Immune‐Informed Mucin Hydrogels Evade Fibrotic Foreign Body Response In Vivo

• Published in: Advanced functional materials Vol. 29; no. 46
• Main Authors: Yan, Hongji, Seignez, Cédric, Hjorth, Morgan, Winkeljann, Benjamin, Blakeley, Matthew, Lieleg, Oliver, Phillipson, Mia, Crouzier, Thomas
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc 01.11.2019
• Subjects: Alginates; B cells; Biological activity; Biomedical materials; Biopolymers; bovine submaxillary mucin; Crosslinking; Cytokines; Fibrosis; foreign body response; Gels; Gene expression; Growth factors; Hydrogels; Immune system; Implantation; Macrophages; Materials science; Mucus; Proteins; Surgical implants; TGF-beta 1; TGF‐β1; Transplants & implants
• ISSN: 1616-301X; 1616-3028; 1616-3028
• DOI: 10.1002/adfm.201902581

The immune‐mediated foreign body response to biomaterial implants can trigger the formation of insulating fibrotic capsules that can compromise implant function. To address this challenge, the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia, is leveraged. By using a bioorthogonal inverse electron demand Diels–Alder reaction, mucins are crosslinked into implantable hydrogels. It is shown that mucin hydrogels (Muc‐gels) modulate the immune response driving biomaterial‐induced fibrosis. Muc‐gels do not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical‐grade alginate hydrogels are covered by fibrous tissues. Further, Muc‐gels dampen the recruitment of innate and adaptive immune cells to the gel and trigger a pattern of very mild activation marked by a noticeably low expression of the fibrosis‐stimulating transforming growth factor beta 1 cytokine. Macrophages recruited to Muc‐gels upregulate the gene expression of the protein inhibitor of activated STAT 1 (PIAS1) and SH2‐containing phosphatase 1 (SHP‐1) cytokine regulatory proteins, which likely contributes to their low cytokine expression profiles. With this advance in mucin materials, an essential tool is provided to better understand mucin bioactivities and to initiate the development of new mucin‐based and mucin‐inspired “immune‐informed” materials for implantable devices subject to fibrotic encapsulation. Mucin hydrogels modulated immune cell recruitment and activity when implanted in the peritoneal cavity of mice and avoided fibrotic insulation after 21 days. In contrast, alginate hydrogels are fully covered by fibrotic capsules. This study shows the potential of using mucin‐inspired “immune‐informed” materials to develop implantable devices subject to fibrotic encapsulation such as sensor and electrodes.