Controlled Release of M2-derived Macrophage Signals to Investigate Role in Foreign Body Response

摘要

Statement of Purpose: Macrophages, the primary cell of the immune response, and fibroblasts, the major producers of extracellular matrix (ECM), have significant roles in wound healing and the foreign body response to implanted biomaterials. Macrophages are highly dynamic cells that exhibit a spectrum of phenotypes, including Ml (stimulated with pro-inflammatory signals like lipopolysaccharide), M2a (stimulated with Th2 cytokines like interleukin-4 (IL4)). Temporal control of macrophage phenotype from M1 to M2a has been shown to be critical in normal wound healing in vivo. Both. M1 and M2a macrophages have been found in the fibrous capsule (Veiseh et al. (2015) Nat Mater 14:643), but the optimal spatial and temporal control of these cells to promote or reduce the foreign body response remains unclear. Additionally, M2a macrophages have been associated with reduced fibrous capsule formation around implanted biomaterials (Hachim, et al. (2017) Biomaterials 112:95) but strongly implicated in fibrosis (Knipper et al. (2015) Immunity 43:803). Therefore, we hypothesized that M2a macrophages play a role in depositing ECM through modulating fibroblast activity. To test this hypothesis, we investigated the effects of macrophage-secreted signals on fibroblast behavior and matrix formation in vitro and developed an M2a-promoting hydrogel to probe the role of M2a in the foreign body response.