From Organs to Whole Humans
Tying together multiple organs on a chip could multiply the research benefits of looking at an individual heart or liver. But engineering tiny systems is a huge challenge.
The human body, of course, is not a single organ, but rather a combination of many organs, all working together in dynamic interplay. So-called human-on-a-chip models aim to mimic those organ-to-organ interactions by connecting multiple organ-on-a-chip devices into physiologically realistic milli- or micro-humans—that is, whole-person models that are one thousand or one million times smaller than a full-size person. “A lot of people are taking a bottom-up view, with everyone making organs,” says John Wikswo, a biological physicist at Vanderbilt University and a collaborator in the Wyss Institute’s DARPA-funded Microphysiological Systems project, which aims to build a working model that connects 10 separate organ chips. “I view myself more as an integrator as well as an organ-builder.”
The challenges of integration include proportionate scaling of organs to one another, and calculating exactly how much fluid the whole system needs to function realistically. The blood or blood surrogate pumped through organ chips delivers not just oxygen and nutrients but also neurotransmitters, hormones and tens of thousands of other molecules that allow organs to “talk” to one another. “The fundamental constraint is how much volume you have to do that,” says Wikswo. “You have about 4.5 liters of blood in you. So a microhuman has 4.5 microliters [millionths of a liter]. The first lung-on-a-chip is one-tenth of a microlung. If you put that together with a liver, a kidney and a couple of other organs, you have 450 nanoliters [billionths of a liter]. You have to figure out how to make your organs without having 10 times that much volume stored in the tubing connecting your organs.”
Wikswo’s lab is working on methods for controlling those small volumes, as well as devising ways to carry out chemical analysis on the tiny samples of fluid that researchers will be able to extract from multi-organ systems without shutting them down. “You don’t bleed a human more than 10%,” he says. “In a microhuman system that means you have to do analytical chemistry in microliters or nanoliters.” Wikswo believes he has a set of tools—including new methods of mass spectrometry, a technique for measuring the atomic mass of molecules in a sample to determine what elements and compounds it contains—that will allow him to do that. “That’s where the engineering lies.”