Inside out – the coming of age of organ-on-a-chip technology

Perhaps the most beautiful thing about pharmacology, and the healthcare industry at large, is the continued pursuit of new ideas and innovations. Not simply for the sake of change, but to develop better, more appropriate solutions that improve the lives of patients around the world.

However, drug development is notoriously slow and expensive. On average, it can take up to ten years for a drug to make it from lab to market, if it even makes it through approvals at all, given that approximately 90% of drugs fail to make it to market.

By law, human and animal testing is required before a drug can be approved. However, this approach has limitations. Take mouse models, for example. In theory, given that mice and humans share 92% of their DNA, drug candidates that successfully target and activate genes in mouse models should achieve the same results in humans. And yet, many drugs fail to make this leap from mouse to human.

Oh, to be a mouse would be a fine thing indeed. The trouble is, that we are not, and so conditions such as Alzheimer’s disease, cancer, and diabetes – ailments that have all been cured in mice – continue to impact patients worldwide.

While animal models have, in the past, played a vital role in developing lifesaving drugs, in an industry where good enough is never really good enough the limitations of this approach naturally became the target for innovative thinkers. In a bid to replace, refine, and reduce reliance on animal models, high-tech alternatives began to emerge, allowing drugmakers to explore new ways to unlock the molecular mechanisms causing modern diseases.

And so began the era of organ-on-a-chip technologies. But how did we get from 2D cell cultures to a series of increasingly complex and connected miniature tissues designed to better mimic human physiology through controlled cell microenvironments and tissue-specific functions?

Let’s find out.


The era of 2D culture

As with many a tale in drug development, the origins of organ-on-a-chip technology begin in the early 1900s, when American biologist and anatomist, Ross Granville Harrison published the results of his successfully cultured frog neuroblasts in a lymph medium. Through his findings, Harrison demonstrated that nerve fibres develop without a pre-existing bridge or chain and that tissues can be grown outside of the body.

During the 1950s, researchers would build on this concept with the development of 2D cell cultures. This method involved growing cells on a flat surface, usually a petri dish, covered in a nourishing material called a growth medium, which allowed cells to form a monolayer that researchers could easily observe and manipulate. Before this, cells were grown in suspension in test tubes, which limited researchers’ ability to study cell behaviour and interactions.

Although the exact inventor of 2D cell cultures is unknown, key pioneers in the field include George Gey, who developed the first permanent cell line, and Jonas Salk, who established the first cell culture laboratory. These and other scientists laid the foundation for the widespread use of 2D cell cultures in cell biology research.


The origins of microfluidics

While it would be another 50 years until organ-on-a-chip technology emerged, the story of this ground-breaking innovation could not be told if it were not for the discovery of microfluidics.

The history of the field can be traced back to the late 1960s, when researchers first began to develop systems for handling small fluidic volumes, typically in the microlitre or nanolitre range.

Over the following two decades, advances in microfabrication technology and materials science led to the development of increasingly sophisticated microfluidic devices, such as lab-on-a-chip systems.

The development of microfluidic technology has been a key enabling factor for organ-on-a-chip technology. Microfluidic devices are used to control the flow of fluids and nutrients in the device, creating a controlled environment that mimics the human body. These devices are typically made from materials such as silicone or plastic and are designed to recreate the physical, chemical, and biological conditions that exist in human organs and tissues. This allows researchers to test drugs and other compounds in a more human-relevant context, providing better predictions of human response and reducing the risk of late-stage clinical failures.

Credit: University of Washington Photo


Cultures enter a new dimension

Recognising the limitations of 2D cell cultures, researchers began to search for a way to represent the complex in vivo microenvironment more accurately. The result: 3D cell cultures. The exact date of the invention of 3D cell cultures is difficult to determine, as it is the result of the collective effort of multiple researchers and scientists over a period of several decades. However, the first use of “three-dimensional culture models” is commonly attributed to early studies published in 1989 and 1992.

