Organ-on-a-chip

Definition

Organs-on-a-chip are small devices designed to replicate as closely as possible the microenvironment and physiological conditions that cells live in within their native tissues and organs to provide more realistic responses than traditional culture experiments. Also known as ‘In Vitro Cell Culture Technology’ and ‘Micro Physiological Systems’, the chips are often made from synthetic transparent materials and contain minute hollow tubes and chambers coated with cells as well as mechanical components to enable more precise simulation of the natural cellular microenvironment. Furthermore the transparency and integration of biosensors can provide more detailed and accurate insights into the molecular and cellular activities that underpin the function of human organs and particular disease states.

Organ-on-a-chip. Credit: Wyss Institute.

Importance

Organ-on-a-chip (Organ Chip) technology promises to be a major tool to address the rising cost and declining efficiency of drug research and development in addition to providing a new approach to personalised medicine. One of the main attractions of Organ Chips is that they provide a better predictive model of drug responses in real human tissues and organs than animal experiments. This is sorely needed because more than 70 percent of all drugs that appear promising in preclinical animal studies go on to fail in human clinical trials because the animal model is often not applicable to humans and the drug proves to toxic and ineffective when tested in humans (Tagle). Many approved drug products also get withdrawn from the market because of unanticipated adverse reactions (Oleaga, Bernabini, Smith).

One of the drivers of this problem is the difficulty of translating safety, toxicity and efficacy data from animal studies to humans. This can have tragic consequences, as shown by the example of TGN1412, a monoclonal antibody drug developed to direct the immune system to destroy cancer cells. Initially found to be safe and effective in rodents and monkeys, it proved catastrophic when first tested in humans in phase I clinical trials because it prompted an adverse immune response caused by a cytokine storm. Subsequent research indicated that this might have been due to a slight difference in the amino acid sequence of the CD28 receptor between the animals and humans (Oleaga, Bernabini, Smith). In a case like this, testing the drug in chips containing human cells prior to the clinical trials would have negated such a problem.

Furthermore, Organ Chips can be loaded with cells unique to an individual patient, providing more accurate predictions of toxicity and efficacy specific to them, thereby opening up a more effective means of personalised medicine. Organ chips could also prove useful for validating potential drug targets identified by genomic and proteomics so they can enhance the drug discovery process. This is particularly important because of the great variability found between different ethnic and genetic groups in their responses to therapy (Ingber 2022). Overall, Organ Chips have the potential to streamline the clinical trial process, which can be one of the most time-consuming and expensive aspects of drug development.

Aside from promising to improve the speed and accuracy of drug testing, Organ Chips, potentially integrated with biosensors to generate large quantities of data, offer researchers a cost-effective mini-laboratory to study disease processes at the cellular level in real-time. Such devices, for example, can be constructed to mimic conditions like cancer (Sontheimer-Phelps Hassell Ingber) or asthma (Nesmith, Agarwal, McCain, Parker) to enable investigators to study the effects of certain immune cells or drugs. Creating separate chips coated with cells taken from the gut of a human or an animal, like a cow or an insect, also enables the possibility of comparing the impact of products like pesticides on the digestive systems of different species, something which would be difficult to do otherwise.

Organ Chip technology has yet to realise its full potential, but research in this area is growing rapidly. It is rooted in the concept of the 3Rs (Reduce, Refine and Replace animal testing) first outlined in 1959 (Russell, Burch), which the European Council implemented in its directive in the use of experimental animals in November 1986 and then more firmly in a new directive passed in September 2010 (Marx, Walles, Hoffmann). The new directive specified that animal experiments should only be conducted when results could not be gathered by any other means. Providing a cheaper and more accurate model of humans, the wider adoption of Organ Chips should help to meet this directive.

Just how quickly the field is moving can be judged by the number of academic publications that have appeared on the topic in recent years. A search of the term 'organ-on-a-chip' on Google scholar reveals that the number of publications in this area rose from just 4 in 2000 to 2,660 in 2021. The number rose particularly strongly from 2016 onwards. Similar growth patterns appeared for the term 'microphysiological systems' (MPS). These numbers are smaller than the number of publications returned for the term 'microfluidics' but are representative of the growth of the field as a whole (see figure 1 and 2). Similar growth trends can be seen from the number of patents issued each year for Organ Chips which grew from just 4 in 2000 to 94 in 2015 (ALTEX). The number of companies being set up around the technology has also been increasing. At least 28 companies were set up between 2011 and 2018 (Zhang, Korolj, Fook, Radisic).

Number of publications that are listed on Google Scholar with the term 'microfluidics' or 'organ-on-a-chip' that appeared for each year between 2000 and 2021

Number of publications that are listed on Google Scholar with the term 'microfluidics' or 'organ-on-a-chip' that appeared for each year between 2000 and 2021.

Number of publications that are listed on Google Scholar with the term 'organ-on-a-chip' or 'microphysiological systems' that appeared for each year between 2000 and 2021

Figure 2: Number of publications that are listed on Google Scholar with the term 'organ-on-a-chip' or 'microphysiological systems' that appeared for each year between 2000 and 2021.

The importance of the technology can also be seen from the partnership established in 2011 between the US National Institutes of Health's National Center for Advancing Translational Sciences (NACT), the Food and Drug Administration (FDA) and the Defense Advanced Research Projects Agency (DARPA) to support the development of Organ Chips to improve the screening process for safe and effective medicines. In January 2016 the European Union's Horizon 2020 research and innovation programme also awarded over €30 million for a six year project, called EU-ToxRisk, to help deliver reliable animal-free systems using advances in cell biology, omics technologies, systems biology and computational modelling to aid the testing of drugs, cosmetics, pesticides and chemicals (EU-ToxRisk). Similarly, in 2017, the Japanese Agency for Medical Research and Development (AMED) launched a project to encourage the development of MPS devices (Ishida).

Further evidence of the importance of the field can be seen by the FDA Modernisation Act of 2021 and the Human Research Testing Act (HR 744) currently passing through the US Congress which questions the over reliance on genetically engineered mice and other animal models for basic scientific research and drug development (Ingber 2022).

How far the field has travelled can also be seen by the fact that in 2021 an Organ Chip platform developed by CN Bio, a British cell culture company founded in 2008 in Cambridge, was ranked second in the 10 top innovations listed by The Scientist, a highly respected magazine which has conferred awards for top innovations in science technology since 2008. CN Bio's platform allows scientists to connect different individual Organ Chips to create a model or a multi-organ system enabling more accurate research into disease conditions and for drug development (Brackley; The Scientist).

Discovery

The development of Organ Chip technology was founded on the back of the long history of cell culture research. Scientists first began finding ways to cultivate eukaryotic cells outside of an organism in the late nineteenth century, and by the early twentieth century it had become possible to maintain such cells for several months (Yao, Asayama). As early as 1876 John Syer Bristowe, a British physician, coined the term ‘organoid’ to denote ‘the smallest functional organ or tissue unit’ (Marx, Andersson, Bahinski). Efforts to create artificial organs were inspired by the work of Henry Van Peters Wilson, a professor of biology and zoology at the University of North Carolina, Chapel Hill. In the early twentieth century, he discovered that if he kept individual tissue cells that he had mechanically separated from Microciona prolifera (a red oyster sponge) in sea water, they naturally clumped together and fused to become new sponges (Costello). Following this, a number of other scientists generated different types of organs using organ tissues taken from different sources, including embryonic chicks (Weiss, Taylor) and frogs (Richter Piwocka Musielak).

Cell culture was greatly aided by the work of Ross Granville Harrison, an American biologist and anatomist at Yale University. In the early 20th century, he managed to grow frog nerve cells using a ‘hanging drop technique’ used in microbiology. His method involved immersing frog nerve cells in droplets of lymph solution on the cover side of a conventional petri dish and then turning the plate upside down. The advantage of his method was the cells could grow without being constricted by the flat plane of a conventional petri dish. Harrison’s three-dimensional cell culture method was subsequently used for growing other cell types (Navis; Linder; Richter Piwocka Musielak).

For a long time living mammalian cells were ‘primarily cultured in nutrient medium under static conditions on 2D substrates coated with serum or extracellular matrix’ optimised to stimulate cell growth. But this often resulted in a loss of tissue-specific functions which made many question the ‘physiological relevance of results from in vitro experiments’. Because of these difficulties scientists began looking for ways to develop MPSs that could better sustain tissue functionality for lengthy periods (Ingber 2022).

New possibilities opened up for cultivating organs as a result of advances in knowledge about stem cells, which became the subject of intensive investigation from the 1960s because of their ability to turn into multiple types of cell and organise into structures found in different tissues. In part they were of interest because of their important role in the process of repair, maintenance and regeneration of tissue within the body. The availability of such cells was limited, however, by the fact that, with the exception of the bone marrow, most organs in the body only produce a small amount of stem cells that have the capacity to differentiate into different cell types. Embryos offer a more malleable source of stem cells, but ethical and political controversies make them highly unattractive for regular use in research. One alternative is to take stem cells from a patient and convert them into the desired cell type for a particular chip. This approach greatly benefited from the discovery in 2007 that adult somatic cells could be genetically reprogrammed into an embryonic, stem-cell-like state. Known as ‘induced pluripotent stem cells’ (IPSCs), whilst the clinical application of these cells has been limited so far due to their tendencies to become malignant, they have made the development of Organ Chips much easier in recent years (Marx, Andersson, Bahinski).

Another critical factor that helped propel Organ Chip technology forward has been the emergence of microfluidics, enabling the manipulation of fluids within microscale channels that are moulded or engraved into the tiny chips. The field was galvanised by a number of different forces. The first was the invention of Integrated Circuits technology and photolithography in late 1940s and early 1950s which opened the door for creating microelectronic chips upon which the semiconductor and computer industry was built. The second was the development of new fluid-handling devices with interconnected microchannels, mixers, valves, pumps, pipettes and flowsensors. A key pioneer in this field was Stephen Terry at Stanford University. In 1979 he and his team created a miniaturised gas chromatograph integrated on a silicon wafer. This laid the foundation for the creation of the first 'laboratory-on-a- chip'. Integrating several laboratory processes on a tiny single integrated circuit, this chip provided a means for automation and high -throughput screening (Terry, Jerman, Angell). The rise of Organ Chips was also greatly helped by a DARPA initiative launched in 1994 to fund the development of portable microfluidic systems to detect chemical and biological weapons. A fourth stimulus came from the explosion of genomics in the 1980s, which required tools with much higher sensitivity and greater throughput than previously needed in biology, such as capilliary electrophoresis, PCR and DNA microarrays (Whitesides). Advances in this area were also helped by advances in new fabrication methods like 3D printing from the 1980s.

