Ultrasound holds great promise for realizing noncontact stimulation and control of cell function. Here, we will present our ongoing efforts in controlling cell responses using two distinct approaches. The first is based on engineered cytotoxic immune cells with thermal switches, where closed-loop controlled MRgFUS-hyperthermia (20-mins at 42 °C) is employed to drive the local production of key transgenes and potentiate anti-tumor responses in brain tumors. The responses are assessed using bioluminescence, cell viability, and cell cytotoxicity assays. The second is based on US pulse sequences designed to promote mechanical effects on cultured cells with the goal to decode US neuromodulation. For our investigations, we employed a high throughput ultrasonic platform designed to monitor and locally control sound and vibration in combination DRG sensory neurons. The later are the most sensitive neuronal type to mechanical stretch and present an excellent experimental system to examine and identify mechanosensitive ion channels sensing sonication-induced membrane stretch. Cell responses are quantified and analyzed for different pulse durations and amplitude, cell culture conditions, and degassing protocols. Together, our findings show that ultrasound thermal and mechanical effects can be employed to control the function of different cell types, albeit cells with thermal switches provide more robust responses.
High-intensity focused ultrasound (HIFU) has seen widespread clinical adoption as a therapeutic tool, as it may be targeted noninvasively and without ionizing radiation. The converging sound waves induce thermal (e.g., ablation) and mechanical (e.g., radiation force) effects that may be localized to manipulate or destroy tissue. In addition to these primary effects, finite-amplitude acoustic influences (e.g., second harmonic generation) become relevant due to the high-pressure levels near the focal region. One of the ways these nonlinear effects occur is when a pressure wave develops at the difference frequency due to the nonlinearity of the medium when an acoustic beam is driven by a signal that contains two high but slightly different frequencies. This is termed as “scattering of sound by sound,” an implication of finite-amplitude propagation is the existence of sum and difference frequencies. Using highly focused ultrasound beams as carrier waves at high amplitudes, we have observed that these nonlinear effects can be localized at scales below its wavelength with sufficient amplitudes. These effects were observed for a water reference medium, and thus are likely to be even more prominent in tissue. Exploring these higher-order acoustic effects for the diagnosis and treatment of human diseases is warranted.
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