Exogenous substance P accelerates wound healing in diabetes,but the mechanism remains poorly understood.Here,we established a rat model by intraperitoneally injecting streptozotocin.Four wounds(1.8 cm diameter) were drilled using a self-made punch onto the back,bilateral to the vertebral column,and then treated using amniotic membrane with epidermal stem cells and/or substance P around and in the middle of the wounds.With the combined treatment the wound-healing rate was 100% at 14 days.With prolonged time,type I collagen content gradually increased,yet type III collagen content gradually diminished.Abundant protein gene product 9.5-and substance P-immunoreactive nerve fibers regenerated.Partial nerve fiber endings extended to the epidermis.The therapeutic effects of combined substance P and epidermal stem cells were better than with amniotic membrane and either factor alone.Our results suggest that the combination of substance P and epidermal stem cells effectively contributes to nerve regeneration and wound healing in diabetic rats. Exogenous substance P accelerates wound healing in diabetes, but the mechanism remains poorly understood. Here, we established a rat model by intraperitoneally injecting streptozotocin. Fur wounds (1.8 cm diameter) were drilled using a self-made punch onto the back, bilateral to the vertebral column, and then treated using amniotic membrane with epidermal stem cells and / or substance P around and in the middle of the wounds.With the combined treatment the wound-healing rate was 100% at 14 days .With prolonged time, type I collagen content gradually increased, yet type III collagen content gradually diminished. Abundant protein gene product 9.5-and substance P-immunoreactive nerve fibers regenerated. Partial nerve fiber endings extended to the epidermis. The therapeutic effects of combined substance P and epidermal stem cells were better than with amniotic membrane and either factor alone. Our results suggest that the combination of substance P and epidermal stem cells accounted contribute to nerv e regeneration and wound healing in diabetic rats.