Development

One of the key pioneers in the Organ Chip field has been Michael Shuler, a chemical engineer at Cornell University, who began pondering the difficulties of testing new drugs as a result of caring for his youngest daughter, who has Down syndrome. As he explains, ‘People with Down syndrome are at much higher risk of certain diseases, such as Alzheimer’s disease and a wide variety of heart defects. In addition, it is difficult to test drugs on this population and their unique genetic makeup increases the chance that a drug may work differently for them than for others'. He was also keen to find a way to help speed up the drug development process so that patients could get the treatments they needed without waiting the many years it took to approve them (Hartman; Kacapyr).

Professor Michael Shuler

Figure 3: Photograph of Professor Michael Shuler, credit: Shuler. Born in 1947 in Jollet, Illinois, Shuler did an undergraduate degree in chemical engineering at Notre Dame and then a doctorate in the area at the University of Minnesota. In 1974 he joined Cornell University where he started as assistant professor in biomedical engineering and became the Director of the School of Chemical Engineering. He later became the Founding Chair for Biomedical Engineering.

Shuler was not the only one active in the field. So too was Andre Kleber and his colleagues at the University of Bern, Switzerland. In 1991 they developed the first in vitro cardiac model by growing myocytes - a type of heart muscle cell - from neonatal rats in a particular pattern within linear channels on conventional glass coverslips (Rohr, Scholly, Kleber). The model helped pave the way for the first biophysical explanation for how electrical impulses can sometimes block the heart beat (Zhang, Korolj, Fook, Radisic).

From 1989 Shuler began developing what he called ‘cell culture analogue’ (CCA) devices to mimic the physiological and toxicological responses of animals and humans to drugs (Shuler Interview). Using tissue cultures of different organ systems in animals, Shuler built the devices based on physiologically based pharmacokinetic models for drug development. Pharmacokinetics is the study of how a drug gets absorbed, distributed, metabolised and eliminated from the body. The CCA device had the advantage that it could operate for over 24 hours and sustain live tissue culture for that period of time. It proved useful for validating toxicology and pharmacology tests (Shuler, Ghanem, Quick).

By the late 1990s Shuler’s team had begun looking for ways to build microscale systems that linked pseudo-organs (artificial organs) together in a way that they appear in the body. They did this in collaboration with Greg Baxter, a specialist in microfluidics, based at Cornell's nanofabrication facility. As Shuler explains ‘Greg and I realised that it was fairly expensive to do this with large cell cultures and flasks and stuff like that and we needed to make it much more efficient in terms of space and cost. By going to the microscale we could get by with cell cultures which are much smaller.' To build their new system they looked to the physiologically based pharmacokinetic computer models that had been developed in the 1960s which made it possible to look at how different organs respond to different doses of drugs (Shuler Interview).

Shuler’s group first developed a prototype of an animal-on-a-chip. First reported in 2001, the chip was created by etching groves into silicon wafers to create tiny compartments to ‘hold gut, liver and fat cells’ to act like organs, ‘all linked by microfluidic channels’ to act like blood vessels (Sin, Baxter, Shuler; Baker). A solution replicating the composition of blood serum could be circulated around the chip, with the help of a pump, together with a test compound to mimic what happens when a drug goes through the body. One of the first experiments the two scientists conducted with the chip was with naphthalene. Often used in mothballs because it has a strong smell, naphthalene is usually harmless in its natural state, but toxic to mammals when metabolised in the liver. Pumped first through the lung chamber and then split between the liver and another cell-less compartment, Shuler and Baxter found that naphthalene was converted in the liver compartment to naphthalene epoxide which circulated to the lung compartment where it caused lung cell death (Anon 2015; Shuler Interview).

The team then moved on to integrating cell culture and microfabrication technology to build human models. These were used for functional characterisation and detection of drugs, pathogens, odorants and toxicants. The advantage of the small size of the systems was that they only required small amounts of samples and reagents. This was helpful because cell culture can be the most expensive part of running toxicology and drug tests (Park, Shuler; Shuler Interview).

In 2008 Shuler and his colleagues began to create a gastrointestinal tract (GIT) microscale cell culture analogue for predicting drug transport within the gut. Within two years, they had successfully developed an in vitro platform that combined microfabrication, microfluidics, and cell culture to help predict human responses to drugs. Their system had multiple compartments, each of which represented a different organ or tissue type (Shuler, Esch).

Shuler soon joined forces with James J. Hickman, an expert in nanoscience and the developer of functional cell constructs that mimic the electrical and mechanical responses of cardiac, neuronal, and muscle tissues to chemicals (Oleaga, Bernabini, Smith) to design multi-tissue, physiologically realistic devices. called 'body-on-a-chip' or 'human-on-a-chip' devices (Sung, Esch, Prot; Tagle). Their aim was to connect chips, each representing individual organs, like the liver or heart, to evaluate the toxicological and efficacy responses of drugs in a similar manner to the use of animal models in the field (Hartman). Hickman brought to the project his expertise in measuring functional responses to stimuli, particularly electrical activity in tissues such as neuronal and cardiac tissues along with measurements of force generation by cells such as muscle. His ability is unusual in the field. Shuler and Hickman were helped in this work by funding from a Common Fund set up by the National Institutes of Health (NIH), in 2010, to support the development of a heart-lung chip model to test the safety and efficacy of drugs (Tagle).

In 2015, Shuler and Hickman co-founded a start-up company in Orlando, called ‘Hesperos’, to commercialise their technology. The company’s work was supported by the NCAT’s Small Business Innovation Research Programme. In the last few years, a number of pharmaceutical companies, including AstraZeneca, Roche, and Sanofi, have partnered with Hesperos to test out its Organ Chip for drug testing (Keown).

Another prominent figure in the organ chip arena is Donald Ingber, a cell biologist and bioengineer based at Harvard University. He originally set out to explore the role of mechanical forces in biology in the 1980s, believing that they were as important as chemicals and genes for health and biological development. This involved investigating how different cell shapes affect cellular activity (Ingber Interview; Ingber 1993). By the early 1990s, Ingber was working with the chemist George Whitesides, also at Harvard, to adapt an inexpensive ‘Soft Lithography’ method Whitesides had originally developed to manufacture computer microchips to ‘print little adhesive islands coated with extracellular matrix’ to help make these models. Their method involves moulding a clear flexible silicone rubber, called poly (dimethylsiloxane) (PDMS), on top of a silicon chip etched on the nano- to micro-scale using photolithographic techniques commonly used to manufacture computer microchips. The rubber stamp is then peeled off and used to pattern chemicals on other substrates. The advantage of this technique was that it enabled precise control at the nanometre to micrometre scale of the environment in which cells live (Ingber Interview). Ingber and Whitesides published their approach in two articles in Science in 1994 and 1997 showing that a cell’s shape governs ‘whether individual cells grow, differentiate, or die, regardless of the type of matrix’ used to mediate adhesion (Chen, Mrksich, Huang).

Professor Donald Ingber, credit: Ingber

Figure 4: Photograph of Professor Donald Ingber, credit: Ingber. Born in East Meadow New York in 1956, Ingber did an undergraduate and master’s degree in molecular biophysics and biochemistry and then did a combined MD and PhD at Yale University. A renowned cell biologist and bioengineer, in 2009 Ingber founded and became the director of the Wyss Institute for Biologically Inspired Engineering, a partnership between Harvard University and its affiliated hospitals. Launched with a $125 million gift from the Swiss billionaire Hansjörg Wyss, the aim of the Wyss Institute is to support high-risk research and leverage new engineering techniques for medicine, including the development of new medical devices.

Whitesides subsequently adapted the method to fabricate microfluidic devices containing little hollow channels with which they can control the flow of solutions through the chip, which he published in 1998 (Duffy, McDonald, Schueller). Industry was already using this strategy to miniaturise instrumentation for diagnostics and analytical systems. Ingber and Whitesides first reported the culture of cells inside the channels of these devices in 1999 (Kane, Takayama, Ostuni). The introduction of PDMS into the field greatly accelerated experimentation in this field because the polymer is non-toxic, and more flexible and much easier to manufacture into microfluidic devices than glass or silicon. It also allows for the incorporation of valves and pumps and does not require expensive clean room facilities (Convery, Gadegaard).

Professor George M Whitesides, credit Wyss Institute

Figure 5: Photograph of Professor George M Whitesides, credit Wyss Institute. Born in Louisville, Kentucky, in 1939, Whitesides’ father had a chemical engineering company. Having worked as a technician in his father’s company, Whitesides studied chemistry at Harvard College and then completed a doctorate in chemistry at the California Institute of Technology. In 1963 he was appointed assistant professor at the Massachusetts Institute of Technology where he remained until 1982 when he gained a position in the Department of Chemistry at Harvard University. The founder of several start-up companies, Whitesides first developed an interest in biological systems while at MIT where he also began working on polymers (Arnaud).

Having worked for years on vascular networks and systems, Ingber wondered if microfluidics could be leveraged to do more than pass fluids between different cell types, and to actually replicate organ-level structures and functions in vitro. His starting point for this was a lung-on-a-chip created by the bioengineer Shuichi Takayama who had been postdoctoral fellow with both Whitesides and Ingber. Takayama’s chip had little channels simulating the microenvironment of the small airway of the lung. Ingber was impressed that Takayama had demonstrated that it was possible to recreate the crackling sound associated with certain lung diseases by passing a little droplet of fluid through the channels of the chip. Ingber was amazed by the sound it made. As he recalls, ‘That noise was exactly the noise I was taught to listen for through a stethoscope when I went to medical school'. For years, nobody had known what caused such a noise, and Takayama ‘basically showed that it was due to little mucus plugs going through bronchioles, small airway-size conduits’ (Ingber Interview). Inspired by Takayama’s result, Ingber launched a project to further develop a living, breathing human lung on a microchip, together with Dan Dongeun Huh, a South Korean postdoctoral researcher who joined his laboratory in 2007 after working with Takayama at the University of Michigan (SLAS; Huh, Fujioka, Tung).

