Tag Archives: lung-on-a-chip

Constructing a liver

Chinese researchers have taken a step closer to constructing complex (lifelike) liver tissue according to a Jan. 27, 2016 American Chemical Society (ACS) news release (also on EurekAlert),

Engineered liver tissue could have a range of important uses, from transplants in patients suffering from the organ’s failure to pharmaceutical testing [this usage is sometimes known as liver-on-a-chip]. Now scientists report in ACS’ journal Analytical Chemistry the development of such a tissue, which closely mimics the liver’s complicated microstructure and function more effectively than existing models.

The liver serves a critical role in digesting food and detoxifying the body. But due to a variety of factors, including viral infections, alcoholism and drug reactions, the organ can develop chronic or acute problems. When it doesn’t work well, a person can suffer abdominal pain, swelling, nausea and other symptoms. Complete liver failure can be life-threatening and can require a transplant, a procedure that currently depends on human donors. To curtail this reliance and provide an improved model for predicting drugs’ side effects, scientists have been engineering liver tissue in the lab. But so far, they haven’t achieved the complex architecture of the real thing. Jinyi Wang and colleagues came up with a new approach.

Wang’s team built a microfluidics-based tissue that copies the liver’s complex lobules, the organ’s tiny structures that resemble wheels with spokes. They did this with human cells from a liver and an aorta, the body’s main artery. In the lab, the engineered tissue had a metabolic rate that was closer to real-life levels than other liver models, and it successfully simulated how a real liver would react to various drug combinations. The researchers conclude their approach could lead to the development of functional liver tissue for clinical applications and screening drugs for side effects and potentially harmful interactions.

Here’s a link to and a citation for the paper,

On-Chip Construction of Liver Lobule-like Microtissue and Its Application for Adverse Drug Reaction Assay by Chao Ma, Lei Zhao, En-Min Zhou, Juan Xu, Shaofei Shen, and Jinyi Wang. Northwest A&F University, China Anal. Chem., Article ASAP DOI: 10.1021/acs.analchem.5b03869 Publication Date (Web): January 7, 2016

Copyright © 2016 American Chemical Society

This paper is behind a paywall.

In a teleconference earlier this month (January 2016), I spoke to researchers at the University of Malaya, Universiti Teknologi Malaysia (UTM), and Harvard University about a joint lung and nanomedicine research project where I asked researcher Joseph Brain (Harvard) about using lung-on-a-chip testing in place of in vivo (animal) testing and he indicated more confidence in the ‘precision cut lung slices’ technique. (You can find out more about the Malaysian project in my Jan. 12, 2016 posting but there’s only a brief mention of Brain’s preferred alternative animal testing technique.)

North Carolina universities go beyond organ-on-a-chip

The researchers in the North Carolina universities involved in this project have high hopes according to an Oct. 9, 2015 news item on Nanowerk,

A team of researchers from the University of North Carolina at Chapel Hill and NC State University has received a $5.3 million, five-year Transformative Research (R01) Award from the National Institutes of Health (NIH) to create fully functioning versions of the human gut that fit on a chip the size of a dime.

Such “organs-on-a-chip” have become vital for biomedical research, as researchers seek alternatives to animal models for drug discovery and testing. The new grant will fund a technology that represents a major step forward for the field, overcoming limitations that have mired other efforts.

The technology will use primary cells derived directly from human biopsies, which are known to provide more relevant results than the immortalized cell lines used in current approaches. In addition, the device will sculpt these cells into the sophisticated architecture of the gut, rather than the disorganized ball of cells that are created in other miniature organ systems.

“We are building a device that goes far beyond the organ-on-a-chip,” said Nancy L. Allbritton, MD, PhD, professor and chair of the UNC-NC State joint department of biomedical engineering and one of four principle investigators on the NIH grant. “We call it a ‘simulacrum,’ [emphasis mine] a term used in science fiction to describe a duplicate. The idea is to create something that is indistinguishable from your own gut.”

