RESUMEN
Electrical stimulation therapy (EST) has been established as an effective strategy to accelerate wound healing by stimulating cell proliferation and migration, ultimately promoting re-epithelialization and vascularization, two key processes that significantly influence the rate of wound healing. Phosphatase and tensin homologue (PTEN), a widely expressed protein in somatic cells, works as a "brake" regulating cell differentiation, proliferation, and migration. Given that this "brake" also works in cell electrical responses, there is a hypothesis that PTEN inhibition may amplify the efficacy of EST in wound treatment. However, long-term inhibition of PTEN may result in DNA damage and reduce DNA repair, which poses a significant challenge to the safe use of PTEN inhibitors. To address this issue, we developed a system that combines PTEN inhibitor loaded electro-responsive hydrogel (BPV@PCP) with a wearable direct current pulse piezoelectric nanogenerator (PENG). The PENG converts the rat's motions into electric fields that synchronously charge the wound edge tissue and BPV@PCP. Electric field intensity was lower when the rat was quiet or anesthetized, which is insufficient to trigger an effective PTEN inhibitor release. However, when the rat was in action, the electric field intensity exceeded 625 mV/mm, resulting in a rapid drug release. This on-demand PTEN inhibition accelerated wound healing by amplifying cell electric responsiveness while avoiding negative effects associated with continuous overinhibition of PTEN. Notably, this system improves vascularization not only by improving endothelial cell electric responsiveness but also through the paracrine pathway, in which electrical stimulation and PTEN inhibition synergically promote VEGF secretion.