The chip that marks the beginning of the end for animal testing

Animals have long been essential to drug development, but not for much longer. Human-on-a-chip technology is seeing dramatic advances, and could soon consign animal research to history

Imagine a world where the medical research industry – the one we rely on for cures, medicines, vaccines and antidotes – has access to technology that made both animal and human test subjects completely obsolete. That reality is a very real proposition, says Elizabeth Wheeler, the principal investigator and researcher of a team at Lawrence Livermore National Laboratory (LLNL) working on the iCHIP (In-vitro Chip-based Human Investigational Platform) project.

“The ultimate goal is to fully represent the human body,” Wheeler says. “Fully functional human-on-chip technology will present a paradigm shift in generating human-relevant data.”

The iCHIP – also known as human-on-a-chip – is a miniature, external replication of the human body, which integrates biology and engineering with a combination of microfluidics and multi-electrode arrays. On it, Wheeler and her team aim to reproduce the four major biological systems vital to life: the brain, or central nervous system (CNS), the peripheral nervous system (PNS), the blood-brain barrier (BBB) and the heart.

Once developed and integrated on the chip, these systems can be used in place of animal and human test subjects: a speedier, ethically sound and infinitely more accurate way to predict the impact of chemicals, viruses, medicine and drugs on the human body.

Research progress

Progress on all four platforms is being made, reports Wheeler. For the CNS platform, the team seeded primary neurons onto a microelectrode array device, which can accommodate up to four brain regions, such as the hippocampus, thalamus, basal ganglia and cortices. Once the cells have grown, stimuli such as caffeine, atropine and capsaicin are introduced, and electrical activity from the neurons is recorded.

Images courtesy of Julie Russell LLNL

Images courtesy of Julie Russell LLNL

Preliminary results on this platform have been promising; the team has shown that hippocampal and cortical cells can survive on the iCHIP for several months while their responses are recorded and analyzed.

“Being able to keep neurons alive for extended periods of time allows us to perform experiments that measure the effects of low-level, long term exposures,” she explains.

LLNL engineer Monica Moya is leading the team working on the BBB platform, which uses tubes and microfluidic chips to simulate blood flow through the brain. The BBB acts as the brain’s gatekeeper, allowing nutrients to enter the brain while filtering out and blocking potential toxins. It’s so efficient at this job that it can also block potentially useful therapeutics, so simulating this system, externally, should enable researchers to better study, understand and potentially unlock the BBB’s permeability.

Research into the PNS, which connects the brain to limbs and organs, is being led by lab scientist Heather Enright. The PNS device boasts arrays of microelectrodes embedded on glass, where primary human dorsal root ganglion (DRG) neurons are seeded, and then exposed to chemical stimuli via a microfluidic cap. Electrical signal readings are then taken, along with microscopic images, to monitor changes in intracellular ion concentrations, such as calcium.

Breaking boundaries

This platform, points out LLNL’s Jeremy Thomas, is the first to demonstrate that “long-term culture and chemical interrogation of primary human DRG neurons on microelectrode arrays is possible”– a boundary-breaking boon for researchers.

“The cardiac platform is our youngest system,” explains Wheeler. “Our approach to recapitulating cardiac function on a microfluidic device has focused on measuring both the electrical function of the cells as well as the contractile force. We are modifying and enhancing the capability of our existing neural electrophysiology platforms to include measuring the beating rate and force of cardiomyocytes (muscle cells).”

The next step, says Wheeler, is integrating the systems in order to create a complete, cohesive and noninvasive testing platform. The noninvasive aspect will be of great interest to animal rights campaigners, who’ve long pointed out that vivisection is not only expensive, time-consuming and ethically questionable, but also frequently unreliable due to difference between human and animal species, producing inaccurate data.

The Dr Hadwen Trust, which was founded in 1970 by Sidney Hicks and named in memory of the physician and anti-vivisectionist Dr Walter Hadwen, is committed to researching and supporting cruelty-free medical research. During the ‘80s, the Trust – which relies solely on donations and legacies and receives no funding from the government – played a central role in developing and pioneer cell culture research, a technique that is used today in virtually every field of medical research, including the iCHIP.

Dr Brett Cochrane, science director at the Dr Hadwen Trust, applauds and supports the iCHIP project “not only (as a means to) reduce/replace research animals, but also to address the continued issues surrounding the potential lack of human-relevancy when animal models are solely relied on. The LLNL enjoys an enviable reputation as a world class science, technology and engineering institute and the reason that I mention that because cross-discipline expertise is – and will continue to be – critical in the development of the technologies and approaches that are urgently required to enhance human health and eliminate the requirement for animals to be used in biomedical research. Technology is key.”

Do we still need animals?

Why – given the science world has historic, established proof that vivisection can be unreliable – do we still employ it? The reasons are many and complex, explains Dr Cochrane, and include (but are not limited to): a lack of funding streams, a lack of cohesion between scientists and funding bodies, differing legal, regulatory and cultural restrictions throughout the world, an unwillingness to explore alternatives and retrain staff in other techniques and huge lobbying pressure from an entire industry dedicated to the supply of laboratory animals, who are, Chochrane points out, “sadly, still considered a dispensable laboratory consumable.”

The enormous concern here for us is that these findings may actually increase the numbers of animals being used

Is animal-testing still the default approach in medical research around the globe? Yes and no, says Cochrane. Regulations and legal requirements that protect animals are becoming more common, particularly in the UK.

