Ellipsoidal porous patch with anisotropic cell inducing ability for inhibiting skin scar formation

During tissue repair, myofibroblasts produce extracellular matrix (ECM) molecules for tissue resilience and strength. Altered ECM deposition can lead to tissue dysfunction and disease. Identification of distinct myofibroblast subsets is necessary to develop treatments for these disorders. We analyzed profibrotic cells during mouse skin wound healing, fibrosis, and aging and identified distinct subpopulations of myofibroblasts, including adipocyte precursors (APs). Multiple mouse models and transplantation assays demonstrate that proliferation of APs but not other myofibroblasts is activated by CD301b-expressing macrophages through insulin-like growth factor 1 and platelet-derived growth factor C. With age, wound bed APs and differential gene expression between myofibroblast subsets are reduced. Our findings identify multiple fibrotic cell populations and suggest that the environment dictates functional myofibroblast heterogeneity, which is driven by fibroblast-immune interactions after wounding.

Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. Engrailed-1 lineage–positive fibroblasts (EPFs) are known to function in scarring, but Engrailed-1 lineage–negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating Engrailed-1 expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives Engrailed-1 activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents Engrailed-1 activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).

We report here an injectable, self-healing coordinative hydrogel with antibacterial and angiogenic properties for diabetic wound regeneration. The hydrogel was prepared by coordinative cross-linking of multi-arm thiolated polyethylene glycol (SH-PEG) with silver nitrate (AgNO3). Due to the dynamic nature of Ag-S coordination bond and bacteria-killing activity of Ag+, the resultant coordinative hydrogel featured self-healing, injectable and antibacterial properties. In this study, we synchronously loaded an angiogenic drug, desferrioxamine (DFO), in the coordinative hydrogel during cross-linking. We finally obtained a multifunctional hydrogel that is manageable, resistant to mechanical irritation, antibacterial and angiogenic in vitro. Our in vivo studies further demonstrated that the injectable self-healing hydrogel could efficiently repair diabetic skin wounds with low bacteria-infection and enhance angiogenic activity. In short, besides diabetic skin wound repair, such dynamic multifunctional hydrogel scaffolds would show great promise in the regeneration of different types of exposed wounds, in particular, in situations with disturbed physiological functions, high risk of bacterial infections, and external mechanical irritation.