Inhibition of biomaterial‐induced complement activation attenuates the inflammatory host response to implantation

Abstract

Although complement is a known contributor to biomaterial-induced complications, pathological implications and therapeutic options remain to be explored. Here we investigated the involvement of complement in the inflammatory response to polypropylene meshes commonly used for hernia repair. In vitro assays revealed deposition of complement activation fragments on the mesh after incubation in plasma. Moreover, significant mesh-induced complement and granulocyte activation was observed in plasma and leukocyte preparations, respectively. Pretreatment of plasma with the complement inhibitor compstatin reduced opsonization >2-fold, and compstatin and a C5a receptor antagonist (C5aRa) impaired granulocyte activation by 50 and 67%, respectively. We established a clinically relevant mouse model of implantation and could confirm deposition of C3 activation fragments on mesh implants in vivo using immunofluorescence. In meshes extracted after subcutaneous or peritoneal implantation, the amount of immune cell infiltrate in mice deficient in key complement components (C3, C5aR), or treated with C5aRa, was approximately half of that observed in wild-type littermates or mice treated with inactive C5aRa, respectively. Our data suggest that implantation of a widely used surgical mesh triggers the formation of an inflammatory cell microenvironment at the implant site through complement activation, and indicates a path for the therapeutic modulation of implant-related complications.

Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters

“…Compstatin analogs have proven to be attractive options for treating complement-related disorders such as sepsis, periodontitis, transplantation, age-related macular degeneration, paroxysmal nocturnal hemoglobinuria, and biomaterial-induced inflammation (Silasi-Mansat et al, 2010; Maekawa et al, 2014; Risitano et al, 2014; Kourtzelis et al, 2013; Chi et al, 2010; Fiane et al, 1999). Considering the prevalence of ESRD and the high frequency and cost of its treatment, any added therapeutic must be cost-effective.…”

Alginate microsphere compositions dictate different mechanisms of complement activation with consequences for cytokine release and leukocyte activation

“…The lack of ability to predict the cell adhesion for Ca/Ba microbeads indicates that other mechanisms could in addition be involved in inducing the cell adhesion. By inhibiting complement C3 or C5aR, the amount of immune cell infiltrated into the implanted meshes was half of that observed for wild-type littermates [11] pointing to complement as an important contributor to the observed immune response. Since the lepirudin whole blood model uniquely allows the interplay between the complement system and the…”

“…4 meshes [11]. The complement system consists of a cascade of serine proteases acting in sequence, initiated through three different pathways: the classical pathway, the lectin pathway, and the alternative pathway.…”

Delivery of therapeutic peptides from thermoplastic polyurethane films

“…It is a 74 amino acid protein fragment, and is reported to interact with two receptors, the G-protein coupled C5a receptor (C5aR, CD88) and the non-G-protein coupled C5a receptor-like 2 receptor (C5L2) (Kohl 2006. Studies have shown that C5aR signalling played an important role in biomaterial-induced complement activation (Kourtzelis, Rafail et al 2013). C5a interacts with the C5a receptor on polymorphonuclear leukocytes, monocytes and mast cells, which can induce classical signaling and cause the release of pro-inflammatory cytokines and chemokines, such as TNF-α, IL-1 and IL-8 (Nilsson, Ekdahl et al 2007).…”

“…Because of the complement system acting as an important mediator of this inflammatory response, many studies emphasize the importance of developing complement compatible biomaterials to prevent adverse inflammatory reactions in vivo (Kourtzelis, Rafail et al 2012, Sokolov, Hellerud et al 2012. Therefore, we proposed that delivery of C5aR antagonists by thermoplastic polyurethanes may be an effective strategy to minimize biomaterial-induced complement-mediated inflammatory responses, which may further prolong the performance of the implanted devices.…”