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The chip craze continues
May 2018
by Kelsey Kaustinen  |  Email the author
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Organs on chips, miniaturized representations of human organs, tissues or internal systems, are becoming one of the most promising fields in pharmaceutical and medical research. These microfluidic technologies enable researchers to test drugs in in-vivo scenarios without risk to patients, and to model diseases to better understand how they progress. As such, it’s no surprise that there’s a wealth of news from multiple organizations hard at work advancing this technology. We’ve gathered some of the most recent efforts in chip-based research and development to share.
 
In a unique approach, a team at Wageningen University & Research in The Netherlands is pursuing this microfluidic technology not just for developing new drugs, but also for potentially developing personalized food. Their approach is called “receptomics,” and consists of measuring the responses of different receptor proteins to a series of extracts or pure substances in a flow cell, and then predicting responses in the human body.
 
All receptor proteins are encoded by different genes, and the receptomics approach involves “printing” the DNA for a variety of receptor proteins on a glass slide. The DNA is rendered as microscopic droplets in a grid pattern, so small that they only cover about one square centimeter, and each droplet also contains DNA that codes for a colored signaling protein to visually convey a receptor’s response.
 
Cells, which absorb the DNA droplets, are grown on the slide on top of the grid pattern. After that, the slide is placed in a device that pumps a thin layer of liquid across the slide, such as an extract or drug, and the colored signaling proteins allow researchers to track the responses. The cells can be washed after each test to remove the trigger and reset them for another round of tests.
 
Maarten Jongsma, molecular biologist at Wageningen University & Research and coordinator of the research, explained that “Some receptor proteins will react to the liquid that runs over the cells. Thanks to the colored signaling protein, we can determine under a microscope which receptor proteins respond and which do not.”
 
Assessing the response goes beyond observing color changes by the signaling proteins, however; the Wageningen team also applies statistics and specifically developed software to quantify any reactions.
 
According to Jongsma, “These living cells often produce a variable and complex response to an extract that is a sum of everything in the extract, the amount of DNA that is being expressed and the nature of the host cell. This was why it was initially difficult to draw conclusions.”
 
Beyond determining patient response to medications, this technique could also be applied in nutrition, to test for a variety of receptors, such as response to gluten. In keeping with the rising trend of genomic testing options for customers, Jongsma posits that this approach could lead to customized nutritional and medical advice in the future. Their work appeared in Sensors, in a paper entitled “Calcium Imaging of GPCR Activation Using Arrays of Reverse Transfected HEK293 Cells in a Microfluidic System.”
 
A bit further east, in Berlin, TissUse GmbH announced the establishment of a three-year cooperating agreement with Roche for the development of human-relevant in-vitro assays based on the former’s Multi-Organ-Chip (MOC) technology.
 
Per the terms of the deal, TissUse will make its MOC technology available as a tool for developing in-vitro assays that can enhance the prediction of safety liabilities in drug candidates earlier in the development process. The two companies will combine their skills and experience as they pursue assays for determining lineage-specific hematopoietic toxicity and the pharmacokinetics of therapeutic antibodies.
 
TissUse’s MOC technology platform is a microfluidic microphysiological systems platform that can maintain and culture miniaturized organ equivalents that mimic the biological functions of full-size organs over long time frames. The organ equivalents include biological features such as pulsatile fluid flow, mechanical and electrical coupling, and physiological tissue-to-fluid and tissue-to-tissue ratios. At present, TissUse offers organ models for multiple systems, including: liver, intestine, skin, vasculature, neuronal tissue, cardiac tissue, cartilage, pancreas, kidney, hair follicle, lung tissue, fatty tissue, tumor models and bone marrow.
 
With the wide range of models provided by the MOC platform, TissUse and Roche hope to develop an assay for long-term, repeated dose testing of drug candidates in a bone marrow model, in order to mimic in-vivo dosing scenarios. The next phase of the project will tackle combining the bone marrow model with a liver model to evaluate candidates’ metabolic activation.
 