Professor Shuichi Takayama, credit Takayama

Figure 6: Photograph of Professor Shuichi Takayama, credit Takayama. Born in Japan, Takayama completed a bachelor of science and master’s degree at Tokyo University and then did a doctorate in chemistry and chemical biology at Scripps Research Institute in 1998. His initial research focused on organic synthesis of molecules that mediate biological chemical communication. Takayama first began constructing microfluidic models of the body when he was Leukemia and Lymphoma Society Fellow at Harvard University. In 2000 he joined the Department of Biomedical Engineering at the University of Michigan. Since 2017 he has been a Georgia Research Alliance Eminent Scholar, and the Price Gilbert, Jr. Chair in Regenerative Engineering and Medicine in the Wallace H. Coulter Department of Biomedical Engineering at the Georgia Institute of Technology and Emory University School of Medicine. His research ranges from the use of microfluidics to understand the fundamental science of cells to the development of assisted reproductive technologies.

By 2010, they had engineered a chip with a pair of microchannels separated by a very thin flexible permeable membrane coated with natural extracellular matrix adhesive molecules. One channel was lined with a layer of primary human cells isolated from the lining of the lung air sac, or alveolar tissue, which after a couple of weeks multiply and differentiate into the cells native to alveolar tissue. These secrete mucus when cultured on the top of the permeable membrane and exposed to air introduced into the upper channel. Human capillary blood vessel cells from the lung were used to line the lower surface of the same membrane with a liquid medium flowing through the lower channel to provide nutrients to both the alveolar and capillary cells as they would in the body. Two hollow chambers were placed on either side of the two microchannels which allowed for cyclic suction to be applied, thereby enabling the rhythmical stretch and relaxation of the engineered 'alveolar-capillary interface' to model the mechanics of breathing. The device provides a means to simulate the effects of air pollution and bacterial infections on the lungs, and to investigate what happens when lungs become inflamed (Huh, Matthews, Mammoto). The complex breathing action of the engineered lung also subsequently opened up new insights into the cause of pulmonary oedema, a serious condition caused by excess fluid in the lungs, and helped predict the activity and toxicity of a new drug developed by GlaxoSmithKline for the disease (Huh, Leslie, Matthews; Kusek).

Being the first microfluidic device to capture organ-level functionality, this lung-on-a-chip marked a major milestone. Heralded as one of the most important research advances in biological and medical science in 2010, the chip provided a prototype for creating other types of organ chips (Anon 2011). Fabricating the chip out of a soft and stretchy material, Ingber and Huh showed it was possible to build a working model of an organ chip and they ‘recorded beautiful movies of immune cells crawling over the surface of the vascular cells, crossing the membrane through the matrix-filled holes in the membrane, passing through the alveolar lining cells, and tracking down a bacterium’ (Borfitz).

Diagram showing the main components of a lung-on-a-chip. Credit: Wyss Institute with adaptation by Daniel Power

Figure 7: Diagram showing the main components of a lung-on-a-chip. Credit: Wyss Institute with adaptation by Daniel Power.

In October 2010, the National Institutes of Health and US Food and Drug Administration awarded Ingber and Kevin Kit Parker at Harvard University $3 million to develop a ‘Heart-Lung Micromachine’. Combining two different organ systems within a single microsystem for the first time, the aim of the device was to help speed up drug safety and efficacy testing (Anon 2011). Ingber’s laboratory subsequently received a further $37 million in funding in 2012 from DARPA for a five-year project to develop a human body-on-chips model with 10 integrated Organ Chips to predict drug pharmacokinetics and accelerate the process of drug discovery and testing the toxicity of new products. Two years later, Ingber founded a spin-out company called ‘Emulate’ to commercialise the technology. Over the course of the next four years the company raised $57 million and went on to raise more than this in subsequent years to fund its work on different Organ Chips, and established partnerships with several pharmaceutical companies including Merck and Johnson & Johnson to test different drugs (Woods; Fassbender).

Lung-on-a-chip under as microscope. Credit: Wyss Institute.

Figure 8: Lung-on-a-chip under as microscope. Credit: Wyss Institute.

According to Ingber, he and his collaborators have been able to make a chip designed to replicate any organ they have taken on as a challenge so far. As he puts it, ‘there were some that we couldn't do because we couldn't get the cells for years, and then we developed a way to get cells using IPSC technology, and then it worked.’ What is particularly gratifying to Ingber is that they can now create chips that not only replicate normal physiology, but also ‘pathophysiology and disease states with high fidelity.’ The fact that the chips can also simulate ‘flow peristaltic-like motions in the intestine, breathing motions in the lung, and rhythmic distortions of the kidney caused by pulses of blood generated with each beat of the heart' is also very important, because we do not see optimal mimicry of in vivo functions unless we replicate these mechanical forces, which he has dedicated his life’s work to investigating (Ingber Interview).

Uwe Marx, a German physician by training, tissue engineer is another key figure in the organ chip field. Since the early 1990s, he has been pioneering micro-physiological systems to mimic human organs in vitro. His first breakthrough was the development of disposable bioreactor-based antibody manufacturing technologies in the late 1990s, which helped contribute to the ban of the production of monoclonal antibodies within animals in Europe. He then co-developed a microfluidic human artificial lymph node model based on a miniaturised and perfused bioreactor which enabled monitoring of the effects of different substances on the human immune system, thereby opening the way to animal-free immune reactivity-testing of new drugs and other biological entities (Giese, Demmler, Ammer).

In 2015 Marx hosted the first stakeholder workshop for the community developing MPS organised by CAAT (Center of Alternatives to Animal testing) Europe. Held in Berlin, this workshop included 35 experts from academia, industry and regulatory bodies. Its aim was to map out the current status of the technology and provide a roadmap for getting it robust enough to be adopted by industry (Marx, Andersson, Bahinski). He subsequently organised a second stakeholder workshop in 2019. Attended by 46 leading international experts from academia, industry and regulatory bodies, this workshop reported that the main obstacles to industry’s adoption of MPS-based models often lay in the technical immaturity of many of the systems and lack of communication between the providers and the end-users (Marx, Akabane, Andersson). He was responsible for the publication of two comprehensive reports on biology inspired MPS put out by t4 (The Transatlantic Think Tank for Toxicology) (Marx, Andersson, Bahinski).

In addition to being an opinion leader in the field, Marx has founded several biotechnology companies to help advance the technology. In 2010 he founded TissUse GmbH, a company he spun out of his laboratory at the Technical University of Berlin. Around this time he also began to develop the concept and principles of organismoid theory to generate miniature, mindless and emotion-free equivalents of a human individual’s body on chips which he believed could revolutionise drug development and the precision of personalised medicines in the future (Marx, Walles, Hoffmann; Marx, Accastelli, David).

Dr Uwe Marx. Credit: Marx.

Figure 9: Photograph of Dr Uwe Marx, 2011. Credit: Marx. Born in Berlin in 1964, Marx completed a doctorate in immunology at Humboldt University, the Charité Berlin. In 1995 he joined the department of Clinical Immunobiology at the University of Leipzig where he began working on protein drug development and tissue engineering. In addition to founding TissUse, Marx co-founded two other German start-up companies: Vita 34 AG and ProBioGen AG.

By 2016 he and his colleagues had managed to build 16 human organ chip models, which were 100,000-fold smaller than the original organs. These chips could be used to simulate diseases like diabetes or cancer and to test the efficacy and side effects of new drugs. Initially using tissue donated from different donors to create individual organs, the subsequent models were created with induced stem cell technology (Laska). Such work formed the basis for the creation of the ‘multi-organ chip’ which mimics various human organs on one device enabling the simulation of human processes over a period of two months (Materne, Maschmeyer, Lorenz).

In 2019 Marx and his colleagues reported that they had managed to combine miniaturised human intestine, liver, brain and kidney equivalents into a four-organ-chip. All four organs had been created with pre differentiated iPSCs from the same healthy donor. These were then integrated into the microphysical system (Ramme, Koenig, Hasenberg).

Linked organ chips Vitruvian man illustration. Credit: Wyss Institute

Figure 10: Linked organ chips Vitruvian man illustration. Credit: Wyss Institute with adaptation by Daniel Power.

Another multi-organ chip has been created by a team led by Frank Sonntag at the Fraunhofer Institute for Material and Beam Technology in Dresden. The team began working on the chip in 2009, for which they received an Innovation Award from the European Association of Research and Technology Organisations in 2018. Measuring about three by ten centimetres, the chip was assembled with the help of a laser to cut chambers in plastic foils for blood vessels and organ cells, which are stacked on top of each other and connected together with the addition of sensors, valves, pumps, mass exchangers, and electronic controls. Already tested for numerous medical applications, the cells in the chip were found to survive much longer than in classical Petri dishes. Another advantage of the system is that it allows for differentiated regulation of the blood supply in each chamber, which is more representative of what happens in the body where different organs and tissues require different amounts of blood. The brain, for example, receives more blood than the eyes. Small microscopic valves incorporated into the chip also make it possible to use the chip to simulate heart attacks and strokes (Fraunhofer).

Largely galvanised by the work of Shuler's group, scientists have intensified their efforts to develop multi organ chips over the past few years. Known as 'body-on-a-chip' or 'human-on-a-chip' these devices aim to replicate the complex body system which is composed of organs and tissues each of which have multiple physiological roles and interactions with each other. Such chips are not able to reproduce all biological responses in the body. But they can help provide insights into heretofore unknown responses which can only be picked up by observing the interactions between different organs in real-time. This information is important to improving the prediction of pharmacokinetic (PK) processes which can help determine how to administer a drug and the dose to be given. It can also help in predictions of pharmacodynamics (PD) which evaluates the pharmacological effect of a drug on the body which is critical to assessing its efficacy (Sung, Srinivasan, Brigitte;Kimura, Sakai, Fujii).

