The foreign body response (FBR) represents a major challenge in the application and clinical success of current
and future biomaterial-based treatments of musculoskeletal injuries and diseases. While macrophages are
known to orchestrate the FBR, a therapeutic synthetic-based biomaterial that effectively targets macrophages
and evades fibrous encapsulation has yet to be developed. This exploratory project examines prostaglandin-E2
(PGE2) signaling as a potential target to prevent the FBR. PGE2 with its four receptors (EP1-EP4) is an important
modulator of inflammation that also affects fibrosis in a range of diseases. Studies have shown that macrophages
synthesize PGE2 in response to an inflammatory stimulus and, through EP2 and EP4, PGE2 limits the severity
of fibrosis. However, PGE2 signaling is complex. While EP2 and EP4 have been shown to attenuate inflammation
EP1 and EP3 potentiate inflammation. An alternative strategy to using PGE2 as a therapeutic is to target the
receptors, EP2 or EP4. In the context of the FBR, the role of EP2 and EP4 has yet to be identified. To this end,
this research tests the hypotheses that a) macrophages limit the severity of the FBR through autocrine and
paracrine signaling via activation of EP2 and EP4 and b) if EP2 is targeted in a biomaterial strategy at the onset
of the FBR, it is possible to abrogate the FBR and prevent fibrous encapsulation. For the latter, we chose to
target EP2 over EP4 for several reasons. EP4 requires internalization to induce signaling, while EP2 does not.
EP4 signaling is more complex, leading to crosstalk that affects pathways not involved in inflammation. Two
specific aims were developed for the proposed project. Specific aim #1 will identify the roles of EP2 and EP4
on macrophages in limiting the FBR. This aim tests the hypothesis that inhibiting either EP2 or EP4 signaling
in macrophages enhances the FBR by sustaining inflammation, which leads to an increase in the number and
size of foreign body giant cells and a thicker fibrous capsule. In this aim, we will develop mouse conditional
knockout models for EP2 and EP4 in macrophages and perform in vitro and in vivo studies to examine the role
of each receptor in inflammatory macrophage activation, macrophage fusion, and fibrous encapsulation.
Specific aim #2 will develop a biomaterial strategy that targets EP2 and assess its ability to suppress the
FBR. This aim tests the hypothesis that activating the EP2 receptor via a selective agonist that is immobilized
on the surface of biomaterial implants inhibits fibrous encapsulation. In this aim, we propose to covalently attach
an EP2 agonist to the biomaterial surface and assess inflammatory macrophage activation, macrophage fusion
and fibrous encapsulation in vitro and in vivo in wild-type mice. At the conclusion of this exploratory project, we
expect to have a better understanding of how macrophages control and limit the FBR. From a translational
perspective, we expect that targeting EP2 will induce immunosuppressive actions in macrophages and in turn
reduce FBGC formation and prevent fibrous encapsulation. This will lay the foundation to investigate new
medical devices and their function when fibrous encapsulation can be evaded.
