location and underlying pathophysiology (patient’s demographic background and health) of the implant site. Thus, the concept of “biocompatibility” is dependent on the current state of the host immune system which is significantly influenced by the host’s age and sex. With an aging population there is a critical need to understand how the age-specific proinflammatory skewed immune system alters the immune response to synthetic material implants. The goal of this proposed work is to identify key biologic factors in the immune system and target these with immunomodulatory synthetic materials for use in the aging population for tissue regeneration. The overarching hypothesis is that the aged immune dysregulation towards an effector state compounds the adverse reaction to synthetic materials. Using a previously described pro-fibrotic scaffold in a chronic non- healing wound mouse model, combined with sequencing techniques, and phenotypic analysis, the experiments in the K99 phase will elucidate the cell-cell communication networks in the aged FBR (Aim 1) as well as the innate and adaptive immune shifts in response to synthetic materials over lifespan by sex (Aim 2). During the independent research phase (R00), we will engineer multi-stage synthetic material systems to control the dysregulated aged immune response in tissue engineering. Developing new immunomodulatory biomaterials is critical to addressing the FBR to reduce unwanted implant related complications. Completion of this research will provide training opportunities to master new technical approaches that will prepare the candidate to become a primary investigator at a top-tier research institution studying the interface of the immune control of wound healing and aging to synthetic biomaterial-based therapies.