In-situ visible-light-crosslinking of mussel-inspired adhesive and anti-inflammatory HMD hydrogel for intrauterine adhesion prevention via paracrine signaling

Intrauterine adhesions (IUAs) is characterized by endometrial fibrosis that mediated by persistent inflammation. Hyaluronic acid (HA) in combination with umbilical cord mesenchymal stem cells (uMSCs) has been considered as promising strategy for intrauterine adhesions (IUAs) prevention. However, the rapid degradation and low adhesivity limited the further application in clinic. Herein, by introduction of methacrylic anhydride (MA) and mussel-inspired dopamine (DA) groups in HA, an injectable endometrium-adhesive and anti-inflammatory HMD hydrogel that could form sol–gel transition through visible light irradiation was innovatively designed, combined with uMSCs to regenerate endometrium and promote fertility for IUAs therapy. Adhesive HMD hydrogel can provide integrin binding sites to enhance paracrine activity of human umbilical cord mesenchymal stem cells (uMSCs), which subsequently promoted immunoregulation, cell proliferation and migration, and angiogenesis in vitro. HMD also significantly prolonged the retention of uMSCs in a rat model of IUAs, beneficial for immunoregulation by immune cell crosstalk, recruitment of macrophage to the injury sites, macrophage M2 polarization and activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling, thereby contributing to endometrial regeneration and reconstruction of fertility. Altogether, the novel adhesive and anti-inflammatory hydrogel may be a good alternative for the treatment of IUAs in clinic.