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Figure 5. Two payloads can be sequentially released from an ARS. Each payload is encapsulated within a separate phase-shift emulsion. The first payload is encapsulated in an emulsion with a lower ADV threshold than the second payload. Sequential ultrasound applications of lower and higher amplitudes release the first and second payloads, respectively. Adapted from Moncion et al. (2018), with permission from Elsevier. these studies highlight the exciting potential of using ADV and ARSs for stimulating blood vessel growth and in developing new treatments for cardiovascular disease. Two Can Be Better Than One: Sequential Release Using Ultrasound Complex, regenerative processes like blood vessel or bone growth require multiple signaling proteins. In addition to their spatial presentation, the temporal sequence of these proteins is critical. For example, bFGF and platelet-derived growth factor BB (PDGF-BB) are both involved in the growth of new blood vessels. bFGF stimulates the initial growth of the blood vessel, particularly the sprouting of endothelial cells that form the inner lining (i.e., lumen) of the vessel. PDGF-BB stimulates other cells to stabilize the outer lining of the vessel, thereby rendering a mature vessel. However, if bFGF and PDGF-BB are present simul- taneously, the proteins will inhibit each other, thereby disrupting blood vessel formation (Tengood et al., 2011). By exploiting the properties of the ADV threshold, ARSs can be designed to enable sequential release of two thera- peutic payloads. This involves encapsulating each payload within separate emulsions. The ARS is then exposed to ultrasound at acoustic conditions that will selectively release the first payload without causing release of the second payload. At a later time point, the ARS is exposed to acoustic conditions that release the second payload. This concept has been demonstrated using two strategies: (1) ADV at a single ultrasound frequency (e.g., 2.5 MHz) using two peak rarefactional pressures (e.g., 2 MPa fol- lowed by 8 MPa) (Figure 5) (Moncion et al., 2018) and (2) ADV at two different ultrasound frequencies (e.g., 8.6 MHz followed by 2.5 MHz) (Aliabouzar et al., 2021). An ultrasound standing wave field has also been used for the sequential release from bilayer ARSs, in which each layer contains a different payload-carrying emulsion (Aliabou- zar et al., 2020a). Use the Force: Control of Biophysical Cues A cell can sense biophysical cues via receptors linking structural proteins within the cell to the microenviron- ment surrounding the cell. Cell behavior is significantly impacted by these biophysical cues. For example, mes- enchymal stromal cells (MSCs) are cells that can change into more specialized types of cells. When grown on hydrogels, MSCs change into different types of special- ized cells based on the stiffness of the hydrogels (Engler et al., 2006). Beyond stiffness, other parameters that impact cellular processes include elasticity, porosity, fiber density, surface roughness, and surface curvature. ADV enables the spatiotemporal modulation of biophysi- cal properties in ARSs. During ADV, the liquid PFC phase within the phase-shift emulsion undergoes a dramatic increase in volume (up to 125-fold) as it is converted into a gas. Stable bubbles grow further in size due to inward diffusion of dissolved gases from the surrounding envi- ronment. In an ARS, stable bubbles remain trapped in the hydrogel matrix, thereby locally impacting both the Summer 2022 • Acoustics Today 19