Blood brain barrier: An overview on strategies in drug delivery, realistic in vitro modeling and in vivo live tracking

Blood brain barrier (BBB) is a group of astrocytes, neurons and endothelial cells, which makes restricted passage of various biological or chemical entities to the brain tissue. It gives protection to brain at one hand, but at the other hand it has very selective permeability for bio-actives and other foreign materials and is one of the major challenges for the drug delivery. Nanocarriers are promising to cross BBB utilizing alternative route of administration such as intranasal and intra-carotid drug delivery which bypasses BBB. In future more optimized drug delivery system can be achieved by compiling the best routes with the best carriers. Single photon emission tomography (SPECT) and different brain-on-a-chip in vitro models are being very reliable to study live in vivo tracking of BBB and its pathophysiology, respectively. In the current review we have tried to exploit mechanistically all these to understand and manage the various BBB disruptions in diseased condition along with crossing the hurdles occurring in drug or gene delivery across BBB.

[1]  M. Nakazato,et al.  Exploratory Trial of Intranasal Administration of Glucagon-Like Peptide-1 in Japanese Patients With Type 2 Diabetes , 2014, Diabetes Care.

[2]  Bethany L Peterson,et al.  Vitamin D Prevents Hypoxia/Reoxygenation-Induced Blood-Brain Barrier Disruption via Vitamin D Receptor-Mediated NF-kB Signaling Pathways , 2015, PloS one.

[3]  L. Fenart,et al.  A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier , 1997, The Journal of cell biology.

[4]  C. Nicholson,et al.  Diffusion in brain extracellular space. , 2008, Physiological reviews.

[5]  C. Daumas-Duport,et al.  Evaluation of Drug Penetration into the Brain: A Double Study by in Vivo Imaging with Positron Emission Tomography and Using an in Vitro Model of the Human Blood-Brain Barrier , 2006, Journal of Pharmacology and Experimental Therapeutics.

[6]  I. Romero,et al.  Transporting therapeutics across the blood-brain barrier. , 1996, Molecular medicine today.

[7]  Yan Li,et al.  A dual-targeting nanocarrier based on poly(amidoamine) dendrimers conjugated with transferrin and tamoxifen for treating brain gliomas. , 2012, Biomaterials.

[8]  C. Nicholson,et al.  Diffusion of epidermal growth factor in rat brain extracellular space measured by integrative optical imaging. , 2004, Journal of neurophysiology.

[9]  S. Schultz Principles of Neural Science, 4th ed. , 2001 .

[10]  O. Ogunshola,et al.  Cell‐specific blood–brain barrier regulation in health and disease: a focus on hypoxia , 2014, British journal of pharmacology.

[11]  Hugh Davson,et al.  Physiology of the CSF and Blood-Brain Barriers , 1996 .

[12]  A. Ebrahimi,et al.  Drug Delivery using genetically modified Mesenchymal Stem Cells: A promising targeted-delivery method , 2013 .

[13]  H. D. de Vries,et al.  Morphogens and blood-brain barrier function in health and disease , 2016, Tissue barriers.

[14]  S. Lorenzl,et al.  Matrix metalloproteinases contribute to the blood—brain barrier disruption during bacterial meningitis , 1998, Annals of neurology.

[15]  V. Sebbage Cell-penetrating peptides and their therapeutic applications , 2009 .

[16]  A. Berg,et al.  BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function , 2013, Biomedical microdevices.

[17]  W. Risau,et al.  Development of the blood-brain barrier , 1990, Trends in Neurosciences.

[18]  M D Ginsberg,et al.  Argon laser-induced arterial photothrombosis. Characterization and possible application to therapy of arteriovenous malformations. , 1987, Journal of neurosurgery.

[19]  F. Douglas,et al.  Effect of Chronic Hypertension on the Blood–Brain Barrier Permeability of Libenzapril , 1992, Pharmaceutical Research.

[20]  N. Saunders,et al.  Barriers in the developing brain and Neurotoxicology. , 2012, Neurotoxicology.