I’ve come across the term ‘simulacrum’ in relation to philosophy so it’s a bit of a surprise to find it in a news release about an organ-on-a-chip where it seems to have been redefined somewhat. Here’s more from the Simulacrum entry on Wikipedia (Note: Links have been removed),

A simulacrum (plural: simulacra from Latin: simulacrum, which means “likeness, similarity”), is a representation or imitation of a person or thing.[1] The word was first recorded in the English language in the late 16th century, used to describe a representation, such as a statue or a painting, especially of a god. By the late 19th century, it had gathered a secondary association of inferiority: an image without the substance or qualities of the original.[2] Philosopher Fredric Jameson offers photorealism as an example of artistic simulacrum, where a painting is sometimes created by copying a photograph that is itself a copy of the real.[3] Other art forms that play with simulacra include trompe-l’œil,[4] pop art, Italian neorealism, and French New Wave.[3]


The simulacrum has long been of interest to philosophers. In his Sophist, Plato speaks of two kinds of image making. The first is a faithful reproduction, attempted to copy precisely the original. The second is intentionally distorted in order to make the copy appear correct to viewers. He gives the example of Greek statuary, which was crafted larger on the top than on the bottom so that viewers on the ground would see it correctly. If they could view it in scale, they would realize it was malformed. This example from the visual arts serves as a metaphor for the philosophical arts and the tendency of some philosophers to distort truth so that it appears accurate unless viewed from the proper angle.[5] Nietzsche addresses the concept of simulacrum (but does not use the term) in the Twilight of the Idols, suggesting that most philosophers, by ignoring the reliable input of their senses and resorting to the constructs of language and reason, arrive at a distorted copy of reality.[6]

Postmodernist French social theorist Jean Baudrillard argues that a simulacrum is not a copy of the real, but becomes truth in its own right: the hyperreal. Where Plato saw two types of representation—faithful and intentionally distorted (simulacrum)—Baudrillard sees four: (1) basic reflection of reality; (2) perversion of reality; (3) pretence of reality (where there is no model); and (4) simulacrum, which “bears no relation to any reality whatsoever”.[7] In Baudrillard’s concept, like Nietzsche’s, simulacra are perceived as negative, but another modern philosopher who addressed the topic, Gilles Deleuze, takes a different view, seeing simulacra as the avenue by which an accepted ideal or “privileged position” could be “challenged and overturned”.[8] Deleuze defines simulacra as “those systems in which different relates to different by means of difference itself. What is essential is that we find in these systems no prior identity, no internal resemblance”.[9]

Getting back to the proposed research, an Oct. (?), 2015 University of North Carolina news release, which originated the news item, describes the proposed work in more detail,

Allbritton is an expert at microfabrication and microengineering. Also on the team are intestinal stem cell expert Scott T. Magness, associate professor of medicine, biomedical engineering, and cell and molecular physiology in the UNC School of Medicine; microbiome expert Scott Bultman, associate professor of genetics in the UNC School of Medicine; and bioinformatics expert Shawn Gomez, associate professor of biomedical engineering in UNC’s College of Arts and Sciences and NC State.

The impetus for the “organ-on-chip” movement comes largely from the failings of the pharmaceutical industry. For just a single drug to go through the discovery, testing, and approval process can take as many as 15 years and as much as $5 billion dollars. Animal models are expensive to work with and often don’t respond to drugs and diseases the same way humans do. Human cells grown in flat sheets on Petri dishes are also a poor proxy. Three-dimensional “organoids” are an improvement, but these hollow balls are made of a mishmash of cells that doesn’t accurately mimic the structure and function of the real organ.

Basically, the human gut is a 30-foot long hollow tube made up of a continuous single-layer of specialized cells. Regenerative stem cells reside deep inside millions of small pits or “crypts” along the tube, and mature differentiated cells are linked to the pits and live further out toward the surface. The gut also contains trillions of microbes, which are estimated to outnumber human cells by ten to one. These diverse microbial communities – collectively known as the microbiota – process toxins and pharmaceuticals, stimulate immunity, and even release hormones to impact behavior.

To create a dime-sized version of this complex microenvironment, the UNC-NC State team borrowed fabrication technologies from the electronics and microfluidics world. The device is composed of a polymer base containing an array of imprinted or shaped “hydrogels,” a mesh of molecules that can absorb water like a sponge. These hydrogels are specifically engineered to provide the structural support and biochemical cues for growing cells from the gut. Plugged into the device will be various kinds of plumbing that bring in chemicals, fluids, and gases to provide cues that tell the cells how and where to differentiate and grow. For example, the researchers will engineer a steep oxygen gradient into the device that will enable oxygen-loving human cells and anaerobic microbes to coexist in close proximity.

