Tag Archives: Massachusetts Instittute of Technology

Body-on-a-chip (10 organs)

Also known as human-on-a-chip, the 10-organ body-on-a-chip was being discussed at the 9th World Congress on Alternatives to Animal Testing in the Life Sciences in 2014 in Prague, Czech Republic (see this July 1, 2015 posting for more). At the time, scientists were predicting success at achieving their goal of 10 organs on-a-chip in 2017 (the best at the time was four organs). Only a few months past that deadline, scientists from the Massachusetts Institute of Technology (MIT) seem to have announced a ’10 organ chip’ in a March 14, 2018 news item on ScienceDaily,

MIT engineers have developed new technology that could be used to evaluate new drugs and detect possible side effects before the drugs are tested in humans. Using a microfluidic platform that connects engineered tissues from up to 10 organs, the researchers can accurately replicate human organ interactions for weeks at a time, allowing them to measure the effects of drugs on different parts of the body.

Such a system could reveal, for example, whether a drug that is intended to treat one organ will have adverse effects on another.

A March 14, 2018 MIT news release (also on EurekAlert), which originated the news item, expands on the theme,

“Some of these effects are really hard to predict from animal models because the situations that lead to them are idiosyncratic,” says Linda Griffith, the School of Engineering Professor of Teaching Innovation, a professor of biological engineering and mechanical engineering, and one of the senior authors of the study. “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.”

These chips could also be used to evaluate antibody drugs and other immunotherapies, which are difficult to test thoroughly in animals because they are designed to interact with the human immune system.

David Trumper, an MIT professor of mechanical engineering, and Murat Cirit, a research scientist in the Department of Biological Engineering, are also senior authors of the paper, which appears in the journal Scientific Reports. The paper’s lead authors are former MIT postdocs Collin Edington and Wen Li Kelly Chen.

Modeling organs

When developing a new drug, researchers identify drug targets based on what they know about the biology of the disease, and then create compounds that affect those targets. Preclinical testing in animals can offer information about a drug’s safety and effectiveness before human testing begins, but those tests may not reveal potential side effects, Griffith says. Furthermore, drugs that work in animals often fail in human trials.

“Animals do not represent people in all the facets that you need to develop drugs and understand disease,” Griffith says. “That is becoming more and more apparent as we look across all kinds of drugs.”

Complications can also arise due to variability among individual patients, including their genetic background, environmental influences, lifestyles, and other drugs they may be taking. “A lot of the time you don’t see problems with a drug, particularly something that might be widely prescribed, until it goes on the market,” Griffith says.

As part of a project spearheaded by the Defense Advanced Research Projects Agency (DARPA), Griffith and her colleagues decided to pursue a technology that they call a “physiome on a chip,” which they believe could offer a way to model potential drug effects more accurately and rapidly. To achieve this, the researchers needed new equipment — a platform that would allow tissues to grow and interact with each other — as well as engineered tissue that would accurately mimic the functions of human organs.

Before this project was launched, no one had succeeded in connecting more than a few different tissue types on a platform. Furthermore, most researchers working on this kind of chip were working with closed microfluidic systems, which allow fluid to flow in and out but do not offer an easy way to manipulate what is happening inside the chip. These systems also require external pumps.

The MIT team decided to create an open system, which essentially removes the lid and makes it easier to manipulate the system and remove samples for analysis. Their system, adapted from technology they previously developed and commercialized through U.K.-based CN BioInnovations, also incorporates several on-board pumps that can control the flow of liquid between the “organs,” replicating the circulation of blood, immune cells, and proteins through the human body. The pumps also allow larger engineered tissues, for example tumors within an organ, to be evaluated.

Complex interactions

The researchers created several versions of their chip, linking up to 10 organ types: liver, lung, gut, endometrium, brain, heart, pancreas, kidney, skin, and skeletal muscle. Each “organ” consists of clusters of 1 million to 2 million cells. These tissues don’t replicate the entire organ, but they do perform many of its important functions. Significantly, most of the tissues come directly from patient samples rather than from cell lines that have been developed for lab use. These so-called “primary cells” are more difficult to work with but offer a more representative model of organ function, Griffith says.

Using this system, the researchers showed that they could deliver a drug to the gastrointestinal tissue, mimicking oral ingestion of a drug, and then observe as the drug was transported to other tissues and metabolized. They could measure where the drugs went, the effects of the drugs on different tissues, and how the drugs were broken down. In a related publication, the researchers modeled how drugs can cause unexpected stress on the liver by making the gastrointestinal tract “leaky,” allowing bacteria to enter the bloodstream and produce inflammation in the liver.

