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Monday, March 30th, 2020
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| 8:51a | Engineers 3D print soft, rubbery brain implants The brain is one of our most vulnerable organs, as soft as the softest tofu. Brain implants, on the other hand, are typically made from metal and other rigid materials that over time can cause inflammation and the buildup of scar tissue. MIT engineers are working on developing soft, flexible neural implants that can gently conform to the brain’s contours and monitor activity over longer periods, without aggravating surrounding tissue. Such flexible electronics could be softer alternatives to existing metal-based electrodes designed to monitor brain activity, and may also be useful in brain implants that stimulate neural regions to ease symptoms of epilepsy, Parkinson’s disease, and severe depression. Led by Xuanhe Zhao, a professor of mechanical engineering and of civil and environmental engineering, the research team has now developed a way to 3D print neural probes and other electronic devices that are as soft and flexible as rubber. The devices are made from a type of polymer, or soft plastic, that is electrically conductive. The team transformed this normally liquid-like conducting polymer solution into a substance more like viscous toothpaste — which they could then feed through a conventional 3D printer to make stable, electrically conductive patterns. The team printed several soft electronic devices, including a small, rubbery electrode, which they implanted in the brain of a mouse. As the mouse moved freely in a controlled environment, the neural probe was able to pick up on the activity from a single neuron. Monitoring this activity can give scientists a higher-resolution picture of the brain’s activity, and can help in tailoring therapies and long-term brain implants for a variety of neurological disorders. “We hope by demonstrating this proof of concept, people can use this technology to make different devices, quickly,” says Hyunwoo Yuk, a graduate student in Zhao’s group at MIT. “They can change the design, run the printing code, and generate a new design in 30 minutes. Hopefully this will streamline the development of neural interfaces, fully made of soft materials.” Yuk and Zhao have published their results today in the journal Nature Communications. Their co-authors include Baoyang Lu and Jingkun Xu of the Jiangxi Science and Technology Normal University, along with Shen Lin and Jianhong Luo of Zheijiang University’s School of Medicine.
The team printed several soft electronic devices, including a small, rubbery electrode. From soap water to toothpaste Conducting polymers are a class of materials that scientists have eagerly explored in recent years for their unique combination of plastic-like flexibility and metal-like electrical conductivity. Conducting polymers are used commercially as antistatic coatings, as they can effectively carry away any electrostatic charges that build up on electronics and other static-prone surfaces. “These polymer solutions are easy to spray on electrical devices like touchscreens,” Yuk says. “But the liquid form is mostly for homogenous coatings, and it’s difficult to use this for any two-dimensional, high-resolution patterning. In 3D, it’s impossible.” Yuk and his colleagues reasoned that if they could develop a printable conducting polymer, they could then use the material to print a host of soft, intricately patterned electronic devices, such as flexible circuits, and single-neuron electrodes. In their new study, the team report modifying poly (3,4-ethylenedioxythiophene) polystyrene sulfonate, or PEDOT:PSS, a conducting polymer typically supplied in the form of an inky, dark-blue liquid. The liquid is a mixture of water and nanofibers of PEDOT:PSS. The liquid gets its conductivity from these nanofibers, which, when they come in contact, act as a sort of tunnel through which any electrical charge can flow. If the researchers were to feed this polymer into a 3D printer in its liquid form, it would simply bleed across the underlying surface. So the team looked for a way to thicken the polymer while retaining the material’s inherent electrical conductivity. They first freeze-dried the material, removing the liquid and leaving behind a dry matrix, or sponge, of nanofibers. Left alone, these nanofibers would become brittle and crack. So the researchers then remixed the nanofibers with a solution of water and an organic solvent, which they had previously developed, to form a hydrogel — a water-based, rubbery material embedded with nanofibers. They made hydrogels with various concentrations of nanofibers, and found that a range between 5 to 8 percent by weight of nanofibers produced a toothpaste-like material that was both electrically conductive and suitable for feeding into a 3D printer. “Initially, it’s like soap water,” Zhao says. “We condense the nanofibers and make it viscous like toothpaste, so we can squeeze it out as a thick, printable liquid.” Implants on demand The researchers fed the new conducting polymer into a conventional 3D printer and found they could produce intricate patterns that remained stable and electrically conductive. As a proof of concept, they printed a small, rubbery electrode, about the size of a piece of confetti. The electrode consists of a layer of flexible, transparent polymer, over which they then printed the conducting polymer, in thin, parallel lines that converged at a tip, measuring about 10 microns wide — small enough to pick up electrical signals from a single neuron.