“The underlying concept – to simply grow a piece of human tissue in a dish – doesn’t seem that groundbreaking,” said Magness. “We have been doing that for a long time with cancer cells, but those efforts do not replicate human physiology. Using native stem cells from the small intestine or colon, we can now develop gut tissue layers in a dish that contains stem cells and all the differentiated cells of the gut. That is the thing stem cell biologists and engineers have been shooting for, to make real tissue behave properly in a dish to create better models for drug screening and cell-based therapies. With this work, we made a big leap toward that goal.”

Right now, the team has a working prototype that can physically and chemically guide mouse intestinal stem cells into the appropriate structure and function of the gut. For several years, Magness has been isolating and banking human stem cells from samples from patients undergoing routine colonoscopies at UNC Hospitals.

As part of the grant, he will work with the rest of the team to apply these stem cells to the new device and create “simulacra” that are representative of each patient’s individual gut. The approach will enable researchers to explore in a personalized way how both the human and microbial cells of the gut behave during healthy and diseased states.

“Having a system like this will advance microbiota research tremendously,” said Bultman. “Right now microbiota studies involve taking samples, doing sequencing, and then compiling an inventory of all the microbes in the disease cases and healthy controls. These studies just draw associations, so it is difficult to glean cause and effect. This device will enable us to probe the microbiota, and gain a better understanding of whether changes in these microbial communities are the cause or the consequence of disease.”

I wish them good luck with their work and to end on another interesting note, the concept of organs-on-a-chip won a design award. From a June 22, 2015 article by Oliver Wainwright for the Guardian (Note: Links have been removed),

Meet the Lung-on-a-chip, a simulation of the biological processes inside the human lung, developed by the Wyss Institute for Biologically Inspired Engineering at Harvard University – and now crowned Design of the Year by London’s Design Museum.

Lined with living human cells, the “organs-on-chips” mimic the tissue structures and mechanical motions of human organs, promising to accelerate drug discovery, decrease development costs and potentially usher in a future of personalised medicine.

“This is the epitome of design innovation,” says Paola Antonelli, design curator at New York’s Museum of Modern Art [MOMA], who nominated the project for the award and recently acquired organs-on-chips for MoMA’s permanent collection. “Removing some of the pitfalls of human and animal testing means, theoretically, that drug trials could be conducted faster and their viable results disseminated more quickly.”

Whodathunkit? (Tor those unfamiliar with slang written in this form: Who would have thought it?)

Asthma on a chip

Harvard University’s Wyss Institute for Biologically Inspired Engineering has found a way to mimic the lung’s muscle action when an asthma attack is being experienced according to a Sept. 23, 2014 news item on Nanowerk,

The majority of drugs used to treat asthma today are the same ones that were used 50 years ago. New drugs are urgently needed to treat this chronic respiratory disease, which causes nearly 25 million people in the United States alone to wheeze, cough, and find it difficult at best to take a deep breath.

But finding new treatments is tough: asthma is a patient-specific disease, so what works for one person doesn’t necessarily work for another, and the animal models traditionally used to test new drug candidates often fail to mimic human responses–costing tremendous money and time.

Hope for healthier airways may be on the horizon thanks to a Harvard University team that has developed a human airway muscle-on-a-chip that could be used to test new drugs because it accurately mimics the way smooth muscle contracts in the human airway, under normal circumstances and when exposed to asthma triggers. [emphasis mine]

A Sept. 23, 2014 Wyss Institute news release (also on EurekAlert*), which originated the news item, provides more details about the technology and its advantages,

The chip, a soft polymer well that is mounted on a glass substrate, contains a planar array of microscale, engineered human airway muscles, designed to mimic the laminar structure of the muscular layers of the human airway.

To mimic a typical allergic asthma response, the team first introduced interleukin-13 (IL-13) to the chip. IL-13 is a natural protein often found in the airway of asthmatic patients that mediates the response of smooth muscle to an allergen.