However, “there is a growing body of evidence emerging that interspecies differences between humans and animals may not, in certain circumstances, be the only issue – but compounded by issues surrounding how the animal study was designed and reported. The enormous concern here for us is that these findings may actually increase the numbers of animals being used.”

The good news is that a number of catalysts are helping to phase out vivisection, says Cochrane. “These include improved, cohesive and collegiate relationships between animal welfare groups, industry and academia and evidenced-based, human-focused approaches to demonstrate to regulators why animal models should no longer be considered the default method to understand human disease mechanisms or to predict human toxicities.

“While technology is of immense importance, development needs to be matched with the willingness to change and move forward. This is to the benefit of both humans and animals.”

Cochrane cites a number of options in what he call the ‘toolbox’ of cruelty-free research alternatives, including organ-on-a-chip tech, tissue engineering, microdosing, ‘Omic technologies, advanced human non-invasive imaging technologies and human induced pluripotent stem cell technology, along with companies such as Kirkstall, CN Bio and XCellR8, who are actively engaged in and committed to pioneering anti-vivisection research techniques.

The iCHIP – once completed and distributed – is sure to be a game-changer in this regard, though Wheeler says a fully developed validated human-on-a-chip is “a few years off yet. We are focusing on an integrated functional brain and blood brain barrier within the next three years.”

iCHIP’s impact

What will fully functional iCHIP tech mean for the science world, and wider society as a whole? “Having systems that accurately reflect human physiology will allow scientists to develop new therapies, investigate the impact of exposure to chemicals and toxins and discover new biological mechanisms ­– all without relying on animal testing,” says Wheeler.

It will also offer the very real potential of personalized medicine, which US Health News defines as: “healthcare that is informed by each person’s unique clinical, genetic, genomic, and environmental information. Because these factors are different for every person, the nature of diseases – including their onset, their course and how they might respond to drugs or other interventions – is as individual as the people who have them.”

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“Personalized medicine allows a physician to tailor therapies to individuals,” explains Wheeler. “Platforms like iCHIP can aid this by providing an ex vivo (meaning that which takes place outside an organism) way to test a patient’s response to numerous medicines. Using the developing stem cell technologies, it will be possible to populate the devices with cells from particular individuals, providing a way to select the best course of action for each individual patient.”

Approximating the cost of making and distributing the iCHIP for mass, global use once the tech is fully developed is tricky at this stage, says Wheeler.

“It’s hard to predict at this point. We’d obviously like it to be as low as possible so that it can have widespread usage. At this point, the tech is still very specialized and it requires a lot of skill to acquire and interpret the data. But we believe that many of the exceptional needs of the system can be streamlined as the platform matures.”

New research claims a video game can improve doctors’ ability to recognise severe trauma in patients

New research has concluded a specifically-designed video game improves doctors’ ability to recognise when patients need to be transferred to a severe trauma centre.

The research, by the University of Pittsburgh School of Medicine and published today in the BMJ, revealed the game Night Shift was better at preparing doctors to recognise patients who needed higher levels of care than reading traditional educational materials.

This was the case even though doctors who were made to play the game, in which doctors play as a fictitious, young emergency physician treating severe trauma patients, enjoyed it less than those who were asked to read relevant materials.

“Physicians must make decisions quickly and with incomplete information. Each year, 30,000 preventable deaths occur after injury, in part because patients with severe injuries who initially present to non-trauma centres are not promptly transferred to a hospital that can provide appropriate care,” said the game’s creator Deepika Mohan, MD, MPH and assistant professor in Pitt’s departments of Critical Care Medicine and Surgery.

“An hour of playing the video game recalibrated physicians’ brains to such a degree that, six months later, they were still out-performing their peers in recognising severe trauma.”

Night Shift was designed by Mohan to tap into the part of the brain that uses pattern recognition and previous experience to make snap decisions by using subconscious mental shortcuts – a process called heuristics.

Doctors in non-trauma centres typically see only about one severe trauma per 1,000 patients. As a result, their heuristic abilities can become skewed toward obvious injuries such as gunshot wounds, and miss equally severe traumas such as internal injuries from falls.

On average, 70% of severely injured patients who present to non-trauma centres are under-triaged and not transferred to trauma centres as recommended by clinical practice.

“There are many reasons beyond the doctor’s heuristics as to why a severe trauma patient wouldn’t be transferred to a trauma centre, ranging from not having an ambulance available to a lack of proper diagnostic tools,” said Mohan.

“So, it is important to emphasize that recalibrating heuristics won’t completely solve the under-triage problem and that the problem isn’t entirely due to physicians’ diagnostic skills. But it’s heartening to know we’re on track to develop a game that shows promise at improving on current educational training.”

For the study, Mohan recruited 368 physicians from across the US who did not work at hospitals specialising in severe trauma. Half were assigned to play the game and half were asked to spend at least an hour reading the educational materials.

Participants then responded to questionnaires and completed a simulation that tested how often they “under-triaged,” or failed to send severe trauma patients to hospitals with the resources necessary to handle them.

Physicians who played the game under-triaged 53% of the time, compared with 64% for those who read the educational materials.

Six months later, Mohan reassessed the physicians and found that the effect of the game persisted, with those who played the game under-triaging 57% of the time, compared to 74% for those who had read the educational materials.

Multimedia courtesy of Schell Games.

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