Calcium Silicate-human Serum Albumin Composite Hydrogel Decreases Random Pattern Skin Flap Necrosis by Attenuating Vascular Endothelial Cell Apoptosis and Inflammation

Abstract Random pattern skin flaps are commonly used in plastic surgery to repair skin defects. However, as flap survival mainly relies on blood supply from the distal pedicle and the wound bed, the distal part of the flap is prone to necrosis. Subsequent pathological reactions, including inflammatory reactions, cell apoptosis, and oxidative stress, also aggravate skin flap necrosis. Calcium silicate (CS) has gained attention for its multiple bioactive functions, including promoting angiogenesis and decreasing cell apoptosis, as well as its excellent biocompatibility and safety. Meanwhile, human serum albumin (HSA) hydrogel exhibits excellent drug carrier characteristics and good viscosity for clinical applications. Here, CS was incorporated into HSA hydrogel to form a bioactive composite hydrogel and to control its gelling time. PBS, CS-PBS, HSA hydrogel, and CS-HSA hydrogel were injected under skin flaps on day (-1) and skin flap surgery was performed on day 0. On day 7, the skin flap necrosis rate of the CS-HSA hydrogel group was significantly decreased with increased blood perfusion. Si ions were consistently released from the CS-HSA hydrogel under the skin flap 7 days after operation. Histological staining showed significantly increased CD31+ blood vessels, decreased cell apoptosis, and CD68+ macrophage infiltration. In vitro assays showed that low concentrations of CS extracts sustained cell viability, migration, and tube formation ability of human umbilical vein endothelial cells (HUVECs). CS extracts also decreased HUVEC apoptosis under glucose/oxygen-deprived conditions. Under these conditions, the macrophage inflammatory response decreased. Based on these results, composite CS-HSA hydrogel is suitable for clinical application, and can improve random pattern skin flap survival by attenuating vascular endothelial cell apoptosis and inflammation.