3D cell cultures aim to better replicate the in vivo conditions by creating a three-dimensional structure for cells to grow in, which more closely resembles the native tissue architecture. This allows for more accurate modelling of cell-cell interactions, signalling, and functions. Key pioneers in the field include András Nagy, who was one of the first to report the successful generation of 3D structures using mouse embryonic stem cells, and Maeve Duffy, who developed a technique to generate 3D structures using hydrogels.

These cell cultures can be generated using a variety of methods, including scaffold-based systems, hydrogels, and organoids. The increased complexity and more physiologically relevant conditions offered by 3D cell cultures have broadened their use in various fields, including drug discovery, disease modelling, and tissue engineering.


The first successful organ-on-a-chip developed

The first organ-on-a-chip was created by researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University in 2010. Led by Donald Ingber, the team developed a “biomimetic microsystem”, capable of reproducing complex integrated organ-level responses to bacteria and inflammatory cytokines in the lung alveolar.

The microfluidic device established a new approach to tissue engineering, as it incorporated two layers of living human-cultured tissues – epithelial cells and endothelial cells – onto a porous, flexible material, approximately the size of an eraser. To mimic the natural responses of living lungs, air is delivered to the lung lining cells, while a rich culture medium flows in the capillary channel to replicate blood flow and cyclic mechanical stretching imitates the breathing process. Together, these unique features enabled researchers to study drug toxicity and disease progression in a way that closely resembled the human body.

To test just how closely this pioneering technology performed as a dupe for the human lung, researchers introduced living E. coli bacteria into the air channel, while simultaneously allowing white blood cells into the capillary channel. Results from the study showed that the lung cells were able to detect and respond to the bacteria’s presence, triggering an immune response that mobilised the white blood cells to destroy the E. coli in the air chamber.

Credit: Wyss Institute, Harvard University
Funded by: NIH Common Fund


Credit: Emulate, Inc.

New materials create new opportunities

As the potential of organ-on-a-chip technologies gained greater attention from researchers within the pharmaceutical industry, advancements in the quality and quantity of materials for their fabrication were inevitable.

While polydimethylsiloxane (PDMS) was – and still remains – the predominant material used for organ-on-a-chip devices, due to its ease-of-use, biocompatibility, and relatively low microfabrication costs, it does have limitations. PDMS is hydrophobic in nature, which restricts the attachment and the spreading of cells.

And researchers began to explore alternatives, including Annabi et al, published in 2013. In the study, the team developed a new technique to address the challenges of PDMS-based devices, by coating microfluidic channels with hydrogels – specifically methacrylated tropoelastin (MeTro) and methacrylated gelatin (GelMA) ­– which provided a suitable environment for cardiomyocyte (CM) attachment inside of the channel. This development, alongside other advancements, opened doors for research to pursue on-chip cardiac cell cultures.


Breaking barriers in biology

The blood-brain barrier is notoriously good at preventing unwanted substances from accessing the brain. More often than not, this is a highly necessary function. However, it does pose a significant impediment for pharma companies, as many potential drug treatments struggle to breach it.

As part of efforts to drive research in the sector, in 2016 researchers at the Wyss Institute developed a blood-brain barrier-on-a-chip, mimicking the barrier that separates the brain from the bloodstream. To form the chip, the team fabricated a long, narrow lumen inside of a clear polymer chip, designed to reflect the shape of a blood vessel, which was filled with a collagen matrix containing human brain astrocyte cells and lined with living human endothelial cells. Human brain pericyte cells were subsequently placed inside the lumen to complete the chip.

Using the blood-brain barrier on-a-chip model enabled the research team at Wyss to study neuroinflammatory response in vitro by introducing a pro-inflammatory protein commonly associated with diseases of the central nervous system, including Alzheimer’s, brain ischemia, multiple sclerosis, stroke, and traumatic brain injury.

That same year, in a slightly unusual turn of events for organ-on-a-chip research, the National Institutes of Health (NIH) teamed up with NASA and the International Space Station (ISS) to launch the Tissue Chips in Space programme. The goal? To better understand the role of microgravity on human health and diseases and translate those findings to improve human health on Earth. The first of these NIH-supported chips was – quite literally – launched in December 2018. This immune-system chip was closely followed by the launch of four additional tissue chip projects: lung and bone marrow, bone and cartilage, the kidney, and the blood-brain barrier.

