Development of Paquinimod‐Loaded Implants to Modulate the Foreign Body Response

ABSTRACT The foreign body response (FBR) is an immune reaction from the host to any foreign material that makes it beyond barrier tissues, resulting in the recruitment of immune cells and fibroblasts. The FBR to medical implants can lead to degradation and encapsulation, affecting their efficacy, lifespan, and safety. A key protein involved in myriad inflammatory responses is S100A9, inducing inflammatory cytokine secretion and leukocyte chemotaxis. Inspired by recent studies indicating that inhibiting systemic S100A9 in mice results in a diminished FBR, we have identified S100A9 as a potential locally‐targetable molecule to reduce FBR. Paquinimod is a potential candidate for local drug delivery, as it is an experimentally available S100A9 inhibitor that has been investigated in autoimmunity and fibrotic disease. We first investigated paquinimod's effects on neutrophil and macrophage cell lines in vitro and found reduced inflammatory cytokine expression. To leverage these effects of paquinimod and assess its ability to mitigate the FBR, we created wet‐spun PCL fibrous scaffolds loaded with varied doses of paquinimod. With these scaffolds, we demonstrate successful loading and release of paquinimod, with higher loading leading to decreased cell invasion and reduced deposition of collagen. These findings suggest paquinimod‐mediated inhibition of S100A9 activity can modulate inflammation in the FBR through decreased cytokine release and cell recruitment and identify S100A9 as a promising target to locally mediate the FBR to medical implants.