[21]  F. Goñi-de-Cerio,et al.  Nanoparticles and blood-brain barrier: the key to central nervous system diseases. , 2014, Journal of nanoscience and nanotechnology.

[22]  Dongliang Wang,et al.  Migration capacity of human umbilical cord mesenchymal stem cells towards glioma in vivo , 2013, Neural regeneration research.

[23]  N. Abbott Anatomy and Physiology of the Blood–Brain Barriers , 2014 .

[24]  W. Risau,et al.  Differentiation-dependent expression of proteins in brain endothelium during development of the blood-brain barrier. , 1986, Developmental biology.

[25]  M. Cipolla,et al.  Cerebral vascular adaptation to pregnancy and its role in the neurological complications of eclampsia. , 2011, Journal of applied physiology.

[26]  W. Hacke,et al.  Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke , 1992, Annals of neurology.

[27]  I. Gonda Systemic delivery of drugs to humans via inhalation. , 2006, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[28]  Kelsey Roe,et al.  West Nile Virus-Induced Cell Adhesion Molecules on Human Brain Microvascular Endothelial Cells Regulate Leukocyte Adhesion and Modulate Permeability of the In Vitro Blood-Brain Barrier Model , 2014, PloS one.

[29]  M. Nair,et al.  Effect of human immunodeficiency virus on blood-brain barrier integrity and function: an update , 2015, Front. Cell. Neurosci..

[30]  T. Nishioku,et al.  Potential role for S100A4 in the disruption of the blood–brain barrier in collagen-induced arthritic mice, an animal model of rheumatoid arthritis , 2011, Neuroscience.

[31]  Tiago R. Oliveira,et al.  Application of hyperthermia induced by superparamagnetic iron oxide nanoparticles in glioma treatment , 2011, International journal of nanomedicine.

[32]  K. Wasan,et al.  Potential role of the low-density lipoprotein receptor family as mediators of cellular drug uptake. , 2004, Advanced drug delivery reviews.

[33]  A. Trapani,et al.  In vitro evaluation on a model of blood brain barrier of idebenone-loaded solid lipid nanoparticles. , 2012, Journal of nanoscience and nanotechnology.

[34]  M. O’Donnell The neurovascular unit , 2015 .

[35]  S. Vinogradov,et al.  Nano-NRTIs: Efficient Inhibitors of HIV Type-1 in Macrophages with a Reduced Mitochondrial Toxicity , 2010, Antiviral chemistry & chemotherapy.

[36]  Xiaoping Zhou,et al.  In vivo tracking of human adipose-derived stem cells labeled with ferumoxytol in rats with middle cerebral artery occlusion by magnetic resonance imaging , 2015, Neural regeneration research.

[37]  Lu Wang,et al.  Two-order targeted brain tumor imaging by using an optical/paramagnetic nanoprobe across the blood brain barrier. , 2012, ACS nano.

[38]  K. Alitalo,et al.  VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia , 2003, The Journal of cell biology.

[39]  Hartwig Wolburg,et al.  Tight junctions of the blood-brain barrier: development, composition and regulation. , 2002, Vascular pharmacology.

[40]  I. Wilhelm,et al.  In vitro models of the blood-brain barrier for the study of drug delivery to the brain. , 2014, Molecular pharmaceutics.

[41]  C. Nicholson,et al.  Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. , 1993, Biophysical journal.

[42]  Joachim Wegener,et al.  The impact of glia-derived extracellular matrices on the barrier function of cerebral endothelial cells: an in vitro study. , 2007, Experimental cell research.

[43]  T. Davis,et al.  The Blood-Brain Barrier/Neurovascular Unit in Health and Disease , 2005, Pharmacological Reviews.

[44]  Nitish V. Thakor,et al.  Efficient Generation of Schwann Cells from Human Embryonic Stem Cell-Derived Neurospheres , 2011, Stem Cell Reviews and Reports.

[45]  N. Abbott Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs , 2015 .

[46]  H. Hammes,et al.  Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor , 2004, Thrombosis and Haemostasis.