Kevin Healy, a professor of bioengineering and materials science and engineering at the University of California at Berkeley, says that this kind of system holds great potential for accurate prediction of complex adverse drug reactions.

“While microphysiological systems (MPS) featuring single organs can be of great use for both pharmaceutical testing and basic organ-level studies, the huge potential of MPS technology is revealed by connecting multiple organ chips in an integrated system for in vitro pharmacology. This study beautifully illustrates that multi-MPS “physiome-on-a-chip” approaches, which combine the genetic background of human cells with physiologically relevant tissue-to-media volumes, allow accurate prediction of drug pharmacokinetics and drug absorption, distribution, metabolism, and excretion,” says Healy, who was not involved in the research.

Griffith believes that the most immediate applications for this technology involve modeling two to four organs. Her lab is now developing a model system for Parkinson’s disease that includes brain, liver, and gastrointestinal tissue, which she plans to use to investigate the hypothesis that bacteria found in the gut can influence the development of Parkinson’s disease.

Other applications include modeling tumors that metastasize to other parts of the body, she says.

“An advantage of our platform is that we can scale it up or down and accommodate a lot of different configurations,” Griffith says. “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.”

The research was funded by the U.S. Army Research Office and DARPA.

Caption: MIT engineers have developed new technology that could be used to evaluate new drugs and detect possible side effects before the drugs are tested in humans. Using a microfluidic platform that connects engineered tissues from up to 10 organs, the researchers can accurately replicate human organ interactions for weeks at a time, allowing them to measure the effects of drugs on different parts of the body. Credit: Felice Frankel

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

Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies by Collin D. Edington, Wen Li Kelly Chen, Emily Geishecker, Timothy Kassis, Luis R. Soenksen, Brij M. Bhushan, Duncan Freake, Jared Kirschner, Christian Maass, Nikolaos Tsamandouras, Jorge Valdez, Christi D. Cook, Tom Parent, Stephen Snyder, Jiajie Yu, Emily Suter, Michael Shockley, Jason Velazquez, Jeremy J. Velazquez, Linda Stockdale, Julia P. Papps, Iris Lee, Nicholas Vann, Mario Gamboa, Matthew E. LaBarge, Zhe Zhong, Xin Wang, Laurie A. Boyer, Douglas A. Lauffenburger, Rebecca L. Carrier, Catherine Communal, Steven R. Tannenbaum, Cynthia L. Stokes, David J. Hughes, Gaurav Rohatgi, David L. Trumper, Murat Cirit, Linda G. Griffith. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-22749-0 Published online:

This paper which describes testing for four-, seven-, and ten-organs-on-a-chip, is open access. From the paper’s Discussion,

In summary, we have demonstrated a generalizable approach to linking MPSs [microphysiological systems] within a fluidic platform to create a physiome-on-a-chip approach capable of generating complex molecular distribution profiles for advanced drug discovery applications. This adaptable, reusable system has unique and complementary advantages to existing microfluidic and PDMS-based approaches, especially for applications involving high logD substances (drugs and hormones), those requiring precise and flexible control over inter-MPS flow partitioning and drug distribution, and those requiring long-term (weeks) culture with reliable fluidic and sampling operation. We anticipate this platform can be applied to a wide range of problems in disease modeling and pre-clinical drug development, especially for tractable lower-order (2–4) interactions.

Congratulations to the researchers!

Gold on the brain, a possible nanoparticle delivery system for drugs

A July 21, 2014 news item on Nanowerk describes special gold nanoparticles that could make drug delivery to cells easier,

A special class of tiny gold particles can easily slip through cell membranes, making them good candidates to deliver drugs directly to target cells.

A new study from MIT materials scientists reveals that these nanoparticles enter cells by taking advantage of a route normally used in vesicle-vesicle fusion, a crucial process that allows signal transmission between neurons.

A July 21, 2014 MIT (Massachusetts Institute of Technology) news release (also on EurekAlert), which originated the news item, provides more details,

The findings suggest possible strategies for designing nanoparticles — made from gold or other materials — that could get into cells even more easily.

“We’ve identified a type of mechanism that might be more prevalent than is currently known,” says Reid Van Lehn, an MIT graduate student in materials science and engineering and one of the paper’s lead authors. “By identifying this pathway for the first time it also suggests not only how to engineer this particular class of nanoparticles, but that this pathway might be active in other systems as well.”

