Injectable Thermosensitive Hydrogel Containing Resveratrol-Laden Nanoparticles Promotes Hypertrophic Scar Repair in Rat Tail.

Our previous study has confirmed that resveratrol (Res) can suppress hypertrophic scar through a variety of mechanisms, such as autophagy inhibition, apoptosis induction, and oxidative stress reduction. However, the primary obstacle to the pharmaceutical use of Res is its poor bioavailability. Here, an injectable and temperature-responsive hydrogel containing mesoporous silica nanoparticles loaded with Res (MSN@Res) was employed for the repair of hypertrophic scars, formulated by fine-tuning the combination of aldehyde-functionalized Pluronic F127 (F127-CHO, FC) and hyaluronic acid modified with adipic dihydrazide (AHA). This hybrid hydrogel exhibited suitable porosity, robust mechanical characteristics, and sustained release capability for Res. In vitro cellular tests indicated that the 8%FC/AHA hydrogel possesses minimal cytotoxicity and excellent biocompatibility. Additionally, the 8%FC/AHA-MSN@Res hydrogel showed nearly full antiproliferative activity against hypertrophic scar fibroblasts. The 8%FC/AHA-MSN@Res hydrogel was subsequently applied to treat hypertrophic scars in the rat tails. The findings indicated that this composite hydrogel significantly improved the overall results, diminished the thickness of both the epidermis and dermis, and reduced the scar size. In addition, the hydrogel could suppress oxidative stress, downregulate the expression of p38-MAPK, HIF-1α, p53, and LC3-II, and upregulate caspase-3 expression in hypertrophic scars, which indicated that the composite hydrogel inhibits cellular autophagy, induces apoptosis of fibroblasts in hypertrophic scars, and then reduces the cell viability and collagen deposition, finally resulting in an acceleration of scar regression. This research validated that this composite hydrogel has the potential to serve as a highly effective therapeutic approach with promising prospects for clinical application in the treatment of hypertrophic scars.