High-frequency noncontact low-intensity pulsed ultrasound modulates Ca²⁺-dependent transcription factors contributing to cell migration

Chronic wounds have negative physical and psychological effects on patients and increase the health care burden. Consequently, chronic wound in the elderly population is an important issue. Ultrasound can be a great modality for treating chronic wounds because of its noninvasive and safety characteristics; it can accelerate in vitro and in vivo wound healing. In this study, we developed a novel noncontact ultrasound for wound treatment. We stimulated human epidermal keratinocyte migration using low-intensity pulsed ultrasound (LIPUS) with a noncontact transducer to avoid direct contact with the wound. We also compared the effects of 15-min contact and noncontact transducer stimulation, where a 1-MHz contact transducer (intensity = 40 or 200 mW/cm²) and a 0.45-MHz noncontact transducer (intensity = 30 mW/cm²) were used. Both contact and noncontact LIPUS considerably increased cell migration and activated the calcium (Ca²⁺)-dependent transcription factors cAMP-responsive element-binding protein (CREB) and nuclear factor of activated T cells (NFAT). Furthermore, noncontact transducer stimulation did not cause cell death or affect cell proliferation but significantly increased the Ca²⁺ influx–mediated intracellular Ca²⁺ levels. Ca²⁺-free medium and Ca²⁺ channel blockers effectively inhibited LIPUS-induced Ca²⁺-dependent transcription factor activation and cell migration.