Focused ultrasound combined with microbubbles in central nervous system applications

The blood–brain barrier (BBB) protects the central nervous system (CNS) from invasive pathogens and maintains the homeostasis of the brain. Penetrating the BBB has been a major challenge in the delivery of therapeutic agents for treating CNS diseases. Through a physical acoustic cavitation effect, focused ultrasound (FUS) combined with microbubbles achieves the local detachment of tight junctions of capillary endothelial cells without inducing neuronal damage. The bioavailability of therapeutic agents is increased only in the area targeted by FUS energy. FUS with circulating microbubbles is currently the only method for inducing precise, transient, reversible, and noninvasive BBB opening (BBBO). Over the past decade, FUS-induced BBBO (FUS-BBBO) has been preclinically confirmed to not only enhance the penetration of therapeutic agents in the CNS, but also modulate focal immunity and neuronal activity. Several recent clinical human trials have demonstrated both the feasibility and potential advantages of using FUS-BBBO in diseased patients. The promising results support adding FUS-BBBO as a multimodal therapeutic strategy in modern CNS disease management. This review article explores this technology by describing its physical mechanisms and the preclinical findings, including biological effects, therapeutic concepts, and translational design of human medical devices, and summarizes completed and ongoing clinical trials.