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.

Mucins are multifunctional glycosylated proteins that are increasingly investigated as building blocks of novel biomaterials. An attractive feature is their ability to modulate the immune response, in part by engaging with sialic acid binding receptors on immune cells. Once assembled into hydrogels, bovine submaxillary mucins (Muc gels) were shown to modulate the recruitment and activation of immune cells and avoid fibrous encapsulation in vivo. However, nothing is known about the early immune response to Muc gels. This study characterizes the response of macrophages, important orchestrators of the material-mediated immune response, over the first 7 days in contact with Muc gels. The role of mucin-bound sialic acid sugar residues was investigated by first enzymatically cleaving the sugar and then assembling the mucin variants into covalently cross-linked hydrogels with rheological and surface nanomechanical properties similar to nonmodified Muc gels. Results with THP-1 and human primary peripheral blood monocytes derived macrophages showed that Muc gels transiently activate the expression of both pro-inflammatory and anti-inflammatory cytokines and cell surface markers, for most makers with a maximum on the first day and loss of the effect after 7 days. The activation was sialic acid-dependent for a majority of the markers followed. The pattern of gene expression, protein expression, and functional measurements did not strictly correspond to M1 or M2 macrophage phenotypes. This study highlights the complex early events in macrophage activation in contact with mucin materials and the importance of sialic acid residues in such a response. The enzymatic glyco-modulation of Muc gels appears as a useful tool to help understand the biological functions of specific glycans on mucins which can further inform on their use in various biomedical applications.

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, we leverage the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia. By using a bioorthogonal inverse electron demand Diels-Alder reaction, we crosslink mucins into implantable hydrogels.We show that mucin hydrogels (Muc-gels) modulate the immune response driving biomaterialinduced fibrosis. Muc-gels did not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical-grade alginate hydrogels (Alg-gels) were covered by fibrous tissues. Further, Muc-gels dampened the recruitment of innate and adaptive immune cells to the gel and triggered a pattern of very mild activation marked by a noticeably low expression of the fibrosis-stimulating TGF-β1 cytokine. With this advance in mucin materials, we provide an essential tool 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.