The paper’s other lead author is Maria Ricci of École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland. The research team, led by Alfredo Alexander-Katz, an associate professor of materials science and engineering, and Francesco Stellacci from EPFL, also included scientists from the Carlos Besta Institute of Neurology in Italy and Durham University in the United Kingdom.

Most nanoparticles enter cells through endocytosis, a process that traps the particles in intracellular compartments, which can damage the cell membrane and cause cell contents to leak out. However, in 2008, Stellacci, who was then at MIT, and Darrell Irvine, a professor of materials science and engineering and of biological engineering, found that a special class of gold nanoparticles coated with a mix of molecules could enter cells without any disruption.

“Why this was happening, or how this was happening, was a complete mystery,” Van Lehn says.

Last year, Alexander-Katz, Van Lehn, Stellacci, and others discovered that the particles were somehow fusing with cell membranes and being absorbed into the cells. In their new study, they created detailed atomistic simulations to model how this happens, and performed experiments that confirmed the model’s predictions.

Gold nanoparticles used for drug delivery are usually coated with a thin layer of molecules that help tune their chemical properties. Some of these molecules, or ligands, are negatively charged and hydrophilic, while the rest are hydrophobic. The researchers found that the particles’ ability to enter cells depends on interactions between hydrophobic ligands and lipids found in the cell membrane.

Cell membranes consist of a double layer of phospholipid molecules, which have hydrophobic lipid tails and hydrophilic heads. The lipid tails face in toward each other, while the hydrophilic heads face out.

In their computer simulations, the researchers first created what they call a “perfect bilayer,” in which all of the lipid tails stay in place within the membrane. Under these conditions, the researchers found that the gold nanoparticles could not fuse with the cell membrane.

However, if the model membrane includes a “defect” — an opening through which lipid tails can slip out — nanoparticles begin to enter the membrane. When these lipid protrusions occur, the lipids and particles cling to each other because they are both hydrophobic, and the particles are engulfed by the membrane without damaging it.

In real cell membranes, these protrusions occur randomly, especially near sites where proteins are embedded in the membrane. They also occur more often in curved sections of membrane, because it’s harder for the hydrophilic heads to fully cover a curved area than a flat one, leaving gaps for the lipid tails to protrude.

“It’s a packing problem,” Alexander-Katz says. “There’s open space where tails can come out, and there will be water contact. It just makes it 100 times more probable to have one of these protrusions come out in highly curved regions of the membrane.”

This phenomenon appears to mimic a process that occurs naturally in cells — the fusion of vesicles with the cell membrane. Vesicles are small spheres of membrane-like material that carry cargo such as neurotransmitters or hormones.

The similarity between absorption of vesicles and nanoparticle entry suggests that cells where a lot of vesicle fusion naturally occurs could be good targets for drug delivery by gold nanoparticles. The researchers plan to further analyze how the composition of the membranes and the proteins embedded in them influence the absorption process in different cell types. “We want to really understand all the constraints and determine how we can best design nanoparticles to target particular cell types, or regions of a cell,” Van Lehn says.

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

Lipid tail protrusions mediate the insertion of nanoparticles into model cell membranes by Reid C. Van Lehn, Maria Ricci, Paulo H.J. Silva, Patrizia Andreozzi, Javier Reguera, Kislon Voïtchovsky, Francesco Stellacci, & Alfredo Alexander-Katz. Nature Communications 5, Article number: 4482 doi:10.1038/ncomms5482 Published 21 July 2014

This article is behind a paywall but there is a free preview available via ReadCube Access.

I last featured this multi-country team’s work on gold nanoparticles in an Aug. 23, 2013 posting.

UK’s National Physical Laboratory reaches out to ‘BioTouch’ MIT and UCL

This March 27, 2014 news item on Azonano is an announcement for a new project featuring haptics and self-assembly,

NPL (UK’s National Physical Laboratory) has started a new strategic research partnership with UCL (University College of London) and MIT (Massachusetts Institute of Technology) focused on haptic-enabled sensing and micromanipulation of biological self-assembly – BioTouch.

The NPL March 27, 2014 news release, which originated the news item, is accompanied by a rather interesting image,

A computer operated dexterous robotic hand holding a microscope slide with a fluorescent human cell (not to scale) embedded into a synthetic extracellular matrix. Courtesy: NPL

A computer operated dexterous
robotic hand holding a microscope
slide with a fluorescent human cell
(not to scale) embedded into a
synthetic extracellular matrix. Courtesy: NPL

The news release goes on to describe the BioTouch project in more detail (Note: A link has been removed),

The project will probe sensing and application of force and related vectors specific to biological self-assembly as a means of synthetic biology and nanoscale construction. The overarching objective is to enable the re-programming of self-assembled patterns and objects by directed micro-to-nano manipulation with compliant robotic haptic control.

