A review of bioeffects induced by focused ultrasound combined with microbubbles on the neurovascular unit

Abstract

Focused ultrasound combined with circulating microbubbles (FUS+MB) can transiently enhance blood-brain barrier (BBB) permeability at targeted brain locations. Its great promise in improving drug delivery to the brain is reflected by a rapidly growing number of clinical trials using FUS+MB to treat various brain diseases. As the clinical applications of FUS+MB continue to expand, it is critical to have a better understanding of the molecular and cellular effects induced by FUS+MB to enhance the efficacy of current treatment and enable the discovery of new therapeutic strategies. Existing studies primarily focus on FUS+MB-induced effects on brain endothelial cells, the major cellular component of BBB. However, bioeffects induced by FUS+MB expand beyond the BBB to cells surrounding blood vessels, including astrocytes, microglia, and neurons. Together these cell types comprise the neurovascular unit (NVU). In this review, we examine cell-type-specific bioeffects of FUS+MB on different NVU components, including enhanced permeability in endothelial cells, activation of astrocytes and microglia, as well as increased intraneuron protein metabolism and neuronal activity. Finally, we discuss knowledge gaps that must be addressed to further advance clinical applications of FUS+MB.

Keywords: Focused ultrasound; blood-brain barrier; cellular effects; molecular effects; neurovascular unit.

Figure 1.

Bioeffects of FUS+MB on neurovascular unit (NVU) components. An illustration of the experimental setup for applying the FUS+MB technique on small animals is provided on the left. Molecular changes and functional effects induced by FUS+MB for each NVU component are listed in boxes. ^*Contradictory results were reported; ^ΔSpatial heterogeneity of the effect on this protein was observed; Molecular markers in red have been studied in diseased animal models. Details regarding focused ultrasound (FUS) parameters, methods of measurement, brain regions where molecular changes were observed, the time post sonication when molecular changes were observed, and how long these changes lasted please refer to Chapter to and Tables 2 to 5.