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BUBBLE-INDUCED TISSUE REGENERATION attract cells that are intravenously injected, which can help revascularize ischemic tissue (Tebebi et al., 2017). Acoustic shock waves, which in addition to LIUS have clinically approved uses, promote healing of bone and soft tissues (Simplicio et al., 2020). Ultrasound can also pattern cells within hydrogels, which assist with the growth of blood vessel-like structures (Garvin et al., 2011). Therefore, as seen with these examples, ultrasound can help drive regeneration in many ways. The (Sort of) New Kid on the Block A new, ultrasound-based approach for controlling bio- chemical and biophysical cues in tissue regeneration involves phase-shift emulsions: shell-stabilized liquid droplets that can be converted into gas bubbles in situ using ultrasound. Phase-shift emulsions use perfluo- rocarbon (PFC) liquids because they have favorable thermodynamic properties as well as a high biocompat- ibility. They also have vapor pressures that are an order of magnitude higher than that of water. The volatility of a PFC liquid provides a thermodynamic driving force for the liquid to phase transition into a gas. The liquid-to-gas transition requires a certain amount of thermal energy or tensile stress (i.e., negative pressure). Ultrasound can trigger a phase transition in a PFC liquid without the generation of heat. Specifically, the negative component of the ultrasound wave reduces the local pres- sure below the vapor pressure of the PFC liquid, thereby making vaporization thermodynamically favorable. A liquid can exist in a metastable state (i.e., below its saturated vapor pressure) while experiencing a negative pressure. Ultimately, as the magnitude of the negative pressure increases, vapor bubbles spontaneously form within the liquid. These bubbles grow until their internal pressure reaches the equilibrium pressure of the liquid (Fisher, 1948). The same concept is employed in phase- shift emulsions where the application of ultrasound induces bubble formation in a process known as acoustic droplet vaporization (ADV). Acoustic Droplet Vaporization The concept of ADV can be traced back to the 1950s and the late Donald Glaser, who was awarded the Nobel Prize in Physics for developing bubble chambers. These chambers contained a superheated liquid and enabled detection of atomic particles that left a path of bubbles as they traversed the liquid. Building on this work, in 1979, the late Robert Apfel (see bit.ly/AT-Apfel), former president of the Acoustical Society of America and recipi- ent of the Society’s Gold Medal, developed a radiation dosimeter in which the superheated liquid was fraction- ated into droplets. Apfel (1998) patented this technology, envisioning that ultrasound, in addition to radiation, could vaporize the droplets (i.e., phase-shift emulsion), which could be used in biomedical applications. The first experimental results on ADV were published by Kripf- gans et al. (2000). Currently, many groups around the world are actively investigating phase-shift emulsions, ADV, and their biomedical applications, as seen in ear- lier articles in Acoustics Today (Burgess and Porter, 2015; Gray et al., 2019). ADV is a threshold phenomenon, with the minimum acoustic pressure required to generate ADV termed the ADV threshold. The ADV threshold depends sig- nificantly on the physical properties of the phase-shift emulsion (e.g., diameter, molecular weight of the PFC species) as well as acoustic parameters (e.g., frequency) (Schad and Hynynen, 2010). For ultrasound frequencies of 1-10 MHz, ADV thresholds are in the megapascal range (i.e., peak negative pressure). Phase-shift emulsions possess some distinct advantages compared with the microbubbles that are used diagnosti- cally as ultrasound contrast agents to visualize blood flow and therapeutically to enhance drug delivery. One such advantage is that emulsions exhibit greater stability than microbubbles because of their liquid cores. Compared with microbubbles that only persist for minutes after injec- tion into the body, emulsions can persist for much longer (e.g., hours to days). Another advantage is that emulsions have a greater drug-loading capacity. Drugs can be loaded into the liquid core of the emulsion compared with micro- bubbles where drugs are loaded into the shell. Phase-shift emulsions for tissue regeneration are not directly injected into the bloodstream, which is typically how the emulsions are used in many other biomedical applications. Rather, the emulsions are incorporated into hydrogels to yield an acoustically responsive scaf- fold (ARS) that can be implanted into the body (Figure 1, B and C). This administration method also enables the use of larger diameter emulsions (e.g., >6 μm), which can be formulated more easily in uniform sizes compared 16 Acoustics Today • Summer 2022