Posted on Aug 20, 2018, 5 p.m.
Brain chip linked to a new organ chip system with 2 blood brain barrier chips to recapitulate interactions between the brain blood vessels reacting to methamphetamine exposure as a human brain would has been developed by scientists at Wyss Institute for Biology Inspired Engineering that has allowed scientists to make new discoveries about blood vessel importance in mental functions, as published in Nature Biotechnology.
One brain chip contains neurons and astrocytes is connected via microfluidic channels to the other 2 brain barrier chips containing endothelial cells with supporting pericytes and astrocytes. Flow of molecules from the vasculature across blood brain barriers into the brain was able to be traced, to find that substances produced by endothelial cells help to maintain neuronal functions.
The human brain is the most complex and delicate organ of the body with over 100 billion neurons that control, every action, thought, and word, it needs extra protection from toxins and other harmful substances. Blood vessels that supply it with nutrients and oxygen are selective over which molecules can cross from blood into the brain and vice versa, these vessels and network of supporting astrocyte and pericyte cells comprise the blood brain barrier, when disrupted as with methamphetamine and other drug exposures the brain’s neurons can become susceptible to harmful damage.
The blood brain barrier is thought to directly interact with the brain and help to regulate functions. Determining how the cells of the blood brain barrier and brain influence each other via models has proven to be a challenge: too simplified in vitro models and too complex in vivo models. Now researchers have developed a new model of blood brain barrier interface using microfluidically linked organ chips that react to methamphetamine as the human brain would, allowing for unprecedented insights into how brain vasculature influences and regulate its metabolic function; opening up another dimension for neurological research no ohe method has been able to, decoupling the dense organ to reveal new interactions between different structures within the brain.
The BBB-Brain Chip Systems consists of 3 chips: One influx blood brain barrier chip; a Brain Chip; and a second efflux blood brain barrier chip, physically distinct from each other all connected with microfluidic channels that allow the exchange of chemicals and other substances between them similar to how supplying blood vessels, neuronal compartment, and draining blood vessels are linked with the brain. Blood brain barrier chip has one channel linked with endothelial cells that culture medium that mimics blood flows separated by porous membranes from a parallel channel containing astrocytes and pericytes perfused with artificial cerebrospinal fluid. Brain Chip has similar cerebrospinal fluid flow channel separated from another semipermeable membrane from a compartment containing human brain neurons with supporting astrocytes to mimic brain tissue. All three chips’ artificial cerebrospinal fluid channels are connected in series together creating a fully linked system in which substances can diffuse from vascular channel across the first blood brain barrier in to artificial cerebrospinal fluid, enter the brain neuronal cell compartments, flow back into the artificial cerebrospinal fluid, and diffuse out across the second blood brain barrier into another vascular channel, as it happens in vivo.
Human cells were cultured in the linked BBB-Brain Chips and exposed to methamphetamine; when meth flowed through blood vessels channel of the chip it compromised junctions of the BBB’s vascular endothelial cells and allowed passage of molecules that typically would not be able to cross. This experiment confirmed the model worked and established it could be used to gain better understandings of drug effects on the human brain and develop treatments.
Chips not exposed to meth expressed proteins by the cells and chips that were fluidically linked and were different from those expressed by cells and unlinked chips, suggesting that different cell types do help each other to maintain proper function. Modular nature of the system allowed all of the molecules secreted by individual cell population alone to be analyzed, and then connect chips to trace where substances travel. Chemicals secreted by cells on uncoupled BBB Chips were related to neuron maintenance and protection which demonstrated molecules produced by the BBB provide chemical cues to neurons.
In order to determine influence of endothelium on metabolites with the brain radioactive carbon labeled glucose, pyruvate, or lactate was administered as an energy supply to chips decoupled from BBB chips to find production of both glutamine and GABA neurotransmitter was lower in unlinked Brain Chips; demonstrating products of the vascular endothelial cell metabolism become substrates for production of neurotransmitter that mediate neuronal cell information processing within the brain, suggesting health of blood vessels may have direct impact on mind function.
According to researchers an unanticipated level of complexity has been demonstrated raising the bar in terms of what it will mean to successfully map out the brain’s connectome with now being able to conduct highly multiplexed, massively parallel metabolomic analysis of many different chemicals produced by different cell types, pushing the limits of how complicated and sophisticated Organ Chips can be to potentially use the decoupling approach to analyze vascular endothelial cells and how they contribute specialized functions of other organs as well.
Materials provided by Wyss Institute for Biologically Inspired Engineering at Harvard.
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Ben M Maoz, Anna Herland, Edward A FitzGerald, Thomas Grevesse, Charles Vidoudez, Alan R Pacheco, Sean P Sheehy, Tae-Eun Park, Stephanie Dauth, Robert Mannix, Nikita Budnik, Kevin Shores, Alexander Cho, Janna C Nawroth, Daniel Segrè, Bogdan Budnik, Donald E Ingber, Kevin Kit Parker. A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells. Nature Biotechnology, 2018; DOI: 10.1038/nbt.4226