Developing new prescription drugs and antidotes to toxins currently relies extensively on animal testing in the early stages. That is not only expensive and time consuming, but it can also give scientists inaccurate data about how humans will respond to such agents.
But what if researchers could predict the impacts of potentially harmful chemicals, viruses, or drugs on human beings without resorting to animal or even human test subjects?
To help achieve that goal, scientists and engineers at Lawrence Livermore National Laboratory are developing a “human-on-a-chip,” a miniature external replication of the human body, integrating biology and engineering. The team is combining microfluidics (networks of tiny tubes and channels) and multi-electrode arrays (devices that connect neurons to electronic circuitry).
The project, known as iCHIP (in-vitro Chip-based Human Investigational Platform), reproduces four major biological systems: the central nervous system (brain), peripheral nervous system, the blood-brain barrier, and the heart.
“It’s a testing platform for exposure to agents whose effects are unknown to humans,” said LLNL engineer Dave Soscia, who co-leads development of the “brain-on-a-chip” device used to simulate the central nervous system. “If you have a system that is engineered to more closely replicate the human environment, you can skip over the really lengthy process of animal testing, which doesn’t necessarily give us information relevant to humans.”
The iCHIP team is focusing its efforts on the brain, where they’re looking to understand how neurons interact with each other and react to chemical stimuli such as caffeine, atropine (a drug used to treat poisonings and cardiac arrest), and capsaicin, the compound that gives chili peppers their hotness, as well as chemical agents in the Lab’s Forensic Science Center.
Unique to the iCHIP platform is combining multiple brain cell types on the same device without barriers between those regions. To study the brain, primary neurons are funneled or “seeded” onto a microelectrode array device, which can accommodate up to four brain regions (such as the hippocampus, thalamus, basal ganglia, and cortices). After the cells grow, a chemical (atropine for example) is introduced, and the electrical activity from the neurons is recorded.
“The idea is that we can look at network-wide effects across different brain regions,” Soscia said. “It adds a level of complexity that has never been done before.”
Preliminary results have shown that hippocampal and cortical cells can survive on the chip for several months while their responses are recorded and analyzed, Soscia said.
The human body features a vital mechanism called the blood-brain barrier, which filters out chemicals and toxins before they reach the central nervous system. LLNL engineer Monica Moya leads the team trying to reproduce it for the iCHIP. The device uses tubes and microfluidic chips (which feature tiny etched channels rather than tubes) to simulate blood flow through the brain. Moya and her team are testing the device with caffeine and other agents to ensure the system is performing and the cells are reacting as they would in a human body.
“The blood-brain barrier is the brain’s gatekeeper, allowing nutrients to enter in the brain from the blood flow while keeping out potential toxins. It works so well that it unfortunately can also block potentially useful therapeutics to the central nervous system,” Moya said. “Having a realistic human lab model of the blood-brain barrier will help researchers study the barrier’s permeability and be incredibly useful as an in vitro model for drug development”
The iCHIP research, Moya said, could have implications for creating new drugs to fight cancer, vaccines, or evaluating the efficacy of countermeasures against bio-warfare agents.
Scientist Heather Enright is leading research into the peripheral nervous system (PNS), which connects the brain to the limbs and organs. The PNS device has arrays of microelectrodes embedded on glass, where neurons from the spinal cord are seeded. Chemicals such as capsaicin (to study pain response) then flow through a small, precise valve to stimulate the cells on the platform.
The microelectrodes record electrical signals from the cells, allowing researchers to determine how the cells are responding to the stimuli non-invasively. This has important advantages over current techniques. “A multi-electrode array approach, like that used on iCHIP, really allows you to interrogate the cells over multiple trials so we can maximize the data we get from them. This is especially important when testing rare primary human cells. When you’re looking at exposure to an unknown chemical for instance, the cells’ response may be different weeks or months compared to hours after exposure. This is a non-invasive way of assessing changes in their health and function over time.”
Additionally, early research is being done to replicate the heart on a chip. Cardiac cells have already been shown to successfully “beat” in response to electrical stimulation, with the intent to simultaneously measure the electrophysiology and movement of the cells.
The next step, according to iCHIP principal investigator Elizabeth Wheeler, is integrating all the systems together to create a complete testing platform to study some fundamental scientific questions.
“The ultimate goal is to fully represent the human body,” Wheeler said. “Not only can the iCHIP provide human-relevant data for vaccines, but it can also provide valuable information for understanding disease mechanisms. The knowledge gained from these human-on-a-chip systems will someday be used for personalized medicine.”