Live imaging the Foreign Body Response reveals how dampening inflammation reduces fibrosis

Abstract

Implanting biomaterials such as surgical sutures leads to wound inflammation and a Foreign Body Response (FBR), which can result in scarring and ultimately biomaterial rejection. To investigate the cell and signalling events that underlie FBR, we use live imaging of zebrafish reporter lines to observe how inflammation and angiogenesis differ between a healthy acute wound versus suture implantation. We observe inflammation extending from the suture margins and correlates with subsequent avascular and fibrotic encapsulation zones: sutures that induce more inflammation result in increased zones of avascularity and fibrosis. Moreover, we capture macrophages as they fuse to become multinucleate foreign body giant cells (FBGCs) adjacent to the most pro-inflammatory sutures. Both genetic and pharmacological dampening of the inflammatory response minimises the FBR (including FBGC generation) and normalises the status of the tissue surrounding these sutures. This new model of FBR in adult zebrafish allows us, for the first time, to live image the process and to modulate it in ways that may lead us towards new strategies to ameliorate and circumvent FBR in humans.