This illustration shows how In the Blood-Brain-Barrier (BBB), thin endothelial capillaries (red) are wrapped by supporting pericytes (green) and astrocytes (yellow), enabling them to generate a tight barrier with highly selective transport functions for molecules entering the brain fluid from the blood stream. Credit: Wyss Institute at Harvard University

Like airport security barriers that either clear authorized travelers or block unauthorized travelers and their luggage from accessing central operation areas, the blood-brain-barrier (BBB) tightly controls the transport of essential nutrients and energy metabolites into the brain and staves off unwanted substances circulating in the blood stream. Importantly, it’s highly organized structure of thin blood vessels and supporting cells is also the major obstacle preventing life-saving drugs from reaching the brain in order to effectively treat cancer, neurodegeneration, and other diseases of the central nervous system. In a number of brain diseases, the BBB can also locally break down, causing neurotoxic substances, blood cells and pathogens to leak into the brain and wreak irreparable havoc.

To study the BBB and drug-transport across it, researchers have mostly relied on animal models such as mice. However, the precise make-up and transport functions of BBBs in those models can significantly differ from those in human patients, which makes them unreliable for the prediction of drug delivery and therapeutic efficacies. Also in vitro models attempting to recreate the human BBB using primary brain tissue-derived cells thus far have not been able to mimic the BBB’s physical barrier, transport functions, and drug and antibody shuttling activities closely enough to be useful as therapeutic development tools.

Now, a team led by Donald Ingber, M.D.,Ph.D. at Harvard’s Wyss Institute for Biologically Inspired Engineering has overcome these limitations by leveraging its microfluidic Organs-on-Chips (Organ Chips) technology in combination with a developmentally-inspired hypoxia-mimicking approach to differentiate human pluripotent stem (iPS) cells into brain microvascular endothelial cells (BMVECs). The resulting ‘hypoxia-enhanced BBB Chip’ recapitulates cellular organization, tight barrier functions and transport abilities of the human BBB; and it allows the transport of drugs and therapeutic antibodies in a way that more closely mimics transport across the BBB in vivo than existing in vitro systems. Their study is reported in Nature Communications.

“Our approach to modeling drug and antibody shuttling across the human BBB in vitro with such high and unprecedented fidelity presents a significant advance over existing capabilities in this enormously challenging research area,” said Wyss Institute Founding Director Ingber. “It addresses a critical need in drug development programs throughout the pharma and biotech world that we now aim to help overcome with a dedicated ‘Blood-Brain Barrier Transport Program’ at the Wyss Institute using our unique talent and resources.” Ingber is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at SEAS.

The BBB consists of thin capillary blood vessels formed by BMVECs, multifunctional cells known as pericytes that wrap themselves around the outside of the vessels, and star-shaped astrocytes, which are non-neuronal brain cells that also contact blood …read more

Source:: Daily times

      

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Enhanced human Blood-Brain Barrier Chip performs in vivo-like drug and antibody transport

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