Fucoidan alginate and sulfated alginate microbeads induce distinct coagulation, inflammatory and fibrotic responses

This study investigates the host response to fucoidan alginate microbeads in comparison to sulfated alginate microbeads, which are relevant for immune protection in cell therapy. While sulfated alginate microbeads reduce fibrosis and inflammation, fucoidan, a kelp-derived polysaccharide rich in sulfate groups, has not been evaluated in this context. The study assesses surface reactivity to acute-phase proteins and cytokines using <i>ex vivo</i> human whole blood and plasma models. It also examines pericapsular overgrowth (PFO) in C57BL/6JRj mice, incorporating protein pattern mapping through LC-MS/MS proteomics. Fucoidan alginate microbeads activated complement and coagulation, while both fucoidan and sulfated alginate microbeads induced plasmin activity. Fucoidan alginate microbeads exhibited a distinct cytokine profile, characterized by high levels of MCP-1, IL-8, IFN-γ, and reduced levels of RANTES, Eotaxin, PDGF-BB, TGF-β isoforms, along with higher PFO. The balance between plasmin activity and coagulation emerged as a potential predictor of fibrosis resistance, favouring sulfated alginate microbeads. Explanted materials were enriched with both complement and coagulation activators (Complement C1q and C3, Factor 12, Kallikrein, HMW-kininogen) and inhibitors (C1-inhibitor, Factor H, Factor I). Fucoidan alginate microbeads predominantly enriched extracellular matrix factors (Fibrinogen, Collagen, TGF-β, Bmp), while sulfated alginate microbeads favoured ECM-degrading proteases (Metalloproteases and Cathepsins). This study reveals significant differences in host responses to fucoidan and sulfated alginate in microbeads. The plasmin activity to coagulation ratio is highlighted as a key indicator of fibrosis resistance. Additionally, the preferential enrichment of ECM-degrading proteases on the material surface post-implantation proved to be another crucial factor.