MIT researchers print flexible circuits (shown here) and other soft electrical devices using new 3-D-printing technique and conducting polymer ink. The team implanted the electrode in the brain of a mouse and found it could pick up electrical signals from a single neuron. “Traditionally, electrodes are rigid metal wires, and once there are vibrations, these metal electrodes could damage tissue,” Zhao says. “We’ve shown now that you could insert a gel probe instead of a needle.” In principle, such soft, hydrogel-based electrodes might even be more sensitive than conventional metal electrodes. That’s because most metal electrodes conduct electricity in the form of electrons, whereas neurons in the brain produce electrical signals in the form of ions. Any ionic current produced by the brain needs to be converted into an electrical signal that a metal electrode can register — a conversion that can result in some part of the signal getting lost in translation. What’s more, ions can only interact with a metal electrode at its surface, which can limit the concentration of ions that the electrode can detect at any given time. In contrast, the team’s soft electrode is made from electron-conducting nanofibers, embedded in a hydrogel — a water-based material that ions can freely pass through. “The beauty of a conducting polymer hydrogel is, on top of its soft mechanical properties, it is made of hydrogel, which is ionically conductive, and also a porous sponge of nanofibers, which the ions can flow in and out of,” Lu says. “Because the electrode’s whole volume is active, its sensitivity is enhanced.” In addition to the neural probe, the team also fabricated a multielectrode array — a small, Post-it-sized square of plastic, printed with very thin electrodes, over which the researchers also printed a round plastic well. Neuroscientists typically fill the wells of such arrays with cultured neurons, and can study their activity through the signals that are detected by the device’s underlying electrodes. For this demonstration, the group showed they could replicate the complex designs of such arrays using 3D printing, versus traditional lithography techniques, which involve carefully etching metals, such as gold, into prescribed patterns, or masks — a process that can take days to complete a single device. “We make the same geometry and resolution of this device using 3D printing, in less than an hour,” Yuk says. “This process may replace or supplement lithography techniques, as a simpler and cheaper way to make a variety of neurological devices, on demand.” |
| 11:00a | “Living drug factories” might treat diabetes and other diseases One promising way to treat diabetes is with transplanted islet cells that produce insulin when blood sugar levels get too low. However, patients who receive such transplants must take drugs to prevent their immune systems from rejecting the transplanted cells, so the treatment is not often used. To help make this type of therapy more feasible, MIT researchers have now devised a way to encapsulate therapeutic cells in a flexible protective device that prevents immune rejection while still allowing oxygen and other critical nutrients to reach the cells. Such cells could pump out insulin or other proteins whenever they are needed. “The vision is to have a living drug factory that you can implant in patients, which could secrete drugs as-needed in the patient. We hope that technology like this could be used to treat many different diseases, including diabetes,” says Daniel Anderson, an associate professor of chemical engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science, and the senior author of the work. In a study of mice, the researchers showed that genetically engineered human cells remained viable for at least five months, and they believe they could last longer to achieve long-term treatment of chronic diseases such as diabetes or hemophilia, among others. Suman Bose, a research scientist at the Koch Institute, is the lead author of the paper, which appears today in Nature Biomedical Engineering. Protective effect Patients with type 1 diabetes usually have to inject themselves with insulin several times a day to keep their blood sugar levels within a healthy range. Since 1999, a small number of diabetes patients have received transplanted islet cells, which can take over for their nonfunctioning pancreas. While the treatment is often effective, the immunosuppressant drugs that these patients have to take make them vulnerable to infection and can have other serious side effects. For several years, Anderson’s lab has been working on ways to protect transplanted cells from the host’s immune system, so that immunosuppressant drugs would not be necessary. “We want to be able to implant cells into patients that can secrete therapeutic factors like insulin, but prevent them from being rejected by the body,” Anderson says. “If you could build a device that could protect those cells and not require immune suppression, you could really help a lot of people.” To protect the transplanted cells from the immune system, the researchers housed them inside a device built out of a silicon-based elastomer (polydimethylsiloxane) and a special porous membrane. “It’s almost the same stiffness as tissue, and you make it thin enough so that it can wrap around organs,” Bose says. They then coated the outer surface of the device with a small-molecule drug called THPT. In a previous study, the researchers had discovered that this molecule can help prevent fibrosis, a buildup of scar tissue