[47]  G. Uziel,et al.  Brain fluorodeoxyglucose PET in adrenoleukodystrophy , 2014, Neurology.

[48]  D. Kaufer,et al.  Blood-brain barrier in health and disease. , 2015, Seminars in cell & developmental biology.

[49]  J. Filosa,et al.  Circulating Angiotensin II Gains Access to the Hypothalamus and Brain Stem During Hypertension via Breakdown of the Blood–Brain Barrier , 2014, Hypertension.

[50]  B. Bleier,et al.  Bypassing the blood–brian barrier using established skull base reconstruction techniques , 2015, World journal of otorhinolaryngology - head and neck surgery.

[51]  Alon Friedman,et al.  Dynamic in vivo imaging of cerebral blood flow and blood–brain barrier permeability , 2010, NeuroImage.

[52]  D. Begley,et al.  Structural and functional aspects of the blood-brain barrier. , 2003, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[53]  K. Plate,et al.  Differentiation of the brain vasculature: the answer came blowing by the Wnt , 2010, Journal of angiogenesis research.

[54]  Seyed Nasrollah Tabatabaei,et al.  Remote control of the permeability of the blood-brain barrier by magnetic heating of nanoparticles: A proof of concept for brain drug delivery. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[55]  B. Frey,et al.  Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder? , 2015, Neural plasticity.

[56]  T. Dalkara,et al.  Transport of a caspase inhibitor across the blood-brain barrier by chitosan nanoparticles. , 2012, Methods in enzymology.

[57]  Li-Li Zou,et al.  Send Orders of Reprints at Reprints@benthamscience.net Cell-penetrating Peptide-mediated Therapeutic Molecule Delivery into the Central Nervous System , 2022 .

[58]  Victor W Pike,et al.  PET radiotracers: crossing the blood-brain barrier and surviving metabolism. , 2009, Trends in pharmacological sciences.

[59]  Natalia Vykhodtseva,et al.  Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI‐guided focused ultrasound , 2007, International journal of cancer.

[60]  Pierre J Magistretti,et al.  Astrocyte-neuron co-culture on microchips based on the model of SOD mutation to mimic ALS. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[61]  J. Nguyen Blood–brain barrier in acute liver failure , 2012, Neurochemistry International.

[62]  M. Rattray,et al.  Induction of aquaporin 1 but not aquaporin 4 messenger RNA in rat primary brain microvessel endothelial cells in culture , 2005, Journal of neurochemistry.

[63]  B. Hoh,et al.  Fighting fire with fire: the revival of thermotherapy for gliomas. , 2014, Anticancer research.

[64]  A. Aly,et al.  Intranasal gene delivery for treating Parkinson’s disease: overcoming the blood–brain barrier , 2015, Expert opinion on drug delivery.

[65]  The neurovascular unit , 2015 .

[66]  G. Knott,et al.  Barriers in the Immature Brain , 2000, Cellular and Molecular Neurobiology.

[67]  S. Rapoport Osmotic Opening of the Blood–Brain Barrier: Principles, Mechanism, and Therapeutic Applications , 2000, Cellular and Molecular Neurobiology.

[68]  U. Dirnagl,et al.  Non-invasive visualization of CNS inflammation with nuclear and optical imaging , 2009, Neuroscience.

[69]  F. Pontén,et al.  Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier. , 2015, Developmental cell.

[70]  B. Halliwell,et al.  Iron, Atherosclerosis, and Neurodegeneration: A Key Role for Cholesterol in Promoting Iron‐Dependent Oxidative Damage? , 2004, Annals of the New York Academy of Sciences.

[71]  N. Bogdanovic,et al.  Blood-brain barrier alterations in ageing and dementia , 2009, Journal of the Neurological Sciences.

[72]  K. Møllgård,et al.  Cerebrovascular permeability to azo dyes and plasma proteins in rodents of different ages , 1993, Neuropathology and applied neurobiology.

[73]  C. Patlak,et al.  Efflux of radiolabeled polyethylene glycols and albumin from rat brain. , 1981, The American journal of physiology.

