Emerging Engineering Technologies for Opening the BBB
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 difficult to deliver drugs to because of the bl
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Emerging Engineering Technologies for Opening the BBB Elisa E. Konofagou
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 difficult 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 noninvasively, locally, and transiently open the BBB. Four of the main challenges to the application of FUS are (1) to assess its safety profile, (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 findings in both small (mice) and large (nonhuman primates) animals, and emphasize the clinical potential for this technique.
E.E. Konofagou (*) Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 1210 Amsterdam Avenue, New York, NY 10027, USA Department of Radiology, Columbia University, New York, NY USA e-mail: [email protected] M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_20, © American Association of Pharmaceutical Scientists 2014
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E.E. Konofagou
Introduction The Blood–Brain Barrier (BBB) Physiology: Structure and Function
The BBB is a specialized substructure of the vascular system, consisting of endothelial cells connected together by tight junctions and surrounded by pericytes and astrocytes (Pardridge 2005). The luminal and abluminal membranes of the brain endothelial cells act as the permeability barrier (Fig. 20.1). The combination of tight junctions and these two membranes result in the BBB exhibiting low permeability to large and ionic substances. However, certain molecules such as glucose and amino acids are exceptions, because they are actively transported. It has also been shown that lymphocytes can traverse the BBB by going through temporarily opened tight junctions of the endothelial cells. The astrocytes have been proven to offer a protective mechanism of the neurons to any mechanical effect (Pardridge 2005; Abbott et al. 2006; Stewart and Tuor 1994).
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The BBB and Neurotherapeutics
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