Application

Where Organ Chips could prove most useful is to reduce the cost and shorten the time needed to develop drugs, which on average take 10 to 12 years each. Much of the drug development cost is related to the clinical trials needed to get the drug approved for use in humans. Organ Chips could also help with personalised medicine through the use of chips for individual patients to help identify which drug is most beneficial and least toxic to them (Knight Interview).

Elsewhere, the technology could help with rare genetic disorders, which are particularly challenging because of the difficulties associated with recruiting sufficient numbers of patients with such diseases to clinical trials. At present, this work is done by replicating the disorders in animals, but it could be done instead with Organ Chips (Shuler Interview). In fact, this was demonstrated by Ingber's team in 2020 when they replicated a rare genetic blood disorder called Shwachman Diamond syndrome by building bone marrow chips starting with blood cells from children with this disorder (Chow, Frismantas, Milton). Ingber and his postdoctoral researcher Ratnakar Potla have also created a chip to mimic cystic fibrosis, a progressive genetic disorder which causes severe damage to the lungs and cells responsible for the production of mucus, sweat and digestive juices. Supported by a grant from the Cystic Fibrosis Foundation, in 2021 they published a human lung airway chip with cells taken from a cystic fibrosis patient which replicated multiple hallmarks of the disease in the lung, 'including enhanced mucus accumulation, increased cilia density, and a higher ciliary beating frequency'. Encouragingly the chip's environment proved conducive to the growth of Pseudomonas aeruginosa bacteria and mimic inflammatory responses that are especially dangerous to patients with cystic fibrosis (Plebani, Potla, Soong).

Organ Chip technology also opens the way to investigating how women and men respond differently to medical treatments. In 2018, for example, Ingber's team received research funding from the FDA to use bone-marrow chips to study 'how male and female bone marrow responds to radiation and drugs known to cause bone marrow damage' (Brownell, Nov 2018). In addition, Organ Chips are now being developed to study specific functions of the female reproductive tract and changes that occur during conception and fertility. A placenta-on-a chip, for example, has been used to study the role of chronic inflammation in poor pregnancy outcomes and also how drugs are transported across the human placenta barrier. Organ Chips also provide a way to screen drugs that cannot normally be done in pregnant women, who are generally excluded from clinical trials because of the risk of harm to a foetus (Blundell Yi Ma; Mancini, Pensabene).

Organ Chip models also provide scope to generate and be mined for large amounts of data, which, when combined with modern computational methods, could yield far greater insights into drug pharmacokinetics and disease mechanisms than animal models can. Such information would help mitigate potential side effects in human clinical trials. It could also provide more precise drug response models to determine appropriate dose administration. Until now this has been done by dose-increase schemes, whereby trial participants are started with low doses which are gradually increased. Organ Chips offer the ability to study controlled environments and simultaneously test different variables, providing better results in cause-and-effect experiments and enabling more specific research questions to be answered. Overall, the more advanced Organ Chip technology gets, the more accurate it will become in replicating real human responses, making the drug development process more effective and giving better predictions of side effects (Ingber Interview).

Another area where Organ Chips could be beneficial is in the development of biological drugs. These medicines are derived from living cells or through biological processes. Such drugs include a diverse selection of compounds with a biological origin, including peptides, nucleic acids, cytokines, replacement enzymes, various replacement proteins, and monoclonal antibodies. Immunotherapies for cancer are one of the most important classes of biologics developed in recent years, spurred on by the improvements they have made to patient survival (Marks, Feb 2018). One of the advantages of biologics is they are highly target-specific, so they are less likely to cause harmful non-target effects. Biologics, however, are difficult, if not impossible, to test in animals because they are highly specific to human biological targets. In addition, only a fraction of patients have so far been found to respond to such drugs. Another problem is that biologics often elicit adverse immune reactions including skin and liver toxicity, colitis, and pneumonitis. In this case, Organ Chips offer an important way forward. Importantly, Organ Chips provide a better simulation of the interactions of a complex multifactorial biological environment than Petri dishes, and offer more accurate human responses to biologics (Shuler Interview; Kerns, Belgur, Petropolis).

Where Organ Chips could also be helpful is to understand the blood-tissue and other biological barriers that play a pivotal role in regulating the transport of molecules within the body, including drugs from the capillaries to targeted organs. The blood-brain barrier is one area where it could provide value. Because it protects the brain from harmful compounds from the blood and ensures a homeostatic environment for the central nervous system, a chip that can model the blood-brain barrier could provide an invaluable key to drug development. Over the last decade a number of researchers have found a way to fabricate some promising chips to study the blood-brain barrier (Zakharova, do Carmo, van der Helm; Shuler Interview). One model published in 2017 by Shuler's team was one of the first to demonstrate in vivo realistic values of permeability in a human model with recirculating flow, and that this was sustained for 10 days. This provided a valuable tool for screening drug candidates (Wang, Abci, Shuler).

Beyond drug testing, Organ Chips could also help eventually eliminate the use of animals in basic scientific research. They are already being investigated for this purpose in cancer research. Until recently, most of the advances in understanding the processes involved in cancer metastasis were learnt by 'taking a piece of a patient's tumour and putting it into an animal, like a mouse, to see how it grows' (Biddle Interview; Yu, Stott, Toner). The advantage of Organ Chips is that they provide a means to study cancer cells taken directly from patients within a human-like environment in the lab.

Furthermore, Organ Chips provide some significant improvements in our modelling of cancers. In the past, researchers relied on growing individual tumours on Petri dishes to understand why each patient responds differently to drugs. Organ Chips offer a way to study cellular interactions at a far higher level of complexity and under much more controlled conditions than animal models. For instance, Peter Friedl, an expert in microscopical imaging of cancer at the University of Nijmegen, has been using engineered in vitro models to study the invasion and migration of cancer cells through human tissues (Beunk, Brown, Nagtegaal; Biddle Interview).

Meanwhile, at Harvard and Massachusetts General Hospital, a team led by the mechanical engineer Shannon Stott has taken advantage of the micro-vortices created by herringbone structures within a chip, observed first by Stroock and colleagues, to enhance the capture of extremely rare cancer cells circulating in the bloodstream of cancer patients. This work could provide earlier diagnosis and a better understanding of how cancer cells spread and kill (Stott, Hsiu, Tsukov).

Professor Shannon Stott, credit: Nancy Gould

Figure 11: Photograph of Professor Shannon Stott, credit: Nancy Gould. Stott trained in mechanical engineering first as an undergraduate at the University of New Hampshire and then as a master's student at the University of Illinois, Urbana-Champaign. She then completed a doctorate in mechanical engineering at Georgia Tech in 2005, following which she became a postdoctoral fellow in the laboratory of the Turkish biomedical engineer, Professor Mehmet Toner, at Massachusetts General Hospital. It was during this time that she became involved in developing the herringbone circulating tumor cell chip. This is not an Organ Chip model but it utilises the same microfluidic discipline that has led to the advance of Organ Chips. Devised to capture cancer cells circulating in the blood stream of localised and metastatic cancer patients, tumor cell chip is now being scaled up for large-scale production for use in multiple cancer centres across the US.

Diagram illustrating how a cell flows through a herringbone chip. Credit: Daniel Power

Figure 12: Diagram illustrating how a cell flows through a herringbone chip. Credit: Daniel Power. The diagram was compiled based on Stott, Hsiu, Tsukov; Yu, Stott, TonerStroock, Dertinger, Adkari.

Similarly Adrian Biddle and his research group at Queen Mary University of London are also investigating microfluidic chip devices to pick out cancer cells from the blood. This research should make it easier to characterise a patient's tumour to help tailor their treatment, thereby enabling more personalised medicine. Organ Chip technology offers a much more sophisticated means of investigating cancer development because it can measure more variables. Furthermore it provides a way to recreate the tumour microenvironment in vitro (Biddle Interview) as well as making it possible to investigate the interactions between cancerous cells in multiorgan systems (Sun, Luo, Lee).

As well as offering a new way to study cancer, Organ Chips are opening a new chapter to investigate complex human-microbiome interactions. Now thought to be pivotal to the process of aging, the immune system, modulation of the central nervous system, and a person's psychological well-being, the human microbiome is now considered one of the essential organs in the human body without which it cannot function (Marks, Sept 2018). In 2019 Ingber and his team reported that they had managed to create an experimental chip with human intestinal cells on which they cultured a complex human gut microbiome containing over 200 different types of microbes (Jalili-Firoozinezhad, Gazzaniga, Calamari).

In addition to the human microbiome, Organ Chip technology could provide a way to better understand infectious diseases. Importantly, it offers a way to model the native tissue microenvironment and mucosal surfaces lining the respiratory, gastrointestinal and urogenital tracts to study the role of the important immune defence system in preventing infection here and a means to understand the host-pathogen interactions (Baddal, Marrazo; Aguilar, da Silva, Saraiva). One such example is a bladder-on-chip which has also shown the technology to be a powerful tool for understanding antibiotic resistance in the case of urinary tract infection recurrences (Free). Such information is vital to improving treatment strategies which will be increasingly important given the rise in antimicrobial resistance (Marks, Nov 2020).

Similarly, in 2018 a group of British scientists led by Marcus Dorner at Imperial College found it was possible to reproduce all the steps of the life cycle of the hepatitis B virus in a liver chip lined with human hepatocytes. Able to be maintained for over 40 days, the chip provides a major step forward for understanding hepatitis B infection which every year claims the lives of more than 900,000 lives worldwide. More infectious than HIV, the hepatitis B virus is particularly worrying because its carriers initially show no symptoms but it can cause serious damage to the liver leading to premature death from cirrhosis or liver cancer many years later (Marks, May 2018). Importantly, the chip replicated similar biological responses to the virus as in a real liver which heretofore has been difficult to do in traditional in vitro models. It therefore provides a new means to dissect the key pathways that the virus uses to replicate and evade the human immune system, thereby opening up new targets for drug development (Ortego-Prieto, Skelton, Wai).

