“Still, each of these approaches too often fall short in their clinical translational merit,” he asserts. “The advent of the microbrain reactor not only would offer a human-cell derived blood-brain barrier with properly expressed, functional drug transport proteins and drug metabolizing enzymes, but it would be malleable with respect to its ability to mimic human disease states known to impact central nervous system (CNS) health and the integrity of the BBB. One could envision a drug discovery organization utilizing the technology to accurately predict the penetration of the CNS by novel small-molecule drug candidates, predict development-limiting drug-drug interactions and even measure a pharmacological response as a result of engaging a key receptor within the human brain microvasculature.”  

 

“What was not doable before was to have in a single model both neurons and blood vessels,” Janigro says. “For example, brain cells can metabolize drugs in an unpredictable manner. This new device allows us to assess what the brain does to the drug and what the drug does to the brain. A limitation is the fact that it is likely that a given disease will have different genetic and environmental backgrounds in different patients. The goal of a truly personalized medicine is yet to come.”  

 

Also potentially important, beyond just the neuroscience applications specifically, is the ability to better explore mechanical changes to cells, says Dr. John A. McLean of the Vanderbilt Institute of Chemical Biology and Vanderbilt Institute of Integrative Biosystems, who is also an assistant professor of chemistry at the university. Sometimes, he notes, mechanical changes to cells can be as important or more so than biochemical changes.

 

One of the key challenges the team has been able to address so far, Wikswo says, is the problem of needing to have the volume of the organ system and each organ on a chip matched, lest one organ dominate the others or paracrine factors secreted by any organ be diluted below physiological threshold by an unnaturally large perfusion volume. This will be especially important for creating humans-on-a-chip, he says, given that in a “milliHuman,” for example, the entire system can have only ~5 mL of perfusate.  

 

In addition, Wikswo says, “The small volumes present clear difficulties in both analytical chemistry and system control, which are addressed by techniques that David Cliffel, John McLean and I have been working on for years, which gives us a very clear path towards characterizing the dynamics of drug responses in our microphysiological systems.”  

 

Wikswo notes that he is involved, for example, on work that is funded through Harvard on the DARPA Microphysiological Systems Program to develop a 10-organ microphysiological system, and another project through the Los Alamos National Laboratory to create a four-organ system on slightly larger scale.

 

But whether creating a human-on-a-chip, multi-organ chip models or a single organ model, the value is clear.

 

“Given the differences in cellular biology in the brains of rodents and humans, development of a brain model that contains neurons and all three barriers between blood, brain and cerebral spinal fluid, using entirely human cells, will represent a fundamental advance in and of itself,” Wikswo says.  

 

That is almost certain to attract industry partners for development at some point, though there are no specific plans to commercialize the microbrain work.  

 

“At present, though, I am searching for an industrial partner to refine and commercialize our new microfluidic pump and valve technology that is critical to the perfusion controller/microclinical analyzer systems we are designing for all of these projects.”