[74]  R. Thorne,et al.  Diffusion of macromolecules in the brain: implications for drug delivery. , 2013, Molecular pharmaceutics.

[75]  D. Matias,et al.  The impact of microglial activation on blood-brain barrier in brain diseases , 2014, Front. Cell. Neurosci..

[76]  B. Engelhardt Development of the blood-brain barrier , 2003, Cell and Tissue Research.

[77]  E. Hansson,et al.  Astrocyte–endothelial interactions at the blood–brain barrier , 2006, Nature Reviews Neuroscience.

[78]  M. Masserini,et al.  Functionalization of liposomes with ApoE-derived peptides at different density affects cellular uptake and drug transport across a blood-brain barrier model. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[79]  C. S. Patlak,et al.  Secretion and Bulk Flow of Interstitial Fluid , 1992 .

[80]  S. Nag,et al.  Blood Brain Barrier, Exchange of metabolites and gases , 2005 .

[81]  Nitish V. Thakor,et al.  Neuromuscular junction in a microfluidic device , 2013, 2013 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC).

[82]  H. D. de Vries,et al.  Blood-brain barrier regulation , 2013, Tissue barriers.

[83]  N. Greig,et al.  Physiology and Pharmacology of the Blood-Brain Barrier , 1992, Handbook of Experimental Pharmacology.

[84]  R. Keep,et al.  Developmental changes in blood‐brain barrier potassium permeability in the rat: relation to brain growth. , 1995, The Journal of physiology.

[85]  M. Khrestchatisky,et al.  Setting-up an In Vitro Model of Rat Blood-brain Barrier (BBB): A Focus on BBB Impermeability and Receptor-mediated Transport , 2014, Journal of visualized experiments : JoVE.

[86]  Peter C. Searson,et al.  The blood-brain barrier: an engineering perspective , 2013, Front. Neuroeng..

[87]  M. Hoehn,et al.  Novel bimodal iron oxide particles for efficient tracking of human neural stem cells in vivo. , 2015, Nanomedicine.

[88]  K. Hynynen,et al.  Noninvasive and targeted drug delivery to the brain using focused ultrasound. , 2013, ACS chemical neuroscience.

[89]  Y. Guan,et al.  Intranasal Delivery of Neural Stem Cells: A CNS-specific, Non-invasive Cell-based Therapy for Experimental Autoimmune Encephalomyelitis. , 2013, Journal of clinical & cellular immunology.

[90]  F. Charron,et al.  The Hedgehog Pathway Promotes Blood-Brain Barrier Integrity and CNS Immune Quiescence , 2011, Science.

[91]  Romain Valabregue,et al.  Triheptanoin improves brain energy metabolism in patients with Huntington disease , 2015, Neurology.

[92]  Xiao-Li Li,et al.  Hyperthermia promotes apoptosis and suppresses invasion in C6 rat glioma cells. , 2012, Asian Pacific journal of cancer prevention : APJCP.

[93]  R. Thorne,et al.  Probing the extracellular diffusion of antibodies in brain using in vivo integrative optical imaging and ex vivo fluorescence imaging. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[94]  E. Aronica,et al.  Status epilepticus, blood–brain barrier disruption, inflammation, and epileptogenesis , 2015, Epilepsy & Behavior.

[95]  H. Caruncho,et al.  Reelin expression in brain endothelial cells: an electron microscopy study , 2015, BMC Neuroscience.

[96]  I. Shelef,et al.  Anatomy and physiology of the blood-brain barrier. , 2015, Seminars in cell & developmental biology.

[97]  D. Rall,et al.  Cerebrospinal Fluid Production by the Choroid Plexus and Brain , 1971, Science.

[98]  Lian Tao,et al.  Brain extracellular space as a diffusion barrier , 2011, Comput. Vis. Sci..

[99]  D. Traver,et al.  Bacterial induction of Snail1 contributes to blood-brain barrier disruption. , 2015, The Journal of clinical investigation.

[100]  R. Ransohoff,et al.  Development, maintenance and disruption of the blood-brain barrier , 2013, Nature Medicine.

