BLOOD-BRAIN BARRIER MODELS IN CHIP DEVICES
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1 BLOOD-BRAIN BARRIER MODELS IN CHIP DEVICES Mária A. Deli Institute of Biophysics, Biological Research Centre Hungarian Academy of Sciences, Szeged, Hungary Centre of Excellence of the European Union
2 WHAT IS THE BLOOD-BRAIN BARRIER? Brain capillaries length: 650 km (Budapest Adriatic sea) surface: m 2 Roles creates homeostasis for neuronal functions provides brain with nutrients defense system against toxic insults communication: periphery CNS
3 WHY THE BLOOD-BRAIN BARRIER IS IMPORTANT? Drug delivery to the brain Limited brain entry water soluble molecules, biotherapeutics, efflux ligands chemotherapeutics, antiepileptics, antibiotics Difficult to treat neurological diseases Diseases affect the BBB Systemic diseases alcoholism, diabetes infectious diseases: NeuroAIDS Neurological diseases neurodegenerative diseases: Alzheimer s disease epilepsy, brain tumors, stroke traumatic brain & spinal cord injury How to study?
4 MODELS TO STUDY THE BLOOD-BRAIN BARRIER Animal studies Experiments with dyes Paul Ehrlich - alizarin blue-s Electron microscopy 1967 Reese and Karnovsky: Tight junctions (TJ) BEC P Resistance measurement of brain vessels 1982 Crone and Olesen: 1870 Ω L TJ Deli MA et al.
5 CULTURE MODELS OF THE BLOOD-BRAIN BARRIER Bowman et al. Brain endothelial cell monolayers on culture inserts Cells Resistance Permeability
6 CO-CULTURE BBB MODEL Transwell TM membrane HE 0.4 µm pore brain endothelial cells pericytes astrocytes Nakagawa et al. Cell Mol Neurobiol Niwa, Nakagawa, Deli, WO , 2007 Nakagawa et al. Neurochem Int. 2009
7 MAJOR APPLICATION OF CO-CULTURE BBB MODELS Physiology Pharmacology Cell interactions Drug effects, ADME Pathology Microbial pathogenesis Invasion of microbes Endothelial cell Pericyte Disease models pathomechanism Astrocyte
8 NEW DIRECTIONS: MICROFLUIDIC BBB MODELS Last 5 years: >25 papers on microfluidic chip BBB models / >7 reviews BBB-chip models Advantages Realistic microenvironment: flow Control over microenvironment Organ-level function co-culture of >2 cell types Real-time readouts microscopy, permeability, TEER, impedance Parallelized testing
9 BARRIER CHIP MODEL MEASUREMENT OF RESISTANCE Walter et al. Sensors and Actuators B: Chemical 2016
10 BARRIER CHIP MODEL FLOW Channel dimensions: 3.7 cm 0.2 cm 0.2 cm Flow: ml/min Shear-stress: 0.15 dyn/cm 2, Pa Walter et al. Sensors and Actuators B: Chemical 2016
11 CO-CULTURE BBB MODEL ON THE CHIP DEVICE brain endothelial cells pericytes astrocytes Walter et al. Sensors and Actuators B: Chemical 2016
12 SUMMARY Integrated microfluidic chip devices Projects Simple design, cheap materials Co-culture of 3-4 types of cells Visualization of the entire cell layer by microscopy real-time Transcellular electrical resistance monitoring (commercial device) Permeability measurements Flow of culture medium Human stem cell based BBB models Other human barrier models (gut, lung) Nanoparticles for drug delivery Possible partners Drug delivery, nanoparticles Brain diseases Barrier pathology
13 ACKNOWLEDGEMENT Biological Barriers Research Group Dr. Zsófia Hoyk Dr. Szilvia Veszelka Dr. Fruzsina Walter Dr. Alexandra Bocsik András Harazin Mária Mészáros Ana Raquel Santa Maria Ilona Gróf Barna Lilla Biomolecular Electronics Research Group Dr. András Dér Dr. Sándor Valkai András Kincses
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