This joint venture, funded by the European Research Council, EPSRC and NPL’s Strategic Research Programme, is a rare blend of interdisciplinary research bringing together expertise in robotics, haptics and machine vision with synthetic and cell biology, protein design, and super- and high-resolution microscopy. The research builds on the NPL’s pioneering developments in bioengineering and imaging and world-leading haptics technologies from UCL and MIT.

Haptics is an emerging enabling tool for sensing and manipulation through touch, which holds particular promise for the development of autonomous robots that need to perform human-like functions in unstructured environments. However, the path to all such applications is hampered by the lack of a compliant interface between a predictably assembled biological system and a human user. This research will enable human directed micro-manipulation of experimental biological systems using cutting-edge robotic systems and haptic feedback.

Recently the UK government has announced ‘eight great technologies’ in which Britain is to become a world leader. Robotics, synthetic biology, regenerative medicine and advanced materials are four of these technologies for which this project serves as a merging point providing thus an excellent example of how multidisciplinary collaborative research can shape our future.

If it read this rightly, it means they’re trying to design systems where robots will work directly with materials in the labs while humans direct the robots’ actions from a remote location. My best example of this (it’s not a laboratory example) would be of a surgery where a robot actually performs the work while a human directs the robot’s actions based on haptic (touch) information the human receives from the robot. Surgeons don’t necessarily see what they’re dealing with, they may be feeling it with their fingers (haptic information). In effect, the robot’s hands become an extension of the surgeon’s hands. I imagine using a robot’s ‘hands’ would allow for less invasive procedures to be performed.

Nicholas Negroponte and Chris Hadfield at TED 2014’s Session 1: Liftoff

Nicholas Negroponte opened the first TED conference in 1984 and has come back for the 30th anniversary. Here’s his TED biography,

The founder of the MIT [Massachusetts Institute of Technology] Media Lab, Nicholas Negroponte pushed the edge of the information revolution as an inventor, thinker and angel investor. He’s the driving force behind One Laptop per Child, building computers for children in the developing world.

media.mit.edu

Negroponte discusses what has changed over the years. When he first started in the 1970s no one thought you’d ever use a touchscreen and putting your fingers on the screen was considered silly. This sort of thinking (touchscreens) is what went into the development of MIT’s Media Lab. He seems to be highlighting some of the high points of his thinking. He finds some of today’s internet of Things thinking to be pathetic (he references some of the sessions earlier today). He (?) started Wired magazine. Negroponte has gotten more interested in computers and learning over the years. He compares iteration to learning and mentions One Laptop Per Child. There was virtually no international aid for that project, the money came from the countries that used the program. After that project, he worked on an initiative where they dropped off computers to children (in Ethiopia and ?) with no instruction. Within days, the children had figured it out and within six months they hacked Android. He now wants to connect 100M people (on the African continent?). He predicts that in 30 years, we will ingest information (swallow a pill where the information travels through the bloodstream and on into the brain).

For some reason, they thought it would be amusing to play the Joe Canadian commercial. Chris Hadfield is then introduced. Here’s his TED biography,

Tweeting (and covering Bowie) from the International Space Station last year, Colonel Chris Hadfield reminded the world how much we love space.

Hadfield (who has a guitar on stage with him) talks about danger (asks the audience what’s the most dangerous thing theyu’ve done) and notes that space travel is dangerous. He then  describes in detail what it’s like to get into a space shuttle and head for the space. He says that a space shuttle is the most complicated machine (?) ever built. He next shows a shuttle launch and  describes being on the International Space Station. You see a sunrise every 25 minutes due to the speed at which you are travelling. He describes his first space walk when his left eye went blind. His left eye teared up while he continued work outside the station.

In space your tears don’t fall, they build up until there’s enough force to push them across the bridge of your nose and land like a small waterfall in your right eye. When the tears wooshed over to his right eye, he became completely blind.

Hadfield asks the audience again about danger and talks about overcoming fear and dealing with real danger as opposed to perceived danger. One of the ways astronauts deal with their fear and danger is to practice until they’ve changed their primal fear.

Hadfield plays a guitar and covers David Bowie’s Space Oddity and ends his talk with these words “Fear Not.”

I am done for today and I hope there aren’t too many mistakes in this post.