**6. Outlook**

As reviewed here, over the past 15 years, numerous pre-clinical studies have demonstrated the potential of US to induce revascularization responses through the oscillation and/or destruction of gas-filled MBs, the delivery of therapeutic genes, proteins, or cells, or the activation of acoustically-responsive biomaterials. These approaches present opportunities for novel non-invasive and spatially-targeted treatments for diseases caused or characterized by insufficient or aberrant vasculature, replacing traditional interventions associated with invasive or high-risk procedures (surgery) or off-target effects (systemic delivery). In particular, we believe that US-mediated revascularization has immense potential for treating central nervous system disorders, where the blood–brain barrier poses a significant challenge to many treatment modalities as well as tissue

engineering and biomaterials where the ability to non-invasively activate an implanted material would allow for highly tunable and versatile therapies that could be easily adapted to meet the needs of individual patients.

Nonetheless, it is also true that, despite this abundance of pre-clinical investigation, ultrasound-mediated approaches for revascularization have not been successfully translated to the clinic. While this is discouraging, the past few years have seen a handful of ultrasound-mediated drug delivery approaches enter into clinical trials, and we submit that these trials have the potential to open doors for many new applications going forward. This includes the use of ultrasound for stimulating revascularization. Indeed, in combination with i.v. microbubbles, ultrasound has now been used to safely open the blood–brain barrier in Alzheimer's disease patients [154] and to deliver chemotherapy to patients with primary brain tumors [155,156]. Moreover, more trials utilizing focused ultrasound and microbubbles for the blood–brain barrier opening are just now getting underway, signaling an acceleration of clinical activity in this space. Meanwhile, ultrasound-microbubble-mediated drug delivery has also entered clinical trials for an application outside of the CNS, with the targeted delivery of gemcitabine having been performed in patients with pancreatic cancer [157]. With these trials serving as the foundation, we are hopeful that the knowledge gained regarding the safety and relative e fficacy of ultrasound-microbubble-mediated treatments will facilitate the adoption of similar approaches for therapeutic revascularization. Overall, we argue that US-based methods of promoting angiogenesis and arteriogenesis still have potential to make an important positive impact on how we treat many vascular pathologies in the future.

**Author Contributions:** Writing—Original Draft Preparation, C.M.G. and J.C.C.; Writing—Review and Editing, C.M.G., J.C.C., and R.J.P.; Supervision, R.J.P.; Funding Acquisition, R.J.P.

**Funding:** This study was supported by National Institutes of Health (Grants R01EB020147 and R21EB024323 to R.J.P.). C.M.G. was supported by the American Heart Association Fellowship (18PRE34030022).

**Conflicts of Interest:** The authors declare no conflict of interest.
