Emerging engineering technologies for opening the BBB

Abstract

Current treatments of neurological and neurodegenerative diseases are limited due to the lack of a truly noninvasive, transient, and regionally selective brain drug delivery method. The brain is particularly diffi cult to deliver drugs to because of the blood–brain barrier (BBB). The impermeability of the BBB is due to the tight junctions between adjacent endothelial cells and highly regulatory transport systems of the endothelial cell membranes. The main function of the BBB is ion and volume regulation to ensure the conditions necessary for proper synaptic and axonal signaling. However, the same permeability properties that keep the brain healthy also present tremendous obstacles to its pharmacological treatment. Until a solution to the trans-BBB delivery problem is found, treatments of neurological diseases will remain impeded. Over the past decade, methods that combine focused ultrasound (FUS) and microbubbles have been shown to offer the unique capability to noninva-sively, locally, and transiently open the BBB. Four of the main challenges to the application of FUS are (1) to assess its safety profi le, (2) to unveil the mechanism by which the BBB opens and closes, (3) to control and predict the opened BBB properties and duration of the opening, and (4) to assess its promise for brain drug delivery. In this chapter, we discuss all of these challenges, along with fi ndings in both small (mice) and large (nonhuman primates) animals, and emphasize the clinical potential for this technique.