Organ Chip platforms are also now being deployed to better understand COVID-19. This includes the Lung Airway Chip and Lung Alveolus Chip developed by Ingber's group. Already used to study the influenza virus, the chips provided a means to study inflammatory responses within the lung to the SARS-COV-2 virus and confirm the safety and efficacy of drug compounds already approved for other conditions against the virus in animal models. One of these drugs is already in COVID-19 clinical trials across many sites in Africa (Si, Bai, Rodas) and an investigational new drug (IND) application has been submitted to the FDA to initiate COVID-19 trials in the United States for another drug found to suppress the cytokine storm (Bai, Si, Jiang). Having both a fluid channel and an air channel the chip can also be used to study the effect of drugs administered either as an injection or breathed through an inhaler (NIH; Brownell June 2020). Elsewhere, Milica Radisic working with Axel Guenther and Edmond Young at the University of Toronto have created tiny models of the nose, mouth, eyes, and lungs to investigate how COVID-19 invades the human body (University of Toronto). Lung alveolus and airway chips also laid the foundation for the discovery of 'a new class of broad-spectrum RNA therapeutics that induce a potent type I interferon response and inhibit infection by SARS-CoV2, SARS-CoV, MERS-CoV, HCoV-NL63 (a common cold virus) and multiple influenza A virus strains' (Si, Bai, Oh).

Another application Organ Chips offer is in the vaccine arena. A team of scientists at Sanofi Pasteur, for example, have patented an artificial immune system consisting of T cells, B cells, and antigen-primed dendritic cells for testing immune responses to vaccines (Warren, Drake, Moser). Ingber's group has also created a model of the human immune system in a microfluidic chip with which they made the unexpected discovery that B and T cells organise themselves into three-dimensional structures that resemble lymphoid follicles, which play a central role in activating the immune response. Furthermore, they found that the chip faithfully replicates human immune responses when vaccinated with a commercial flu vaccine (Irving). The attraction of the Organ Chip technology is it could potentially replace non-human primates as a more accurate and cheaper model for vaccine development (Ingber Interview; Goyal, Prabhala, Mahajan).

Issues

Organ Chips are often confused with the term 'organoids'. Both have 3D structures grown from stem cells with organ-level structures, but the Organ Chip is more heavily engineered with microfluidic channels lined with specific living human organ cells. While organoids provide a more realistic model of a developing tissue within an organ, its environment is less easy to control than an Organ Chip and it is difficult to study transport, absorption, or interactions among different types of tissues that comprise a living organ or with living microbiome (Salig Penn).

Currently, Organ Chip technology is still primarily being used at various stages in the drug development process or as a form of validating existing data. Shuler believes that true acceptance of the utility of Organ Chips will only happen once the first drug that was pre-clinically tested in an Organ Chip has been approved. One of the pivotal challenges is that regulators still need to see convincing data proving that Organ Chip produces better results compared to animal models or 2D cell culture (Shuler interview). The validation process is in itself highly complex and has yet to be fully standardised. Over the last few years the European Union Reference Laboratory for Alternatives to Animal Testing, established in 2011, has provided funding to help support validation studies for alternative methods to animal testing (European Commission). But the task remains so difficult that many companies, particularly small spin-outs with limited funding, often give up pursuing it. In this context it is the regulatory issues, rather than technical obstacles, that are hampering the innovation of Organ Chip technology (Low, Mummery, Berridge).

While the technology still needs to be improved to be fully reliable, some progress has begun to be made on the regulatory front. In April 2022 the pharmaceutical company, Sanofi Pasteur, announced that it had submitted a FDA Investigational New Drug (IND) application to launch clinical trials for a drug to treat rare neuromuscular diseases with data collected from a tissue chip containing two cell types: motoneurons, which transmit messages from the brain to muscles, and Schwann cells which help the signals to move more quickly. It was designed to mimic the biology of chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. The FDA had already been approved the drug for a different condition. This marked a major milestone as it was the first time a pharmacautical company used data from an Organ Chip to back up an IND. Critically the chip made it possible to see how the drug was working by evaluating how far the drug was slowing down the brain's messages to muscles (NIH 2022).

The development of Organ Chips requires input from a wide range of experts from different disciplines including stem cell biology, microfabrication, microelectronics, computer modelling, and liquid plastics. This can make the process expensive and also poses challenges in terms of standardisation, which can make validation difficult. At the moment, each research group and company uses their own approach and different materials to manufacture their chips. Chambers and plate sizes, for example, can vary, and diverse methods are used to feed the cell culture media into the chambers.

Organ Chips are reliant on having access to live human cells. Most human cell lines used in industrial in vitro assays are derived from adult donors. The advantage of these cell lines are they can be easily expanded, have relative stability, and can be stored for a long time. One of the first such cell lines was derived from a sample of cancer cells taken from Henrietta Lacks, who died from an aggressive form of cervical cancer in 1951. Found to have an extraordinary capacity to survive and reproduce, her cells became known as the HeLa cell line. Shared widely without Henrietta's consent or knowledge, her cells are now the 'workhorse of biological research' (Editorial). Human cancer-derived cell lines have proven useful for studying the biology of cancer and testing the efficacy of anti-cancer drugs. But not all cancer cell lines have equal value as tumour models (Gillet, Varma, Gottesman).

Thousands of human patient-derived cell lines from different organ/tissue types can now be ordered to use in Organ Chips (Marx, Andersson, Bahinski). Another method is to take a few primary cells from a healthy human donor. This can be useful in the case of creating a chip for personalised medicine to tailor a treatment to a specific patient. However, such cells are a limited resource and thus cannot be used to generate chips for multiple experiments over a number of years, or for carrying out drug screening. A more promising source is to use IPSCs. First pioneered in 2007, these cells have made the development of Organ Chips much easier in recent years. However, such cells are expensive and involve long complex protocols to create the differentiated cells needed for organ models, and often these cells do not fully develop into adult specialised cells (Knight Interview). Organoids also serve as an useful source of adult stem cells as they can be dissociated and cultured within Organ Chips, thus taking advantage of the best features of both technologies.

Many considerations go into the material used to create the microfluidic system or chip. It needs to be transparent to allow for real-time monitoring and detection of cell activity. It also has to be amenable to providing an integrated environment for cell maintenance. PDMS has particular attractions for cell culturing because it is non-toxic, transparent, and is permeable to gases. Its flexibility also gives it the capacity for cyclic stretching of cell culture surfaces. But the downside is its high permeability can sometimes lead to the compromising of results due to small molecules, such as tracers, drugs, toxicants, and water diffusion (Knight Interview; Balijepalli, Sivaramakrishan; Allwandt, Ainscough, Viswanathan). A number of new materials are now being developed for fabricating Organ Chips to help get over this problem but have yet to be widely adopted (Zhang, Korolj, Fook, Radisic).

Compared to a simple Petri dish experiment, a chip is quite expensive, but Organ Chips promise to be more cost-effective overall than conventional animal testing. Some idea of the difference in cost is offered by the Liverchip commercialised by C.N. Bioinnovations, which in 2015 cost US$22,000 with potential additional payments to the company depending on the success of drug testing. By comparison, the same year animal testing cost between US$6,500 and US$800,000 depending on the complexity and amount of time required for the testing. The costs associated with animal testing does not include the husbandry costs required for housing and caring for animals, which need to be constantly looked after and monitored by technicians (Knight Interview; Balijepalli, Sivaramakrishan).

Overall, Organ Chips are predicted to help reduce the cost of drug research and development by 10-26 percent (Franzen, van Harten, Retél). While this makes them an attractive option for larger pharmaceutical companies, they largely remain too expensive for smaller companies and academic researchers who have smaller budgets. Blank microfluidic chips offer a slightly cheaper solution. Supplied by various companies, academics and others can put their own cells inside such chips to build their own bespoke models (Knight Interview).

One of the reasons for the high price associated with Organ Chips is that companies have to spend a lot of money to develop the technology, so they need to find a way to recoup that cost. How much is charged for a chip depends on how complex it is. The big question now is working out just how much of the in vivo environment needs to be replicated on a chip. Much depends on what it is being designed to do. Martin Knight, the director of Queen Mary+Emulate Organs-on-chips Centre in London, illustrates the complexity of the issues to consider when designing a chip for researching arthritis. As he argues, 'We need a functioning human knee that moves and is loaded in the same way as our actual knees and that is aged in the same way as our bodies age, because we want to look at ageing as well. To do all of that would be unrealistic. It would take years of development and at the end of that you've only got a knee. What about all the other joints and all the other things?' (Knight Interview).

While development of Organ Chips has come a long way in the last decade, progress remains relatively slow. Knight argues that in part this is because 'it is not particularly fancy science, you're not necessarily going to win a Nobel Prize or publish a top paper if all you do is … work out how to make a model that replicates an aspect of a particular disease'. Another key obstacle is that much more research still needs to be done to demonstrate whether or not Organ Chip models can outperform existing simple in vitro models or animal models in predicting human physiology, disease, and response to therapeutics. Until this is done companies will 'prefer to go on using the existing models.' As Knight puts it, ' Until we can work out how to fund the development and validation of those models, progress will be slow' (Knight Interview).

Authors

This piece was written in April 2022 by Lara Marks, Daniel Power and Nomthandazo Ziba.

Acknowledgements

Many thanks go to Donald Ingber, Lindsay Brownell, Michael Shuler, Uwe Marx, Sebastien Farnaud and Martin Knight for reading earlier drafts of this piece.

