Low-Frequency Ultrasound Mechanostimulation for Targeting Fibrotic Cells for Proliferative Vitreoretinopathy Treatment.

Proliferative vitreoretinopathy (PVR) is a retinal disorder characterized by migration of retinal pigment epithelial cells (RPE) into the vitreous cavity through the retinal tear and their epithelial-to-mesenchymal transition (EMT), followed by the development of a fibrotic condition. Here, we demonstrate that low-frequency ultrasound (LFU) applied using a controlled ultrasonic actuation platform selectively induces apoptosis in EMT-activated RPE cells through LFU-mediated mechanical forces, without damaging normal RPE cells. Furthermore, LFU treatment disrupts myosin IIA-mediated contractility and decreases the 2D migration of activated RPE cells. MicroRNA-21 (miR-21) secreted by activated RPE cells reduces the expression of the mechanosensory cytoskeletal protein tropomyosin 2.1 (Tpm2.1) in these cells, rendering them susceptible to mechanoptosis. Surprisingly, normal RPE cells that retain Tpm2.1 expression remain unaffected under identical conditions. These findings suggest that cell-state-dependent mechanical vulnerability of RPE cells signifies a therapeutic opportunity and could establish LFU as a noninvasive treatment to selectively kill fibrotic RPE cells, with potential applications in retinal and fibrotic disorders.