that results when the immune system attacks foreign objects. The device contains a porous membrane that allows the transplanted cells obtain nutrients and oxygen from the bloodstream. These pores must be large enough to allow nutrients and insulin to pass through, but small enough so that immune cells such as T cells can’t get in and attack the transplanted cells. In this study, the researchers tested polymer coatings with pores ranging from 400 nanometers to 3 micrometers in diameter, and found that a size range of 800 nanometers to 1 micrometer was optimal. At this size, small molecules and oxygen can pass through, but not T cells. Until now, it had been believed that 1-micrometer pores would be too large to stop cellular rejection. Drugs on demand In a study of diabetic mice, the researchers showed that transplanted rat islets inside microdevices maintained normal blood glucose levels in the mice for more than 10 weeks. The researchers also tested this approach with human embryonic kidney cells that were engineered to produce erythropoietin (EPO), a hormone that promotes red blood cell production and is used to treat anemia. These therapeutic human cells survived in mice for at least the 19-week duration of the experiment. “The cells in the device act as a factory and continuously produce high levels of EPO. This led to an increase in the red blood cell count in the animals for as long as we did the experiment,” Anderson says. In addition, the researchers showed that they could program the transplanted cells to produce a protein only in response to treatment with a small molecule drug. Specifically, the transplanted engineered cells produced EPO when mice were given the drug doxycycline. This strategy could allow for on-demand production of a protein or hormone only when it is needed. This type of “living drug factory” could be useful for treating any kind of chronic disease that requires frequent doses of a protein or hormone, the researchers say. They are currently focusing on diabetes and are working on ways to extend the lifetime of transplanted islet cells. “This is the eighth Nature journal paper our team has published in the past four-plus years elucidating key fundamental aspects of biocompatibility of implants. We hope and believe these findings will lead to new super-biocompatible implants to treat diabetes and many other diseases in the years to come,” says Robert Langer, the David H. Koch Institute Professor at MIT and an author of the paper. Sigilon Therapeutics, a company founded by Anderson and Langer, has patented the use of the THPT coating for implantable devices and is now developing treatments based on this approach. The research was funded by JDRF. Other authors of the paper include Lisa Volpatti, Devina Thiono, Volkan Yesilyurt, Collin McGladian, Yaoyu Tang, Amanda Facklam, Amy Wang, Siddharth Jhunjhunwala, Omid Veiseh, Jennifer Hollister-Lock, Chandrabali Bhattacharya, Gordon Weir, and Dale Greiner. |
| 1:30p | Discerning the texture of urban resilience If you’ve ever turned down a city street only to be blasted with air, you’ve stepped into what is known as an urban canyon. Much like their geological counterparts, urban canyons are gaps between two tall surfaces — in this case, buildings. The gusts they channel, however, have real implications. They can magnify a hurricane’s winds or increase a city’s air temperature depending on their arrangement — an arrangement known as city texture. The problem is, according to researchers at the MIT Concrete Sustainability Hub (CSHub), that current hazard mitigation practices don’t consider city texture. Consequently, they frequently underestimate damages, in some cases by as much as a factor of three. Reconsidering current practices To understand the potential impact of city texture, CSHub researchers first investigated the current construction practices. One of the practices they examined were building codes. According to the Federal Emergency Management Agency, “Building codes are sets of regulations governing the design, construction, alteration, and maintenance of structures.” One of their purposes is to protect the inhabitants of a building from natural disasters by specifying the strength of that building. To keep buildings safe from wind hazards, codes stipulate how a building must interact with the wind, a value known as a drag coefficient. The drag coefficient of a building determines the amount of air resistance it will experience when exposed to the wind. As a building’s drag coefficient increases, so does its likelihood of damage. “Design codes assume that buildings have fixed drag coefficients. And in a way, that makes sense — the shape of a building doesn’t change much,” says Jake Roxon, a researcher at CSHub. “However, we’ve found that it’s not just the shape of the building that affects its drag coefficient, but also the local configuration of adjacent buildings, which we refer to as urban texture.” Urban texture measures the probability of finding a neighboring building at a certain distance away from a given building. Roxon calculates it by drawing rings of a certain diameter around each building in a city. Then he counts the number of buildings in each ring. The more buildings in each ring, the greater the probability is of finding a building at that distance. And the higher the probability, the more ordered and regular the local texture is, while the lower the probability, the more disordered and unpredictable. To capture a whole city’s texture, Roxon averages together the texture of each of its