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      The blood-brain barrier: an engineering perspective

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          Abstract

          It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore, advances in our understanding of the structure and function of the blood-brain barrier are key to developing effective treatments for a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex, dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

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          Most cited references193

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          Membrane transporters in drug development.

          Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labelling.
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            The Expensive-Tissue Hypothesis: The Brain and the Digestive System in Human and Primate Evolution

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              Uniquely hominid features of adult human astrocytes.

              Defining the microanatomic differences between the human brain and that of other mammals is key to understanding its unique computational power. Although much effort has been devoted to comparative studies of neurons, astrocytes have received far less attention. We report here that protoplasmic astrocytes in human neocortex are 2.6-fold larger in diameter and extend 10-fold more GFAP (glial fibrillary acidic protein)-positive primary processes than their rodent counterparts. In cortical slices prepared from acutely resected surgical tissue, protoplasmic astrocytes propagate Ca(2+) waves with a speed of 36 microm/s, approximately fourfold faster than rodent. Human astrocytes also transiently increase cystosolic Ca(2+) in response to glutamatergic and purinergic receptor agonists. The human neocortex also harbors several anatomically defined subclasses of astrocytes not represented in rodents. These include a population of astrocytes that reside in layers 5-6 and extend long fibers characterized by regularly spaced varicosities. Another specialized type of astrocyte, the interlaminar astrocyte, abundantly populates the superficial cortical layers and extends long processes without varicosities to cortical layers 3 and 4. Human fibrous astrocytes resemble their rodent counterpart but are larger in diameter. Thus, human cortical astrocytes are both larger, and structurally both more complex and more diverse, than those of rodents. On this basis, we posit that this astrocytic complexity has permitted the increased functional competence of the adult human brain.
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                Author and article information

                Journal
                Front Neuroeng
                Front Neuroeng
                Front. Neuroeng.
                Frontiers in Neuroengineering
                Frontiers Media S.A.
                1662-6443
                30 August 2013
                2013
                : 6
                : 7
                Affiliations
                [1] 1Department of Materials Science and Engineering, Johns Hopkins University Baltimore, MD, USA
                [2] 2Institute for Nanobiotechnology, Johns Hopkins University Baltimore, MD, USA
                [3] 3The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University Baltimore, MD, USA
                [4] 4Brain Sciences Institute, Johns Hopkins University Baltimore, MD, USA
                Author notes

                Edited by: Jay Nadeau, McGill University, Canada

                Reviewed by: Hari S. Sharma, Uppsala University, Sweden; Antonio Malgaroli, Vita-Salute San Raffaele University, Italy

                *Correspondence: Peter C. Searson, Institute for Nanobiotechnology, Johns Hopkins University, 120 Croft Hall, 3400 North Charles Street, Baltimore, MD 21218, USA e-mail: searson@ 123456jhu.edu

                This article was submitted to the journal Frontiers in Neuroengineering.

                Article
                10.3389/fneng.2013.00007
                3757302
                24009582
                b32ac8f0-984c-4e56-a60d-3b7534521364
                Copyright © 2013 Wong, Ye, Levy, Rothstein, Bergles and Searson.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 April 2013
                : 07 August 2013
                Page count
                Figures: 9, Tables: 0, Equations: 13, References: 276, Pages: 22, Words: 20112
                Categories
                Neuroscience
                Review Article

                Neurosciences
                blood-brain barrier,neurovascular unit,capillary,microvasculature,transport
                Neurosciences
                blood-brain barrier, neurovascular unit, capillary, microvasculature, transport

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