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   Figure 1. A: constructs used in tissue engineering and regenerative medicine consist of a scaffold loaded with biochemical cues and/or cells. The construct is implanted within the body to facilitate regeneration at a particular location. A limitation of this common, preprogrammed paradigm is the inability to actively modulate biochemical and/or biophysical cues within the construct after implantation. B: an acoustically responsive scaffold (ARS) can be noninvasively controlled using ultrasound, thereby enabling spatiotemporal modulation of cues after implantation. The phase-shift emulsion within the ARS is responsive to ultrasound. C: acoustic droplet vaporization (ADV) is the process by which a phase-shift emulsion in the ARS is converted into gas bubbles using ultrasound. ADV enables modulation of biochemical and biophysical cues within the ARS. polymer network and cross-linking conditions impact the rate at which biochemical cues are released from the hydrogel as well as its stiffness. But the preprogrammed design may not be best for the specific site of implanta- tion. Or the design could be well suited at the time of implantation, but then its suitability decreases over time. After implantation, the ability to dynamically modulate cues within a preprogrammed construct, and hence tissue regeneration, in an on-demand manner defined by a physician or even a patient is extremely limited. From a basic science perspective, the reliance on a pre- programmed design has hampered elucidating the roles of fundamental, biochemical, and biophysical cues in situ. In fact, this points to the need for a better understanding of these cues to help drive the development of new, regen- erative therapies. Indeed, from an applied perspective, the preprogrammed design hinders real-time personal- ization of regenerative therapy for the simple reason that there is no way to easily adjust the performance of a pre- programmed construct in situ. These shortcomings have led to the development of constructs in which biochemi- cal and/or biophysical cues can be externally controlled using light, heat, electricity, and magnetic fields. However, these stimuli are limited by factors such as a superficial depth of penetration, the need for invasive procedures, and/or poor spatial localization. The Sound of Healing: Ultrasound and Regeneration Ultrasound has been exploited in many regenerative applications because it can noninvasively produce desired thermal and mechanical bioeffects in a spatiotemporally regulated manner. These bioeffects can be produced at depths of up to 10 centimeters within the human body. Low-intensity ultrasound (LIUS) is one of the most stud- ied ultrasound techniques and can be used to induce a myriad of biological responses including blood vessel growth and bone repair. The exact mechanisms underpin- ning the actions of LIUS in regeneration are being actively investigated. Studies highlight the involvement of mecha- notransduction, whereby mechanical forces generated by LIUS activate mechanically sensitive receptors in cells, which leads to biochemical signaling (Sato et al., 2014). Pulsed, focused ultrasound with a higher intensity than LIUS has been shown to transiently increase levels of sig- naling proteins within tissue. This, in turn, can locally Summer 2022 • Acoustics Today 15 


































































































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