buildings. “On average, we have found that areas with disordered textures have more resilience,” says Roxon. “If you are unable to predict which angle the wind will come from, it will offer the greatest level of protection. On the other hand, for an ordered city with the same density of buildings, you would expect to see more damage during an extreme hazard event.” The reason behind the resilience of disordered streets is how they distribute wind. By distributing wind more randomly, disordered cities like Boston or Paris experience less of the magnification that occurs as the wind travels the corridors of ordered cities, such as New York. In some cases, cities with more ordered textures can magnify hurricane winds from a Category 3 to a Category 4, Roxon has found. The impact of city texture on drag coefficients and wind loads appeared prominently during Hurricane Irma in 2017, which passed through West Florida. “An example of the texture effect is Sarasota and Lee counties in Florida during Irma,” explains Ipek Bensu Manav, a CSHub researcher collaborating with Roxon. “Those counties are situated close to each other geographically, so they experience a similar hurricane risk. And when you look at the building stocks, they are also similar — mostly single and two-floor single-family houses.” However, the two counties differed in terms of texture. “Sarasota County has a less-ordered texture, falling less onto a typical grid, and Lee County has a more orderly texture,” says Manav. “When looking at Lee County we saw more structural damage — some buildings collapsed completely. There were more flooding and overturning of vegetation as well. So, Irma caused a lot more damage in the county that had a higher texture effect.” It turns out, too, that ordered textures have a similar effect on heat. “We have found this to be the case with temperature as well — specifically, the urban heat island effect,” says Roxon. “Ordered cities experience the greatest temperature difference between them and their rural surroundings at night.” Code cracking So, then, if layouts of streets greatly influence hazard damage, why don’t building codes account for them? Simply put, it’s currently too difficult to incorporate them. Right now, the standard tool for investigating the drag coefficients of a building is computational fluid dynamics (CFD). CFD simulations measure the drag coefficient of a building and its hazard risk by modeling the flow of heat and wind. Though highly accurate, CFD simulations demand prohibitively intense time and computing requirements at scale. “Using current resources, CFD simulations simply don’t work on the scale of cities,” says Roxon. “New York City, for example, has over 1 million buildings. Running a simulation would take a long time. And if you make just one small adjustment to the arrangement of buildings or the direction of the wind, you have to rerun the simulation.” Despite their imperfections, CFD simulations remain an important tool for understanding wind flow. But Roxon believes his city texture model can compensate for CFD’s limitations and, in the process, make cities more resilient. “We have found that there are certain variables derived from city texture that allow us, with relative accuracy, to estimate the drag coefficients for buildings and identify areas vulnerable to risks of damage. Then we can run CFD simulations to determine precisely where that damage will occur.” Essentially, city texture serves as a first-line tool for stakeholders, allowing them to assess risk and then use their resources, including CFD, more efficiently to identify vulnerable buildings for retrofit and, in turn, save lives. The complete picture In addition to the loss of life, natural disasters inflict an immense financial toll. According to the National Oceanographic and Atmospheric Administration, 258 natural disasters have caused more than $1.75 trillion of damage in the United States since 1980. While numerous practices can predict and mitigate these costs, Manav has found that they still leave a lot on the table — namely, city texture. By collaborating with Roxon, she has discovered that by discounting community characteristics like city texture, current models underestimate losses, often dramatically. To apply texture to hurricane losses, Manav looked once again to Florida’s Sarasota and Lee counties. She conducted a conventional loss estimation and a city texture-adjusted loss estimation for each county based on the 95th percentile of annual expected hazard events — equivalent to some of the strongest hurricanes, like Irma. She found that the expected losses increased when she incorporated city texture into her estimations. The increase was particularly acute in Lee County, whose ordered texture would likely magnify wind loads. “In Sarasota County, we saw an increase in the expected loss from 1 percent to 6 percent of average home’s value when incorporating city texture,” says Manav. “But doing the same for Lee County, we saw an appreciably higher amount of damage, equivalent to approximately 9 percent of an average home’s value.” Without incorporating city texture, then, these conventional estimations dramatically underestimate damages. This makes residents unaware of their hazard risk, and consequentially leaves them vulnerable. The incentives for resilience As sobering as these loss estimations are, Manav hopes they may yet help communities become more hazard-resilient. Currently, she notes, hazard resilience has not become broadly implemented because most remain unaware of its cost benefits. “One reason hazard-mitigation practices are not being implemented is that their benefits are not being communicated thoroughly,” she says. “Obviously, there is the cost of constructing to better standards. But to balance out these costs there are the benefits of reduced repair costs following hazard events.” These reduced damage costs are significant. Actions as simple as choosing hardier shingles, improving roof-to-wall connections, and adding shutters and impact-rated windows can mitigate hazard damages enough to pay back in as little as two years in hazard-prone areas like coastal Florida. By using city texture to calculate hazard costs, Manav and Roxon hope homeowners, developers, and policymakers will choose to implement these relatively simple practices. The only key is making their incentives widely known. |