[101]  Andrew K. Dunn,et al.  Laser Speckle Contrast Imaging of Cerebral Blood Flow , 2011, Annals of Biomedical Engineering.

[102]  M. Wiley,et al.  Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail--chick transplantation chimeras. , 1981, Developmental biology.

[103]  S. Beg,et al.  Dendrimers as novel systems for delivery of neuropharmaceuticals to the brain. , 2011, CNS & neurological disorders drug targets.

[104]  J. Nathans,et al.  Norrin/Frizzled4 Signaling in Retinal Vascular Development and Blood Brain Barrier Plasticity , 2012, Cell.

[105]  S. Meuth,et al.  Blood-brain barrier modeling: challenges and perspectives , 2015, Neural Regeneration Research.

[106]  O. Grontoft Intracranial haemorrhage and blood-brain barrier problems in the new-born; a pathologico-anatomical and experimental investigation. , 1954, Acta pathologica et microbiologica Scandinavica. Supplementum.

[107]  S. Tatter,et al.  Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment , 2015, Pharmaceutics.

[108]  D. Janigro,et al.  A Dynamic in vitro BBB Model for the Study of Immune Cell Trafficking into the Central Nervous System , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[109]  M Kiessling,et al.  Cerebrovascular and metabolic effects on the rat brain of focal Nd:YAG laser irradiation. , 1990, Journal of neurosurgery.

[110]  Patrick E. Trapa,et al.  Strategies to minimize CNS toxicity: in vitro high-throughput assays and computational modeling , 2012, Expert opinion on drug metabolism & toxicology.

[111]  Karen J. Ferguson,et al.  Willis on narcolepsy , 2003, Journal of neurology, neurosurgery, and psychiatry.

[112]  X. Vignon,et al.  Evidence for the effectiveness of the blood--CSF barrier in the fetal rat choroid plexus. A freeze-fracture and peroxidase diffusion study. , 1984, Tissue & cell.

[113]  W. Hsieh,et al.  Effects of surface modification of PLGA-PEG-PLGA nanoparticles on loperamide delivery efficiency across the blood–brain barrier , 2013, Journal of biomaterials applications.

[114]  Bernd Fritzsch,et al.  Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. , 2003, Developmental cell.

[115]  N. Joan Abbott,et al.  Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology , 2004, Neurochemistry International.

[116]  Andrew P. McMahon,et al.  Canonical Wnt Signaling Regulates Organ-Specific Assembly and Differentiation of CNS Vasculature , 2008, Science.

[117]  Kelvin H. Lee,et al.  The effect of astrocytes on the induction of barrier properties in aortic endothelial cells , 2011, Biotechnology progress.

[118]  P. Schiller,et al.  Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. , 2010, Biomaterials.

[119]  L. Fenart,et al.  Physiological pathway for low-density lipoproteins across the blood-brain barrier: transcytosis through brain capillary endothelial cells in vitro. , 2008, Endothelium : journal of endothelial cell research.

[120]  Y. Olsson,et al.  Blood-brain barrier to albumin in embryonic new born and adult rats , 1968, Acta Neuropathologica.

[121]  T. Osaki,et al.  Antitumor effects of high-temperature hyperthermia on a glioma rat model , 2014, Oncology letters.

[122]  M. Schwartz,et al.  TNF-like weak inducer of apoptosis promotes blood brain barrier disruption and increases neuronal cell death in MRL/lpr mice. , 2015, Journal of autoimmunity.

[123]  B. Barres,et al.  Pericytes are required for blood–brain barrier integrity during embryogenesis , 2010, Nature.

[124]  T. Davis,et al.  Transporters at CNS barrier sites: obstacles or opportunities for drug delivery? , 2014, Current pharmaceutical design.

[125]  Yoav Mayshar,et al.  Mfsd2a is critical for the formation and function of the blood–brain barrier , 2014, Nature.

[126]  K. Plate,et al.  Wnt/β-catenin signaling controls development of the blood–brain barrier , 2008, The Journal of cell biology.

