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BUBBLE-INDUCED TISSUE REGENERATION Figure 6. A: in a strain-stiffening material like fibrin, ADV locally compacts and stiffens the fibrin matrix surrounding the bubble. B: the fluorescently labeled fibrin matrix was visualized with confocal microscopy. After ADV, the bubble compacted the matrix, causing an increase in fluorescence intensity that persisted over the course of days. Scale bar, 20 μm. Reprinted from Humphries et al. (2022), with permission from Wiley. C: Young’s modulus was mapped adjacent to the bubble in a location denoted by yellow box in B. Note the higher moduli proximal to the bubble (yellow) versus the lower moduli distal to the bubble (green). Reprinted from Farrell et al. (2022), with permission from Elsevier. structural and mechanical properties of the hydrogel (Fabiilli et al., 2013; Aliabouzar et al., 2020b). In ARSs made with fibrin, bubbles radially compacted the fibrin matrix surrounding them while simultaneously increasing its stiffness and decreasing its porosity (Figure 6). Fibrin is a protein found in blood clots and is an incredibly biocom- patible hydrogel for cells. As bubbles grew in size, there was additional compaction and stiffening of the matrix. In fibrin, matrix compaction leads to an increase in matrix stiffness, a behavior known as strain stiffening. ADV-induced stiffening can have broad biomedical applications. A recent study investigated the ability to change fibroblasts into myofibroblasts in ARSs (Far- rell et al., 2022). Fibroblasts are a common cell type found in connective tissue that can change into myo- fibroblasts when in a stiffened environment. Cells in stiffened regions of fibrin adjacent to bubbles exhibited more characteristics of myofibroblasts compared with cells in less stiffened regions further away from bubbles. Myofibroblasts play a key role in the repair of connec- tive tissues. Thus, ADV could assist with understanding fibrosis, a disease characterized by the sustained pres- ence of myofibroblasts, as well as developing therapies for chronic wounds that contain insufficient numbers of myofibroblasts. In another study, cellular signaling in a cancer model was modulated in ARSs using ADV (Humphries et al., 2022). Therefore, ADV could help elucidate how biophysical changes to the extracellular matrix impact tumor biology, which could lead to novel treatment approaches. In contrast to bubbles that grow over time, ADV can also generate liquid-filled pores within ARSs. These pores are generated based on the collapse of the ADV-generated bubble, which causes localized erosion of the hydrogel matrix in the ARS. It has been shown that generation of pores within an ARS, in combination with bFGF release, increased migration of host cells into the implant (Lu et al., 2020). These host cells were cells that were initially surrounding the ARS on implantation. Comparatively, stable bubbles hindered host cell migration into an ARS. Thus, ADV can modulate cell migration, which can assist in directing regenerative processes. 20 Acoustics Today • Summer 2022