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Organ-on-a-chip: timeline of key events

D Huh, BD Matthews, A Mammoto, M Montoya-Zavala, HY Hsin, DE Ingber (25 June 2010) 'Reconstituting organ-?level lung functions on a chip. Science 328, 1662–68. 2022-05-18T03:55:37+0000John Syer Bristowe, a physician at St Thomas Hospital, used term to denote the 'smallest functional organ or tissue unit' in his book 'A Treatise on the Theory and Practice of Medicine (1876). 1876-01-01T00:00:00+0000Achieved by Wilhelm Rous, the feat established the priciple of tissue culture. 1885-01-01T00:00:00+0000Henry Van Peters Wilson found he could keep individual lobes cut from a red oyster sponge alive by wrapping them in fine bolting silk and squeezing the bag under sea water until cells flowed out of the silk as loose cells and small cell clumps. He noticed that the cells and clumps came together to form new sponges. He published his findings in 'A new method by which sponges may be artificially reared', Science, 25 (1907) :912-15 and in 'On some phenomena of coalescence and regeneration in sponges' Journal of Experimental Zoology, 5 (1907). 245-58.1907-01-01T00:00:00+0000The method involved attaching cells or tissue fragment to a coverslip and bathed in a drop of serum of partially coagulated lymph. Once inverted so that a clot hangs the coverslip was attached and sealed to a microscope slide with a glass impression which allowed the drop to hang. It was devised by Ross Harrison. 1910-01-01T00:00:00+0000The media was developed by Margaret R. Lewis and Warren H. Lewis. It consisted of sea water, serum, embryo extract, salts and peptones. 1911-01-01T00:00:00+0000The rubber-like colourless substance was pioneered by Frederic S Kipping, an English chemist based at Nottingham University. Silcones are now used for many different applications. 1927-01-01T00:00:00+00001943-01-01T00:00:00+0000The idea was patented by the German physicist and engineer Werner Jacobi while working at Siemens AG. 1949-01-01T00:00:00+0000The patent was taken out by Siemens-Elma. 1951-01-01T00:00:00+0000Known as HeLa, the cell line was created by George Gey from cervical cells taken without consent from Henrietta Lacks who died from cervical cancer on 4 October 1951. The cells taken from Lacks were the first human cells grown in the laboratory that did not die after a few cell divisions. The cell line proved enormously beneficial for medical and biological research. It was first published in WF Scherer, JT Syverton, GO Gey, 'Studies on the propagation in vitro of poliomyelitis viruses. IV. Viral multiplication in a stable strain of human malignant epithelial cells (strain HeLa) derived from an epidermoid carcinoma of the cervix', Journal Experimental Medicine, 97/5 (1953), 695–710.1952-05-01T00:00:00+0000Working at Bell Labs, Jules Andrus and Walter L Bond began adapting photoengraving techniques already used to make patterns on printed circuit boards to produce fine patters on the surface of silicon wafers. 1955-01-01T00:00:00+0000The circuits were made by two American engineers working independently of each other. The first was produced by Jack Kilby at Texas Instruments as part of a programme sponsored by the US Army Signal Corps to create easily assembled circuits. The second was created by Robert Noyce, a physicist and co-founder of Fairchild Semiconductor, a startup company. 1958-11-01T00:00:00+0000The patent was awarded to Jay Lathrop and James R. Nall of the U.S. Army's Diamond Ordnance Fuse Laboratories in Maryland. Their techique involved depositing thin-film metals strips, about 200 micrometers wide, to connect tiny transitors on a ceramic substate. 1959-06-09T00:00:00+0000The device was developed by Stephen C Terry, Hal Jerman and James B Angell at Stanford University. It was designed to integrate several laboratory functions on a tiny single integrated circuit only millimetres to a few squares in size to enable automation and high-throughput screening. The chip was published in SC Terry, JH Herman, JB Angell (1979) 'A gas chromatographic air analyzer fabricated on a silicon wafer', IEEE Transactions on Electron Devices, 26/12, 1880-86. 1980-01-01T00:00:00+0000The system was created by Andrea Manz, a Swiss analytical chemist, and his team at Ciba-Geigy. Being the first time microchip to be applied to chemistry, Manz's work helped shrink the size of a laboratory to a chip. One of its advantages was it allowed for a number of experiments to be run in parallel. A Manz, N Graber, and HM Widmer (1990), 'Miniaturized total chemical analysis systems: a novel concept for chemical sensing,” Sensors and Actuators B1, 244–48.1990-01-01T00:00:00+0000S Rohr, DM Scholly, AF Kleber, AF (1991) 'Patterned growth of neonatal rat heart cells in culture. Morphological and electrophysiological characterization', Circulation Research, 68, 114–130.1991-01-01T00:00:00+0000Fabricated out of Pyrex glass using micromachining the chip opened up the feasibility of a developing a miniaturised laboratory-on-a-chip for complex analyses. It was published in DJ Harrison, K Fluri, K Seiler, et al (1993) 'Micromachining a miniaturized capillary electrophoresis-based chemical analysis system on a chip', Science, 261/ 5123, 895–97. 1993-08-01T00:00:00+00001994-01-01T00:00:00+0000M Shuler, D Ghanem, M Quick, M et al (1996) 'A self-regulating cell culture analog device to mimic animal and human toxicology responses,' Biotechnology and Bioengineering, 52/1, 45-60.1996-01-01T00:00:00+0000The technique involved using polydimethylsiloxane (PDMS) which made microchips much simpler and cheaper to fabricate and accessible to molecular chemists. It was first published in X Xia, G Whitesides (16 March 1998) 'Soft lithography', Annual Review Material Science, 28, 153-84.1998-01-01T00:00:00+00001998-01-01T00:00:00+0000The new technique allowed for the rapid manipulation of discrete microdroplets over a surface opening up new possibilities for fabrication of lab-on-a-chip. It was published in MC Pollack, RB Fair (2000) 'Electrowetting-based actuation of liquid droplets for microfluidic applications', Applied Physics Letters, 77, 1725.2000-01-01T00:00:00+0000They were developed by two separate groups. One was published by a group led by Stephen Quake as Marc A. Unger, Hou-Pu Chou, Todd Thorsen, Axel Scherer, Stephen Quake, 'Monolithic Microfabricated Valves and Pumps by Multilayer Soft Lithography”, Science, 2000, 288, 113–16. Another was published by Kazuo Hosokawa and Ryutaro Maeda, 'A pneumatically-actuated three-way microvalve fabricated with polydimethylsiloxane using the membrane transfer technique', Journal of Micromechanics and Microengineering, 10/3, 415. 2000-01-01T00:00:00+0000A Sin, GT Baxter, ML Shuler, ML (28 Sept 2001) 'Animal on a chip: A microscale cell culture analog device for evaluating toxicological and pharmacological profiles', Proceedings of SPIE 4560, Microfluidics and BioMEMS, doi: 10.1117/12.443045.2001-09-28T00:00:00+0000SG Harris, ML Shuler (2003) 'Growth of endothelial cells on microfabricated silicon nitride membranes for an in vitro model of the blood-?brain barrier', Biotechnolology Bioprocess Engineering, 8, 246–51.2003-01-01T00:00:00+0000A Sin, KC Chin, MF Jamil, et al (2004) 'The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors', Biotechnology Progress, 20, 338-452004-01-01T00:00:00+0000PJ Hung, PJ Lee, P Sabounchi, et al (2005) 'A novel high aspect ratio microfluidic design to provide a stable and uniform microenvironment for cell growth in a high throughput mammalian cell culture array', Lab on a Chip, 5, 44-48.2004-11-02T00:00:00+0000SW Rhee, AM Taylor, Christina Tu et al (2005) 'Patterned cell culture inside microfluidic devices', Lab on a Chip, 5/1, 102-7. 2005-01-01T00:00:00+0000C Giese, CD Demmler, R Ammer, R, et al (Oct 2006) 'A human lymph node in vitro-challenges and progress', Artificial Organs, 30/10, 803-08., BioTechniques.2006-10-01T00:00:00+0000PJ Lee., PJ Hung, LP Lee 'An artificial liver sinusoid with a microfluidic endothelial-?like barrier for primary hepatocyte culture. Biotechnology and Bioenginering. 97, 1340–1346 (2007).2007-02-07T00:00:00+0000D Huh, H Fujika, Y-C Tung, S Takayama (2007) 'Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems', PNAS, 104/48, 18886-91. 2007-11-27T00:00:00+0000K Jang, K Sato, K Igawa, U-I Chung, T Kitamori, (2008) 'Development of an osteoblast-?based 3D continuous-perfusion microfluidic system for drug screening', Analytical and Bioanalytical Chemistry, 390, 825–32. 2007-12-15T00:00:00+00002008-01-01T00:00:00+0000H Kimura, T Yamamoto, H Sakai, Y Sakai, T Fujii (2008) 'An integrated microfluidic system for long-?term perfusion culture and on-?line monitoring of intestinal tissue models', Lab on a Chip, 8, 741–46.2008-05-01T00:00:00+0000MT Lama, Y-C Huang, RK Birla, S Takayama (Feb 2009) 'Microfeature guided skeletal muscle tissue engineering for highly organized 3-dimensional free-standing constructs', Biomaterials, 30/6, 1150-55.2009-02-01T00:00:00+0000JH Sung, ML Shuler (2009) 'A micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs', Lab on a chip, 9/10, 1385e94.2009-02-20T00:00:00+0000GJ Mahler, MB Esch, RP Glahn, LM Shuler (2009) 'Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity'. Biotechnology Bioengineering, 104, 193–205.2009-09-01T00:00:00+0000JH Sung, C Kam, ML Shuler (2010) 'A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip', Lab on a Chip, 10/4, 446-55.2010-01-05T00:00:00+0000K-J Jang, K-Y Suh (2010) 'A multi-layer microfluidic device for efficient culture and analysis of renal tubular cells', Lab on a Chip, 10/1. 36-42. 2010-01-07T00:00:00+0000M Shuler, MB, Esch (2010) 'Body-on-a chip: Using microfluidic systems to predict human responses to drugs', Pure Applied Chemistry, 82/8, 1635-452010-06-08T00:00:00+0000The new device made it possible to investigate the inflammation response in a human lung. D Huh, BD, Matthews, A Mammoto, et al (2010) 'Reconstituting Organ-Level Lung Functions on a Chip', Science, 328, 1662-68.2010-06-10T00:00:00+0000Y Nakao, H Kimura, Y Sakai, T Fujii, (2011), 'Bile canaliculi formation by aligning rat primary hepatocytes in a microfluidic device', Biomicrofluidics, 5, 022212. doi:10.1063/1.3580753.2011-06-01T00:00:00+0000WL Warren, D Drake, J Moser et al (6 Dec 2011) 'Co-culture lymphoid tissue for an artificial immune system' US Patent 8,071,373 B2.2011-12-06T00:00:00+0000HJ Kim, D Huh, G Hamilton, DE Ingber (2012) 'Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow', Lab on a Chip, 12.2012-01-01T00:00:00+0000C Franco, H Gerhardt (22 Aug 2012) 'Blood vessels on a chip', Nature, 488, 465–66.2012-08-12T00:00:00+0000Wei-Xuan Li et al ( April 2013) 'Artificial uterus on a microfluidic chip', Chinese Journal of Analytical Chemistry, 41/4, 467-72. 2013-02-26T00:00:00+0000K-J Jang, AP Mehr, GA Hamilton, LA McPartlin, S Chung, K-Y Suh, D Ingber (2013) 'Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment', Integrative Biology, 2013-04-25T00:00:00+0000Y-S Torisawa, CS Spina, T Mammoto et al (June 2014) 'Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro', Nature Methods, 11/6, 663-9. 2014-06-01T00:00:00+0000The workshop was organised by the Center of Alternatives to Animal testing in Europe· 2015-01-01T00:00:00+0000JiSoo Park, Bo Kyeong Lee, Gi Seok Jeong, Jung Keun Hyun, C Justin Lee, Sang-Hoon Lee (Jan 2015) 'Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer's disease', Lab on a Chip, 15/1, 141-50. 2015-01-07T00:00:00+0000C Oleaga, C Bernabini, AST Smith, et al (2016) 'Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs', Scientific Reports, 6/ 200030.2016-02-03T00:00:00+0000PM Rosa, N Gopalakrishnan, H Ibrahim, et al (2016) 'The intercell dynamics of T cells and dendritic cells in a lymph node-on-a-chip flow device', Lab on a Chip, 16/19, 3728-40. 