Man in protective suit holding cutting-edge device depicting a digital brain

Organs on a chip: observing the body at microscale

  • Organ chips create complex human body-like system for use in preclinical drug testing
  • Body-on-chip platform could speed up drug discovery
  • Advanced brain-on-a-chip could soon emulate the real deal
  • Using OOAC technology to find better cancer-fighting drugs

For some time now, researchers have been working to find a more cost-effective and humane alternative to animal testing and a more efficient alternative to clinical trials. Besides being tedious and painfully slow for those awaiting new medication, clinical trials are also excruciatingly expensive. In fact, estimates show that global spending on clinical trials is set to reach $68.9 billion a year by 2025. Given that the overall probability of success in clinical trials for all drugs and vaccines is a little over 20 per cent, it is crucial that scientists find a solution that would reduce the time and costs of developing and testing new medicines. One promising option might be the organ-on-a-chip (OOAC) system that mimics the functioning of human organs.

Organ chips create complex human body-like system for use in preclinical drug testing 

Back in 2010, Professor Donald Ingber and his team at the Wyss Institute of Harvard University proposed the first biomimetic microsystem that reproduces lung functions. The team tested the effects of silica nanoparticles on the lungs, studying organ-level responses to bacteria and inflammatory cytokines, small signalling protein molecules which enable “cell to cell communication in immune responses and stimulate the movement of cells towards sites of inflammation, infection and trauma.”  And in the paper published two years later, the team described their use of the lung-on-a-chip device to test a new treatment for pulmonary oedema. 

The microfluid device is simple yet elegantly clever in design. It’s the size of a computer memory stick and made from clear polymer with microchannels no bigger than tens to hundreds of microns. Though minute, the microchannels have a large surface area and high mass transfer. This allows for precision control of chemical and physical properties that are similar to those in living organs. To put it simply, the device comprises two paralleled hollow channels separated by a porous membrane. Organ-specific cell cultures are placed in one, and endothelial cells which imitate blood vessels are placed on the other side of the channel. The porous membrane in between allows the exchange of molecules such as drugs and cytokines. 

The development of this system provides a solid base to create a more complex system that mimics the physiology of the human body. This will enable scientists to observe pharmacokinetics (how medicine is distributed and metabolised), and pharmacodynamics, (how medicine works across the system and the effects on the exposed system). 

Body-on-chip platform could speed up drug discovery

Now, the team has managed to create a body-on-a-chip platform, comprising 10 different biomimetic organ-on-a-chip microdevices. The model consists of a blood-brain barrier, brain, heart, lung, kidney, liver, intestinal tract, and skin. The connected system could allow researchers to observe new drugs or treatment efficacy on the whole body, as Dr Donald Ingber, Wyss Founding Director, Judah Folkman Professor of Vascular Biology at Harvard Medical noted.  “The linked organs within the body-on-chip model can predict which drug administration regimens produce optimal efficacy at the target organ while minimising toxicity in other organs.” 

The team published two papers on the subject in January 2020. The first paper presents the model, while the second paper is dedicated to outlining their computational scaling method. In simple terms, they managed to come up with a system that can translate the experiments conducted on the organ chips to their respective measures that correspond to the human body. The “Intergoator instrument” comprises liquid handling robotics, software, and an integrated mobile microscope. Dr Richard Novak, a co-first-author on both studies and Senior Staff Engineer at the Wyss Institute, and the man behind the device design, emphasised the importance of the study as it shows that it is now possible to predict how a substance distributes across the connected system.

“In this study, we serially linked the vascular channels of eight different organ chips, including intestine, liver, kidney, heart, lung, skin, blood-brain barrier and brain, using a highly optimised common blood substitute, while independently perfusing the individual channels lined by organ-specific cells. The instrument maintained the viability of all tissues and their organ-specific functions for over three weeks and, importantly, it allowed us to quantitatively predict the tissue-specific distribution of a chemical across the entire system.” Ingber added that this approach allowed them “to create a physiologically coupled human body-on-chips and take samples from this flow at every point in the system.”

Advanced brain-on-a-chip could soon emulate the real deal

The human brain is one of the most complex organs of the human nervous system, comprising billions of cells, each behaving differently. And to reproduce the cellular composition of the brain on a chip is quite a challenge. Lawrence Livermore National Laboratory (LLNL) researchers have, however, managed to first culture rodent-derived neurons on a 2D brain-on-a-chip device, and replaced them with brain cell types that are responsible for neuronal health and function. The key element of the study is that it enables a more accurate representation of the brain and its complexity. It also shows the model’s ability to mimic the behaviour of cells in an animal brain. 

“It was clear from what we had done in the earlier work that we needed to enhance the cellular complexity of these devices to more accurately recapitulate the function of the brain in an animal system,” explained the study lead, biomedical scientist Heather Enright. “The goal was to include these other key cell types in ratios that were relevant. We hypothesized that the neurons in these complex cultures would behave similarly as they do in the brain, and we did see some indication of that.”

Using OOAC technology to find better cancer-fighting drugs

Just like designing chips whose structure imitates human organs, modelling tumours, cancer progression, and metastases is just as complex. Kyoto University researchers have devised a new ‘tumour-on-a-chip’ system with improved ability to mimic the environment inside the body. The size of a coin, the chip has a one-millimetre well at the centre to host the cell culture. Cells that serve as blood vessels are placed along the ‘microposts’ surrounding the well. Once the cell culture is placed in its position, blood vessels develop and attach to the culture. “This ‘perfusable vasculature’ allows us to administer nutrients and drugs into the system to mimic the environment in the body,” explains first author Nashimoto, concluding that “at low doses, the benefit of the nutrient flow outweighs the effect of the anti-tumor drug.” 

The future at microscale

Pre-clinical drug testing usually involves either exposing animals to a new drug and observing the effects or in-vitro studies where biological properties are observed in a test tube. Neither, however, yield accurate results as drug-human organ interactions and the important effects this may have on the human body cannot be studied properly this way. This is why a different approach was required.

Organs-on-a-chip systems are promising an effective and more humane way of designing and testing drugs. And while we’re still far from achieving a microsystem that perfectly mimics the complex behaviour of human organs, breakthroughs such as OOAC tech offer some hope that soon we’ll be able to find working drugs much faster and at lower cost. We’re fighting disease, and our biggest and strongest weapon might turn out to be the tiniest!

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