Credit: Neurovascular unit, blood brain barrier, TEM. Khuloud T. Al-Jamal & Houmam Kafa. Attribution 4.0 International (CC BY 4.0)


Credit: Vanderbilt University

US FDA sets its sights on Organs-on-Chips technology

Recognising the rapid advancement of microfluidic devices and the multiple different organs now replicated in chip form, in April 2017 the US Food and Drug Administration (FDA) announced plans to enter into a multi-year cooperative research and development agreement (CRADA) with Emulate. First unveiled in 2014, Emulate – a spin-out from Harvard University’s Wyss Institute – had already amassed a comprehensive portfolio of organ-on-a-chip products.

Under the deal, Emulate and the FDA set out to evaluate and qualify the use of Emulate’s Organs-on-Chips technology as a platform for toxicology testing in order to meet regulatory evaluation criteria for products – including foods, dietary supplements, and cosmetics.


Organ-on-a chip takes the main stage of pharma

Having racked up multiple success stories of organ-on-a-chip technologies demonstrated by research teams around the world, it wasn’t long before big-name industry players began to pay attention to this burgeoning sector.

As such, 2018 was a big year for partnerships between organ-on-a-chip start-ups and Big Pharma companies.

In February, Roche and Takeda announced plans to partner with Emulate. Through the three-year partnership, the pharma giants gained access to Emulate’s array of organ-chips for testing the efficacy and safety of new antibody therapeutics and combination therapies.

Later that year, AstraZeneca also signed on to partner with Emulate and incorporate organ-on-a-chip technology into the pharma giant’s R&D programme. This built on previous work between the two companies, which began back in 2013.

Credit: National Center for Advancing Translational Sciences


Credit: Wyss Institute at Harvard University

Enter the OCTOPUS

If you hadn’t already guessed, this is not an actual octopus. The Organoid Culture-based Three-dimensional Organogenesis Platform with Unrestricted Supply of soluble signals (OCTOPUS) is, in fact, an organoid device developed by a research team at the University of Pennsylvania School of Engineering and Applied Science.

Lead by Dan Huh, a notable figure in the early development of organ-on-a-chip devices at Wyss Institute, OCTOPUS is designed to bring us closer to finally achieving the goal of a “human-on-a-chip”.

Although immature organoids can generate a wealth of valuable information for researchers, when it comes to replicating the true complexity of living human organs, maturity is key. As such, finding ways to nurture organs-in-a-dish to greater levels of maturity has been a notable area of research. This is where the team behind OCTOPUS claims to have significantly advanced the frontiers of organoid research.

OCTOPUS, they claim, reimagines the 3D geometry of the hydrogel culture material, splitting this scaffold into a tentacled configuration to better mimic the complex and dynamic environment of the human body. These thin culture chambers sit on top of a circular dish, approximately the size of a US quarter coin. With this format, Huh and his team demonstrated accelerated production of intestinal organoids with significantly enhanced structural and functional maturity, as well as continuous development over a four-week period.


A new era for research enters US law

Heading into a new year, the US Government marked a clear turning of the tide for clinical R&D with the introduction of the FDA Modernization Act 2.0. Signed by President Biden at the very tail end of December 2022, the Act repealed a long-standing requirement that experimental treatments be studied in animal models before they can be considered for human trials.

Instead, the legislation authorises the use of alternative methods – such as organ-on-a-chip – alongside animal studies, to investigate the safety and effectiveness of a drug.

While this Act is unlikely to transform the R&D landscape overnight, it is a clear sign that regulators, industry experts, and researchers are confident that organ-on-a-chip technologies, organoids, and computer models, have an important role to play in advancing the future of medicine.

Image credit: Wyss Institute at Harvard University

About the author

Eloise McLennan is the editor for pharmaphorum’s Deep Dive magazine. She has been a journalist and editor in the healthcare field for more than five years and has worked at several leading publications in the UK.

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