2016-08-25T00:00:00+0000JU Lind, TA Valentine, AD Pasqualini, S Francesco, H Yan (2016) 'Instrumented cardiac microphysiological devices via multimaterial three-?dimensional printing' Nature Materials, 16/3 303–308 (2016).2017-03-01T00:00:00+0000A Skardal, SV Murphy, M Devarasetty, et al (2017) 'Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform', Scientific Reports, 7, 8837. 2017-08-18T00:00:00+0000BA Hassell, G Goyal, E Lee et al (2017) 'Human Organ Chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro', Cell Reports, 21/2, 508-16.2017-10-10T00:00:00+00002019-01-01T00:00:00+0000AP Ramme, L Koenig, T Hasenberg, T, et al (10 Sept 2019) 'Autologous induced pluripotent stem cell-derived four-organ-chip', Future Science OA, 5/8, FSO413. doi: 10.2144/fsoa-2019-00652019-09-10T00:00:00+0000Si, N Bai, H, Rodas, M et al (Aug 2021) 'A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics', Nature Biomedical Engineering, 5/8, 815-29.2021-08-01T00:00:00+0000The drug, Azeliragon, had previously be shown to be safe in trials exploring its use for Alzheimer’s disease and diabetic nephropathy. Studies with the chip, created by Ingber and his team at the Wyss Institute, revealed the small molecule drug blocked inflammation-causing cytokines including IL-6, IL-8, and IP-10 as well as RANTES, a major proinflammatory cytokine produced by virus-infected lung cells. Based on the results Phase 2 clinical trials were planned to investigate the drug further for patients hospitaled with severe COVID-19, and in other pulmonary inflammatory diseases including chronic obstructive pulmonary disease and steroid refractory asthma. 2022-02-23T00:00:00+0000H Bai, L Si, A Jiang, A, et al (8 April 2022) 'Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip', Nature Communications, 13/1928.2022-04-08T00:00:00+0000The chip was created by researchers at Hesperos to test therapies for treating rare neuromuscular diseases. It contains two cell types: motoneurons, which transmit messages from the brain to muscles, and Schwann cells which help the signals to move more quickly. The chip was developed to mimic the biology of chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. It was funded by a research grant from the NIH’s National Center for Advancing Translational Sciences. 2022-04-19T00:00:00+0000
Date Event People Places
18 May 2022First time the term 'Organ-on-a-chip' is usedHuh, Matthews, Mammoto, Montoya-Zavala, Hsin, IngberHarvard University, Wyss Institute
1876'Organoid' coined for first timeSyer BristoweSt Thomas' Hospital
1885Chick embryos maintained in saline culture for several daysWilhelm Rous 
1907Individual tissue cells taken from living organism kept alive in sea waterVan Peters WilsonUniversity of North Carolina
1910Nerve fibres shown to form from cells Ross HarrisonYale University
1911First growth medium developed for cultivating cellsLewis 
1927First silicon polymers (silicones) developed KippingUniversity of Nottingham
1943Dow Corning Corporation founded to commercialise silicone technologyDow Corning
1949First idea proposed for integrated-circuit-like semiconductor amplifying deviceJacobiSiemens AG
1951First inkjet printer patentedSiemens-Elma
1 May 1952First immortal human cell line (HeLa) developedLacks, Gey, Scherer, SyvertonUniversity of Minnesota, Johns Hopkins University
1955Silicon devices made using photolithography techniquesAndrus, BondBell Labs
November 1958 - Jan 1959First silicon based integrated circuits producedKilby, NoyceTexas Instruments, Fairchild Semiconductor
9 Jun 1959First patent awarded for photolithography Lathrop, Nall 
January 1980First 'laboratory-on-a-chip' producedTerry, Jerman, AngellStanford University
January 1990Miniaturised chemical analysis system (µ-TAS) developed for continuous chemical sensingManz, Graber, WidmerCiba-Geigy AG
1991First in vitro cardiac model reportedRohr, Schooly, KleberUniversity of Bern
August 1993µ-TAS system created on a glass chip shown to perform capillary electrophoresis of amino acids in few secondsHarrison, Fluri, Seiler, Fan, Effenhauser, Manz, University of Alberta, Ciba-Geigy
1994US Defense Advanced Research Projects Agency launches funding for development of lab-on-a-chip for biodefence research 
1 Jan 1996First cell culture analogue device constructed to mimic the physiological and toxicological responses of animals and humans to drugsShuler, Ghanem, D Quick, Wong, MillerCornell University
1998Introduction of soft-lithography using polymer moulds enabled the fabrication of cheap microfluidic devices Xia, Whitesides Harvard University
1998First microfluidic devices start to appear for cell biology applications 
1 Jan 2000Introduction of digital microfluidics, a new liquid-handling technology Pollack, Fair Duke University
2000PDMS pneumatic microvalves introduced for the first time Unger, Hou-Pu Chou, Thorsen, Scherer, Quake, Stanford University, AIST Tsukuba East
28 Sep 2001First animal-on-a-chip reported for testing drugsSin, Baxter, ShulerCornell University
2003First chip produced modelling the blood-brain barrierSabrina Harris, ShulerCornell University
2004Cell culture analogue device fabricated to replicate lung, liver and other tissues for studying the toxicology and pharmacology of chemical compoundsAaron Sin, Katherine Chin, Muhammad Jamil, Yordan Kostov, Govind Rao, ShulerCornell University, University of Maryland
2 Nov 2004Microfluidic device designed to culture cells inside an array of microchambers with continuous perfusion of mediumPaul Hung, Philip Lee, Sabounchi, Aghdam, Lin, Luke LeeUniversity of California Berkeley
January 2005Method published allowing for patterned cell culture inside microfluidic devicesRhee, Anne Taylor, Christina Tu, Cribbs, Cotman, JeonUniversity of California at Irvine
October 2006Microfluidic human artificial lymph node model developed to monitor effects of different substances on human immune systemGiese, Demmler, Ammer, Hartmann, Lubitz, Lilja Miller, Riccarda Müller, Uwe MarxProBioGen AG
7 Feb 2007Chip produced with liver cells for modelling drug toxicity drug screeningPhilip Lee, Paul Hung, Luke LeeUniversity of California Berkeley
27 Nov 2007Lung-on-a-chip shown to recreate the crackling sound of lung injuryTakayama, Huh, Fujika, TungUniversity of Michigan
15 Dec 2007Chip produced with osteoblast cells to replicate the bone environment for drug testingJang, Sato, Igawa, Chung, KitamorUniversity of Tokyo
20083D printing begins to be applied to microfluidics 
May 2008Chip created to model intestinal tissueKimura, Yamamoto, Sakai, Sakai, FujiiUniversity of Tokyo
February 2009First chip produced with cells taken from skeletal muscle tissueTakayama, Lam, Huang, BirlaUniversity of Michigan
20 Feb 2009Micro cell culture analogue designed with liver, colon cancer and bone marrow cells used to assess the pharmacokinetic and pharmacodynamic profiles of anti-cancer drug Sung, ShulerCornell University
1 Sep 2009Gastrointestinal gut modelled on a chip to predict drug toxicityMahler, Esch, Glahn, Shuler Cornell University
5 Jan 2010First pharmacokinetics–pharmacodynamics model-on-a-chip publishedSung, Kam, Shuler Cornell University
7 Jan 2010Chip designed with kidney cellsKyung-Jin Jang, Kahp-Yang SuhSeoul National University
8 Jun 2010'Body-on-a-chip' reported to help predict human responses to drugsShuler, EschCornell University
10 Jun 2010Lung-on-a-chip with alveolar-capillary interface produced to mimic the breathing action of a human lung Dongeun Huh, Benjamin Matthews, Mammoto, Montoya-Zavala, Hsin, IngberHarvard University, Wyss Institute
June 2011Microfluidic device mimicking the microscopic function in liver tissue reportedNakao, Kimura, Sakai, FujiiUniversity of Tokyo
6 Dec 2011Artificial immune system patented for testing immune responses to vaccinesWarren, Drake, Moser, Inderpal Singh, Haifeng Song, Mishkin, TewSanofi Pasteur
2012Human gut-on-a-chip publishedHyun Jung Kim, Dongeun Huh, Geraldine Hamilton, IngberHarvard University, Wyss Institute
12 Aug 2012Blood vessels on a chip createdFranco, GerhardtVascular Patterning Laboratory, KU Leuven
26 Feb 2013Uterus on a chip publishedWei-Xuan Li, Guang-Tie Liang, Yan Wei, Qiong Zhang, Wei Wang, Xiao-Mian Zhou, Yu LiuGuangzhou Medical University
25 Apr 2013Human-kidney on a chip developed to assess drug transport and toxicityKugng-Jin, Jang, Mehr, Geraldine Hamilton, McPartlin, Seyoon Chung, Kahp-Yang Suh, D IngberHarvard University, Wyss Institute
June 2014Bone-marrow-on-a-chip publishedTorisawa, Spina, Tadanori Mammoto, Akiko Mammoto, Weaver, Tat. Collins, IngberHarvard University, Wyss Institute
2015First stakeholder workshop hosted for developing microphysiological systemsUwe Marx 
January 2015Brain-on-a-chip created to model Alzheimer's diseasePark, Kyeong Lee, Jeong, Hyun, C Justin Lee, Sang-Hoon Lee Korea University
3 Feb 2016Four organ chip integrating human liver, cardiac, skeletal muscle and neuronal cells found to successfully model multi-organ toxicity with 5 drugs over 14 days Oleaga, Bernabini, Alec Smith, Srinivasan, Max Jackson, McLamb, Platt, Bridges, Cai, Santhanam, Berry, Akanda, Guo, Martin, Esch, Langer, Ouedraogo, Cotovio, Breton, Shuler, HickmanCornell University, University of Central Florida, L’Oreal Research and Innovation
25 Aug 2016Lymph node-on-a-chip device publishedRosa, Gopalakrishnan, Ibrahim, Markus Haug, HalaasNorwegian University of Science
1 Mar 2017First organ-on-a-chip produced entirely with 3D printingLind, Busbee, Valentine, Pasqualini, Yuan, Yardid, Sung-Jin Park, Kotkian, Nesmith, Patrick campbell, Vlassak, Jennifer Lewis, Kevin ParkerHarvard University, Wyss Institute
18 Aug 2017Three-tissue organ-on-a-chip platform created to assess drug responseSkardal, SeanMurphy, Devarasetty, Mead, Hyun-Wook Kang, Young-Joon Seol, Shrike Zhang, Su-Ryon Shin, Liang Zhao, Aleman, Adam Hall, Shupe, Dokmeci, Sang Jin Lee, John Jackson, James Yoo, Hartung, Khademhosseini, Soker, Bishop, Atala Harvard University, Wyss Institute, Wake Forest School of Medicine, Massachusetts Institute of Technology, Johns Hopkins University, University of Konstanz, Konkuk University, King Abdulaziz University
10 Oct 2017Chip created to mimic orthotopic lung cancer growthHassell, Goyal, Esak Lee, Sontheimer-Phelps, Oren Levy, Christopher S Chen, IngberHarvard University, Wyss Institute, University of Freiburg
2019Second stakeholder workshop held for microphysiological systemsUwe Marx 
10 Sep 2019Four-organ-chip created integrating miniaturised human intestine, liver, brain and kidney equivalentsRamme, Leopold Koenig, Tobias Hasenberg, Schwenk, Magauer, Faust, Lorenz, Anna-Catarina Krebs, Drewell, Schirrmann, Vladetic, Grace-Chiaen Lin, Pabinger, Neuhaus, Bois, Lauster, Uwe Marx, DehneTissUse GmbH, Technische Universität Berlin, University of Manchester, Austrian Institute of Technology GmbH, INERIS
August 2021Human-airway-on-a-chip used to identify antiviral drugs and prophylactics against SARS-CoV-2 virus Longlong Si, Haiqing Bai, Rodas, Wuji Cao, Crystal Yuri Oh, Amanda Jiang, Moller, Daisy Hoagland, Kohei Oishi, Shu Horiuchi , Skyler Uhl, Blanco-Melo, Randy Albrecht, Wen-Chun Liu, Tristan Jordan, Nilsson-Payant , Golynker, Justin Frere?, James Logue?, RHarvard University, Wyss Institute, Icahn School of Medicine at Mount Sinai, University of Maryland School of Medicine, University of Chieti-Pescara, University of Pittsburgh
23 Feb 2022Human Lung Alveolus Chip demonstrated drug to significantly inhibit production of inflammation-causing cytokines triggered by SARS-CoV-2 and other viral infectionsIngberHarvard University, Wyss Institute, Cantex Pharmaceuticals
8 Apr 2022Human lung aveolus chip reveals mechanical control of immune responses against viral infectionHaiqing Bai, Longlong Si, Amanda Jiang, Chaitra Belgur, Yunhao Zhai, Plebani, Crystal Yuri Oh, Melissa Rodas, Patil, Nurani, Gilpin, Rani Powers, Girija Goyal, Prantil-Baun, IngberHarvard University, Wyss Institute, University of Chieti-Pescara
19 Apr 2022First Organ-on-a-chip used in FDA Investigational New Drug application to get authorisation for testing a drug in a clinical trial Hickman, ShulerHesperos, Cornell University