Then they introduced acetylcholine, a neurotransmitter that causes smooth muscle to contract. Sure enough, the airway muscle on the chip hypercontracted – and the soft chip curled up – in response to higher doses of the neurotransmitter.

They achieved the reverse effect as well and triggered the muscle to relax using drugs called β-agonists, which are used in inhalers.

Significantly, they were able to measure the contractile stress of the muscle tissue as it responded to varying doses of the drugs, said lead author Alexander Peyton Nesmith, a Ph.D./M.D. student at Harvard SEAS and the University of Alabama at Birmingham. “Our chip offers a simple, reliable and direct way to measure human responses to an asthma trigger,” he said.

The team then investigated what happened on a cellular level in response to the IL-13 and confirmed, for example, that the smooth muscle cells grew larger in the presence of IL-13 over time – a structural hallmark of the airways in asthma patients as well. They also documented an increased alignment of actin fibers within smooth muscle cells, which is consistent with the muscle in the airway of asthma patients. Actin fibers are super-thin cellular components involved in muscle contraction.

Next they observed how IL-13 changes the expression of contractile proteins called RhoA proteins, which have been implicated in the asthmatic response, although the details of their activation and signaling have remained elusive. To do this they introduced a drug called HA1077, which is not currently used to treat asthmatic patients – but targets the RhoA pathway. It turns out that the drug made the asthmatic tissue on the chip less sensitive to the asthma trigger – and preliminary tests indicated that using a combined therapy of HA1077 plus a currently approved asthma drug worked better than the single drug alone.

“Asthma is one of the top reasons for trips to the emergency room – particularly for children, and a large segment of the asthmatic population doesn’t respond to currently available treatments,” said Wyss Institute Founding Director Don Ingber, M.D., Ph.D. “The airway muscle-on-a-chip provides an important and exciting new tool for discovering new therapeutic agents.”

The scientists have provided an illustration of healthy and asthmatic airways,

Schematic comparing a healthy airway (few immune cells, normal airway diameter) to an asthmatic airway (many immune cells, constricted airway). Credit: Harvard's Wyss Institute and Harvard SEAS [School of Engineering and Applied Sciences]

Schematic comparing a healthy airway (few immune cells, normal airway diameter) to an asthmatic airway (many immune cells, constricted airway). Credit: Harvard’s Wyss Institute and Harvard SEAS [School of Engineering and Applied Sciences]

Here’s link to and a citation for the paper,

Human airway musculature on a chip: an in vitro model of allergic asthmatic bronchoconstriction and bronchodilation by Alexander Peyton Nesmith, Ashutosh Agarwal, Megan Laura McCain and Kevin Kit Parker.Lab Chip, 2014,14, 3925-3936 DOI: 10.1039/C4LC00688G First published online 05 Aug 2014

This paper is open access provided you have registered yourself for free at the site.

* EurekAlert link added Sept. 24, 2014.

University of British Columbia (Canada) discovers the ‘organ-on-a-chip’ and plans to host a July 2014 workshop

My latest piece about an ‘organ-on-a-chip’ project was a July 26, 2012 posting titled Organ chips for DARPA (Defense Advanced Research Projects Agency) featuring the Wyss Institute (which pops up again in the latest news I have from the University of British Columbia [UBC; located in Vancouver, Canada)]). First, here’s more about that 2012 announcement,,

The Wyss Institute will receive up to  $37M US for a project that integrates ten different organ-on-a-chip projects into one system. From the July 24, 2012 news release on EurekAlert,

With this new DARPA funding, Institute researchers and a multidisciplinary team of collaborators seek to build 10 different human organs-on-chips, to link them together to more closely mimic whole body physiology, and to engineer an automated instrument that will control fluid flow and cell viability while permitting real-time analysis of complex biochemical functions. As an accurate alternative to traditional animal testing models that often fail to predict human responses, this instrumented “human-on-a-chip” will be used to rapidly assess responses to new drug candidates, providing critical information on their safety and efficacy.

This unique platform could help ensure that safe and effective therapeutics are identified sooner, and ineffective or toxic ones are rejected early in the development process. As a result, the quality and quantity of new drugs moving successfully through the pipeline and into the clinic may be increased, regulatory decision-making could be better informed, and patient outcomes could be improved.

