The foreign body reaction is the body's defense mechanism against the intrusion of foreign objects. Unfortunately, it is also responsible for inhibiting the therapeutic functions of long-term implanted medical devices. Despite significant research to understand its precise mechanism of action, relatively few biomaterials that abrogate the foreign body reaction are available. In this work, the mouse subcutaneous implant model is used to study cell signaling at the site of implanted sphere-templated porous hydrogels. These materials undergo improved healing compared to other biomaterials by causing increased vascularization and reduced fibrosis. The goal of this research was to use sphere-templated porous hydrogels to determine the underlying cell signaling events that lead to improved healing in the foreign body reaction.;Macrophages are the immune cell thought to coordinate the foreign body reaction, and macrophage polarity refers to the activation state of macrophages where M1 is pro-inflammatory and M2 is pro-healing. This study shows that macrophages become polarized at porous implant sites based on the location of the cells. Specifically, macrophages increase expression of M1 markers and decrease expression of M2 markers when in the pores of these implants compared to macrophages in the surrounding foreign body capsule. This polarization was enhanced when the pore size of the implant was optimized to improve healing. In vitro studies supported a model in which M1 cells in implant pores inhibit fibrosis.;Finally, the underlying cell signaling pathways in the foreign body reaction were explored. Activation of Wnt/beta-catenin signaling in macrophages within porous implants was found, leading to the additional finding that these macrophages are positive for the myofibroblast marker a-smooth muscle actin. Well-documented Wnt signaling in macrophages is rare, and these signaling events may indicate fundamental shifts in the biology of those cells due to porous implants. Overall, this research provides an improved understanding of macrophage cell signaling in the foreign body reaction and contributes towards the goal of improving medical device design.
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