18 May 2022

First time the term 'Organ-on-a-chip' is used

1876

'Organoid' coined for first time

1885

Chick embryos maintained in saline culture for several days

1907

Individual tissue cells taken from living organism kept alive in sea water

1910

Nerve fibres shown to form from cells

1911

First growth medium developed for cultivating cells

1927

First silicon polymers (silicones) developed

1943

Dow Corning Corporation founded to commercialise silicone technology

1949

First idea proposed for integrated-circuit-like semiconductor amplifying device

1951

First inkjet printer patented

1 May 1952

First immortal human cell line (HeLa) developed

1955

Silicon devices made using photolithography techniques

Nov 1958 - Jan 1959

First silicon based integrated circuits produced

9 Jun 1959

First patent awarded for photolithography

Jan 1980

First 'laboratory-on-a-chip' produced

Jan 1990

Miniaturised chemical analysis system (µ-TAS) developed for continuous chemical sensing

1991

First in vitro cardiac model reported

Aug 1993

µ-TAS system created on a glass chip shown to perform capillary electrophoresis of amino acids in few seconds

1994

US Defense Advanced Research Projects Agency launches funding for development of lab-on-a-chip for biodefence research

1 Jan 1996

First cell culture analogue device constructed to mimic the physiological and toxicological responses of animals and humans to drugs

1998

Introduction of soft-lithography using polymer moulds enabled the fabrication of cheap microfluidic devices

1998

First microfluidic devices start to appear for cell biology applications

1 Jan 2000

Introduction of digital microfluidics, a new liquid-handling technology

2000

PDMS pneumatic microvalves introduced for the first time

28 Sep 2001

First animal-on-a-chip reported for testing drugs

2003

First chip produced modelling the blood-brain barrier

2004

Cell culture analogue device fabricated to replicate lung, liver and other tissues for studying the toxicology and pharmacology of chemical compounds

2 Nov 2004

Microfluidic device designed to culture cells inside an array of microchambers with continuous perfusion of medium

Jan 2005

Method published allowing for patterned cell culture inside microfluidic devices

Oct 2006

Microfluidic human artificial lymph node model developed to monitor effects of different substances on human immune system

7 Feb 2007

Chip produced with liver cells for modelling drug toxicity drug screening

27 Nov 2007

Lung-on-a-chip shown to recreate the crackling sound of lung injury

15 Dec 2007

Chip produced with osteoblast cells to replicate the bone environment for drug testing

2008

3D printing begins to be applied to microfluidics

May 2008

Chip created to model intestinal tissue

Feb 2009

First chip produced with cells taken from skeletal muscle tissue

20 Feb 2009

Micro cell culture analogue designed with liver, colon cancer and bone marrow cells used to assess the pharmacokinetic and pharmacodynamic profiles of anti-cancer drug

1 Sep 2009

Gastrointestinal gut modelled on a chip to predict drug toxicity

5 Jan 2010

First pharmacokinetics–pharmacodynamics model-on-a-chip published

7 Jan 2010

Chip designed with kidney cells

8 Jun 2010

'Body-on-a-chip' reported to help predict human responses to drugs

10 Jun 2010

Lung-on-a-chip with alveolar-capillary interface produced to mimic the breathing action of a human lung

Jun 2011

Microfluidic device mimicking the microscopic function in liver tissue reported

6 Dec 2011

Artificial immune system patented for testing immune responses to vaccines

2012

Human gut-on-a-chip published

12 Aug 2012

Blood vessels on a chip created

26 Feb 2013

Uterus on a chip published

25 Apr 2013

Human-kidney on a chip developed to assess drug transport and toxicity

Jun 2014

Bone-marrow-on-a-chip published

2015

First stakeholder workshop hosted for developing microphysiological systems

Jan 2015

Brain-on-a-chip created to model Alzheimer's disease

3 Feb 2016

Four organ chip integrating human liver, cardiac, skeletal muscle and neuronal cells found to successfully model multi-organ toxicity with 5 drugs over 14 days

25 Aug 2016

Lymph node-on-a-chip device published

1 Mar 2017

First organ-on-a-chip produced entirely with 3D printing

18 Aug 2017

Three-tissue organ-on-a-chip platform created to assess drug response

10 Oct 2017

Chip created to mimic orthotopic lung cancer growth

2019

Second stakeholder workshop held for microphysiological systems

10 Sep 2019

Four-organ-chip created integrating miniaturised human intestine, liver, brain and kidney equivalents

Aug 2021

Human-airway-on-a-chip used to identify antiviral drugs and prophylactics against SARS-CoV-2 virus

23 Feb 2022

Human Lung Alveolus Chip demonstrated drug to significantly inhibit production of inflammation-causing cytokines triggered by SARS-CoV-2 and other viral infections

8 Apr 2022

Human lung aveolus chip reveals mechanical control of immune responses against viral infection

19 Apr 2022

First Organ-on-a-chip used in FDA Investigational New Drug application to get authorisation for testing a drug in a clinical trial

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