| 1:40p | Newly discovered enzyme “square dance” helps generate DNA building blocks How do you capture a cellular process that transpires in the blink of an eye? Biochemists at MIT have devised a way to trap and visualize a vital enzyme at the moment it becomes active — informing drug development and revealing how biological systems store and transfer energy. The enzyme, ribonucleotide reductase (RNR), is responsible for converting RNA building blocks into DNA building blocks, in order to build new DNA strands and repair old ones. RNR is a target for anti-cancer therapies, as well as drugs that treat viral diseases like HIV/AIDS. But for decades, scientists struggled to determine how the enzyme is activated because it happens so quickly. Now, for the first time, researchers have trapped the enzyme in its active state and observed how the enzyme changes shape, bringing its two subunits closer together and transferring the energy needed to produce the building blocks for DNA assembly. Before this study, many believed RNR’s two subunits came together and fit with perfect symmetry, like a key into a lock. “For 30 years, that’s what we thought,” says Catherine Drennan, an MIT professor of chemistry and biology and a Howard Hughes Medical Institute investigator. “But now, we can see the movement is much more elegant. The enzyme is actually performing a ‘molecular square dance,’ where different parts of the protein hook onto and swing around other parts. It’s really quite beautiful.” Drennan and JoAnne Stubbe, professor emerita of chemistry and biology at MIT, are the senior authors on the study, which appeared in the journal Science on March 26. Former graduate student Gyunghoon "Kenny" Kang PhD ’19 is the lead author. All proteins, including RNR, are composed of fundamental units known as amino acids. For over a decade, Stubbe’s lab has been experimenting with substituting RNR’s natural amino acids for synthetic ones. In doing so, the lab realized they could trap the enzyme in its active state and slow down its return to normal. However, it wasn’t until the Drennan lab gained access to a key technological advancement — cryo-electron microscopy — that they could snap high-resolution images of these “trapped” enzymes from the Stubbe lab and get a closer look. “We really hadn’t done any cryo-electron microscopy at the point that we actively started trying to do the impossible: get the structure of RNR in its active state,” Drennan says. “I can’t believe it worked; I’m still pinching myself.” The combination of these techniques allowed the team to visualize the complex molecular dance that allows the enzyme to transport the catalytic “firepower” from one subunit to the next, in order to generate DNA building blocks. This firepower is derived from a highly reactive unpaired electron (a radical), which must be carefully controlled to prevent damage to the enzyme. According to Drennan, the team “wanted to see how RNR does the equivalent of playing with fire without getting burned.” First author Kang says slowing down the radical transfer allowed them to observe parts of the enzyme no one had been able to see before in full. “Before this study, we knew this molecular dance was happening, but we’d never seen the dance in action,” he says. “But now that we have a structure for RNR in its active state, we have a much better idea about how the different components of the enzyme are moving and interacting in order to transfer the radical across long distances.” Although this molecular dance brings the subunits together, there is still considerable distance between them: The radical must travel 35-40 angstroms from the first subunit to the second. This journey is roughly 10 times farther than the average radical transfer, according to Drennan. The radical must then travel back to its starting place and be stored safely, all within a fraction of a second before the enzyme returns to its normal conformation. Because RNR is a target for drugs treating cancer and certain viruses, knowing its active-state structure could help researchers devise more effective treatments. Understanding the enzyme’s active state could also provide insight into biological electron transport for applications like biofuels. Drennan and Kang hope their study will encourage others to capture fleeting cellular events that have been difficult to observe in the past. “We may need to reassess decades of past results,” Drennan says. “This study could open more questions than it answers; it’s more of a beginning than an end.” This research was funded by the National Institutes of Health, a David H. Koch Graduate Fellowship, and the Howard Hughes Medical Institute. |
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