[127]  F. Theil,et al.  Confounding parameters in preclinical assessment of blood-brain barrier permeation: an overview with emphasis on species differences and effect of disease states. , 2013, Molecular pharmaceutics.

[128]  Joshua S Kaminker,et al.  Death receptors DR6 and TROY regulate brain vascular development. , 2012, Developmental cell.

[129]  Hanseup Kim,et al.  Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). , 2012, Lab on a chip.

[130]  Manho Kim,et al.  The protective effect of growth hormone on Cu/Zn superoxide dismutase-mutant motor neurons , 2015, BMC Neuroscience.

[131]  Barbara Ruozi,et al.  Polymeric nanoparticles for the drug delivery to the central nervous system , 2008, Expert opinion on drug delivery.

[132]  D. Bobilya A model for transport studies of the blood-brain barrier. , 2010, Methods in molecular biology.

[133]  M. Alexander,et al.  Principles of Neural Science , 1981 .

[134]  C. Capobianco,et al.  Immunolocalization of tight junction proteins in the adult and developing human brain , 2004, Histochemistry and Cell Biology.

[135]  T. Coleman,et al.  Pathogen-inspired drug delivery to the central nervous system , 2014, Tissue barriers.

[136]  Jun Qian,et al.  Overcoming the blood-brain barrier for delivering drugs into the brain by using adenosine receptor nanoagonist. , 2014, ACS nano.

[137]  I. Wilhelm,et al.  In vitro models of the blood-brain barrier. , 2011, Acta neurobiologiae experimentalis.

[138]  M. Tian,et al.  Multimodality Molecular Imaging of Stem Cells Therapy for Stroke , 2013, BioMed research international.

[139]  M. Dehouck,et al.  Receptor-mediated transcytosis of transferrin through blood-brain barrier endothelial cells. , 1996, The American journal of physiology.

[140]  M. Cipolla,et al.  Increased oxidized low‐density lipoprotein causes blood‐brain barrier disruption in early‐onset preeclampsia through LOX‐1 , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[141]  Jonghee Yoon,et al.  Minimally invasive molecular delivery into the brain using optical modulation of vascular permeability , 2011, Proceedings of the National Academy of Sciences.

[142]  L. Di,et al.  Blood-Brain Barrier in Drug Discovery: Optimizing Brain Exposure of CNS Drugs and Minimizing Brain Side Effects for Peripheral Drugs , 2015 .

[143]  Maria Antfolk,et al.  In Vitro Blood-Brain Barrier Models-An Overview of Established Models and New Microfluidic Approaches. , 2015, Journal of pharmaceutical sciences.

[144]  J. Cuevas,et al.  A modular approach to create a neurovascular unit-on-a-chip. , 2013, Lab on a chip.

[145]  N. Saunders Development of the Blood—Brain Barrier to Macromolecules , 1992 .

[146]  Stina Syvänen,et al.  On The Rate and Extent of Drug Delivery to the Brain , 2007, Pharmaceutical Research.

[147]  J. Greenwood,et al.  The Effect of Bile Salts on the Permeability and Ultrastructure of the Perfused, Energy-Depleted, Rat Blood-Brain Barrier , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[148]  A. Wolka,et al.  Pain and the blood-brain barrier: obstacles to drug delivery. , 2003, Advanced drug delivery reviews.

[149]  Calvin J Kuo,et al.  Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis , 2009, Proceedings of the National Academy of Sciences.

[150]  R. Egleton,et al.  Protection against hypoxia-induced blood-brain barrier disruption: changes in intracellular calcium. , 2004, American journal of physiology. Cell physiology.

[151]  Michael L Shuler,et al.  Murine in vitro model of the blood-brain barrier for evaluating drug transport. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[152]  Bryson M. Brewer,et al.  Glia co-culture with neurons in microfluidic platforms promotes the formation and stabilization of synaptic contacts. , 2013, Lab on a chip.

[153]  Satoru Hayasaka,et al.  Remote spatiotemporally controlled and biologically selective permeabilization of blood-brain barrier. , 2015, Journal of controlled release : official journal of the Controlled Release Society.