Suspendable and Scalable Ultrasound-Actuated ZnO-Nanosheet-Based Piezoelectric Microdevices for Wireless Electrical Stimulation of Cells.

Electrical stimuli play a crucial role in activating cell signaling pathways and promoting essential functions such as migration, proliferation, and differentiation, while also enabling communication between specific cell types. Bioelectronics aims to modulate the biological activity of living tissues and organs through minimally invasive electrical stimulation. This work aims to develop and validate cytocompatible, subcellular-sized wireless microdevices fabricated through a scalable silicon microtechnology process. These microdevices consist of a micrometer-scale silicon dioxide platform integrating ZnO nanosheets (NSs) as the active piezoelectric material. They establish electromechanical interactions with cells, driven by intrinsic cellular forces or by external ultrasound actuation in the biomedical range. This study demonstrates the underpinning mechanism of this electromechanical interaction. Mechanical forces, whether generated intrinsically by cells or applied through ultrasound, deform the nanostructures and generate localized piezopotentials that depolarize the membrane and trigger calcium transients. Pharmacological studies revealed that calcium entry occurs mainly through voltage-gated calcium channels (VGCCs) and stretch-activated cation channels (SACCs), with a minor contribution from intracellular stores. Membrane potential imaging confirmed dynamic depolarization events, validating direct cell-nanogenerator coupling. Ultrasound actuation further enhanced the effect, with 58% of cells activated, underscoring the promise of piezoelectric nanogenerators for minimally invasive cellular-level bioelectronic interfaces and biomedical applications.