Jesse Goodman, FDA Chief Scientist and Deputy Commissioner for Science and Public Health, commented that the automated human-on-chip instrument being developed “has the potential to be a better model for determining human adverse responses. FDA looks forward to working with the Wyss Institute in its development of this model that may ultimately be used in therapeutic development.”

It’s nice to see that there’s interest in this area of research at UBC. From the Dec. 30, 2013 UBC news release by Gian-Paolo Mendoza which describes James Feng’s (professor in biological and chemical engineering) interest in the future possibilities offered by ‘organ-on-a-chip’ research,

“The potential is tremendous,” says Feng. “The main impact of organs grown this way will be on the design of drugs; the understanding of the pathological processes.”

Dr. Feng’s group carries out research in three broad areas: mechanics of biological cells and tissues, interfacial fluid dynamics, and mechanics and rheology of complex fluids.

The group has an inter-disciplinary flavour–crosscutting applied mathematics, cell biology, soft-matter physics and chemical and biomedical engineering—that is well-suited for exploring this burgeoning technology.

Feng cites a Harvard study [Ed. Note: This is the work being done at the Wyss Institute] using a small silicon device that holds a thin layer of real cell membranes capable of producing motion similar to the heaving and breathing of a lung.

Organ models designed this way have the potential to be more accurate in drug and treatment trials, says Feng, as they can better mimic the functions of human organs, as opposed to animal models which are the current research standard.

“It’s more controlled and you can simplify the process much faster,” said Feng.

“Harvard researchers also injected drugs into their chip model to see how it changed its behaviour and to see the tissue’s reaction to mechanical or chemical disturbance,” he added.

“It’s very important for drug design and discovery and the pharmaceutical industry would be tremendously interested in that.”

In addition, organs on a chip present a less controversial option for organ model testing compared to stem cell research. According to Feng, this is because their ultimate goals are very different from each other.

“The research that tried to grow organs directly from stem cells is aiming for eventually implantable organs,” he said. “The idea of making the chip is to work toward replacing animal models, so as to be more accurate and realistic like human organs. While the ability to replicate a complex human organ function remains far off, the direction appeals to anyone who is hoping to reduce the use of animals in research.”

Here’s the ‘lung-on-a-chip’ video the Wyss Institute has produced,

By contrast with ‘organ-on-a-chip’, the ‘lab-on-a-chip’ does not simulate the action of organs responding to various experimental therapeutic measures but makes standard testing and diagnostic procedures, such as blood tests, much faster, cheaper, and, in some cases, much less invasive as per my February 15, 2011 posting  which included some information about a local (Vancouver, Canada) project, the PROOF.(Prevention of Organ Failure) Centre.

The ‘organ-on-a-chip’ will help make clinical trials easier and faster according to Feng (from the news release),

Feng says this kind of organ testing offers the possibility of greatly reducing cost and time required for clinical trials.

“By using computer simulations we can generate results and insights, and run virtual tests much more easily and quickly,” he says.

“We can test maybe hundreds or thousands of designs of organ chips to be able to tell you whether you should try those ten designs instead of the hundreds one by one.”

Feng, who has a background in aerospace engineering, says this new bio-technology has the potential to transform the development of artificial organs and drugs the way computer simulations have replaced the use of wind tunnels for designing aircrafts.

“That used to be the dominant mode of designing crafts,” he said, “but that’s being replaced by online computer simulations because we understand the principles of aerodynamics so well.”

There’s also recognition that UBC is a little late to the ‘party’,

While UBC’s efforts in the field are in the early stages, Feng is reaching out to researchers from other backgrounds. He will be inviting leading scientists to UBC in July 2014 for a workshop that will centre on the growth of artificial organs and computer simulations. He is also exploring ideas of his own.

“I have a collaboration with an engineering colleague on how to use the microfluidic chip, the technology used to emulate the lung in the Harvard study, as a way of measuring malaria-infected red cells,” he said, suggesting that this is just one of the countless ways this new technology could be used to fuel future innovation.

And since it’s Friday (Jan. 3, 2014), I thought it was time for a music video, and Pink’s ‘Let’s get the party started’ seems to fit the bill,,

Have a good first weekend of the year 2014!