“We are excited to form this long-term partnership which will address fundamental aspects of antibody kinetics and organ-specific NCE toxicity by applying our Multi-Organ-Chip technology,” Dr. Uwe Marx, CEO of TissUse, commented in a statement. “Combining several organ models in a circulatory system is the next necessary step to assess systemic toxicity and establish complex in-vitro disease models in order to bring innovative medicine faster to the patient.”
 
In an even more ambitious approach, a Massachusetts Institute of Technology (MIT) team has found a way to link multiple organ chips in a microfluidic platform, connecting tissues from up to 10 organs. According to a news feature on the MIT website penned by Anne Trafton, they can replicate and study organ-organ interactions for weeks at a time, allowing for more accurate modeling of how drugs affect the body as a whole. While modeling individual organs on chips provides a great deal of information on drug metabolism and effects, no organ is an island, and a more connected model should demonstrate how a drug affects different organs and hopefully reveal any off-target side effects.
 
The research team included Linda Griffith, the School of Engineering Professor of Teaching Innovation, a professor of biological engineering and mechanical engineering and a senior author of the study; senior author David Trumper, an MIT professor of mechanical engineering; senior author Murat Cirit, a research scientist in the Department of Biological Engineering; and lead authors Collin Edington and Wen Li Kelly Chen, both of whom are former MIT postdocs. Their work was published in Scientific Reports, in an article titled “Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies.”
 
Most drug candidates fail in late-stage clinical trials due to unforeseen toxicity issues. While drugs might demonstrate efficacy and no visible toxicity in in-vitro culture samples, isolated samples don’t accurately reflect how drugs interact in the whole body. Likewise, promising safety profiles in animal models are not a promise of safe administration in humans, as the kinds of compounds that are toxic for rats or monkeys can be vastly different than those for humans, as seen with something like chocolate, which is fine for humans but toxic to dogs. As the drug development process becomes more expensive, non-animal-based methods for testing toxicity earlier in the process represent a rapidly growing need.
 
“Some of these effects are really hard to predict from animal models because the situations that lead to them are idiosyncratic,” said Griffith. “With our chip, you can distribute a drug and then look for the effects on other tissues and measure the exposure and how it is metabolized.”
 
The research team has been working to develop a “physiome on a chip” as part of a project led by the Defense Advanced Research Projects Agency. Their new system differs from current closed microfluidic systems, which make it difficult to manipulate what is being tested on chips and require external pumps. The MIT system is an open system adapted from technology previously developed (and commercialized via CN BioInnovations), with on-board pumps that control liquid flow between “organs” and allow for the use of larger engineered tissues. In the paper, the authors write that “Microphysiological systems (MPSs) are in-vitro models that capture facets of in-vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion.”
 
The MIT chip features up to 10 “organs,” each of which is comprised of clusters of one million to two million cells, according to the press release, and most of the tissues come from patient samples rather than lab-developed cell lines. The team developed multiple version of the chip, and were able to link up a variety of organ types, including the liver, lung, gut, endometrium, brain, heart, pancreas, kidney, skin, and skeletal muscle. Each “organ” consists of clusters of 1 million to 2 million cells.
 
The connected system enabled the MIT team to deliver a drug to the gastrointestinal tissue and track as it was dispersed to the other “organs,” allowing them to track where the drugs traveled, how different organs were affected and how the drugs were metabolized.
 
As noted in the paper’s abstract, “We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and two-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for three weeks (7-way) and four weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism.”
 
According to Griffith, the initial uses for this linked organ system will likely consist of two to four organs. In fact, her lab is working to engineer a model for Parkinson’s disease, comprised of brain, liver and gastrointestinal tissue, “to investigate the hypothesis that bacteria found in the gut can influence the development of Parkinson’s disease,” as per Trafton’s MIT press release.
 
“An advantage of our platform is that we can scale it up or down and accommodate a lot of different configurations,” Griffith commented. “I think the field is going to go through a transition where we start to get more information out of a three-organ or four-organ system, and it will start to become cost-competitive because the information you’re getting is so much more valuable.”
 
Code: E051803

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