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.
Tumor cell can be significantly influenced by various chemical groups of the extracellular matrix proteins. However, the underlying molecular mechanisms involved in the interaction between cancer cells and functional groups in the extracellular matrix remain unknown. Using chemically modified surfaces with biological functional groups (CH 3 , NH 2 , OH), it was found that hydrophobic surfaces modified with CH 3 and NH 2 suppressed cell proliferation and induced the number of apoptotic cells. Mitochondrial dysfunction, cytochrome c release, Bax upregulation, cleaved caspase-3 and PARP, and Bcl-2 downregulation indicated that hydrophobic surfaces with CH 3 and NH 2 triggered the activation of intrinsic apoptotic signaling pathway. Cells on the CH 3 - and NH 2 -modified hydrophobic surfaces showed downregulated expression and activation of integrin β1, with a subsequent decrease of focal adhesion kinase (FAK) activity. The RhoA/ROCK/PTEN signaling was then activated to inhibit the phosphorylation of PI3K and AKT, which are essential for cell proliferation. However, pretreatment of MDA-MB-231 cells with SF1670, a PTEN inhibitor, abolished the hydrophobic surface-induced activation of the intrinsic pathway. Taken together, the present results indicate that CH 3 - and NH 2 -modified hydrophobic surfaces induce mitochondria-mediated apoptosis by suppressing the PTEN/PI3K/AKT pathway, but not OH surfaces. These findings are helpful to understand the interaction between extracellular matrix and cancer cells, which might provide new insights into the mechanism potential intervention strategies for tumor prognosis.
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