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  • richardmitnick 11:46 am on December 31, 2017 Permalink | Reply
    Tags: , , , Daniel Vogt, Falkor research vessel, , NOAA’s Office of Ocean Exploration and Research, , PIPA-Phoenix Islands Protected Area, , ROV-remotely operated underwater vehicle, , , Squishy fingers help scientists probe the watery depths, WYSS Institute at Harvard   

    From Wyss Institute: “Squishy fingers help scientists probe the watery depths” 2017 

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    Wyss Institute

    October 28, 2017
    Lindsay Brownell

    Wyss researcher Daniel Vogt tests out soft robotics on deep sea corals in the South Pacific.

    As an engineer with degrees in Computer Science and Microengineering, Wyss researcher Daniel Vogt usually spends most of his time in his lab building and testing robots, surrounded by jumbles of cables, wires, bits of plastic, and circuit boards. But for the last month, he’s spent nearly every day in a room that resembles NASA ground control surrounded by marine biologists on a ship in the middle of the Pacific Ocean, intently watching them use joysticks and buttons to maneuver a remotely operated underwater vehicle (ROV) to harvest corals, crabs, and other sea life from the ocean floor.

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    The squishy fingers are made of a soft, flexible material that is more dexterous and gentle than ROVs’ conventional grippers. Credit: Schmidt Ocean Institute.


    Deep corals of the Phoenix Islands Protected Area: How Wyss Institute researchers are changing underwater exploration. Credit: Schmidt Ocean Institute.

    This particular ROV’s robotic metal arm is holding the reason why Vogt is here: what looks like a large, floppy toy starfish made of blue and yellow foam. “Devices like this are extremely soft – you can compare them to rubber bands or gummy bears – and this allows them to grasp things that you wouldn’t be able to grasp with a hard device like the ROV gripper,” says Vogt, watching the TV screen as the “squishy fingers” gently close around a diaphanous bright pink sea cucumber and lift it off the sand. The biologists applaud as the fingers cradle the sea cucumber safely on its journey to the ROV’s collection box. “Nicely done,” Vogt says to the ROV operators.

    This shipful of scientists is the latest in a series of research voyages co-funded by NOAA’s Office of Ocean Exploration and Research and the Schmidt Ocean Institute, a nonprofit founded by Eric and Wendy Schmidt in 2009 to support high-risk marine exploration that expands humans’ understanding of our planet’s oceans. The Institute provides marine scientists access to the ship, Falkor, and expert technical shipboard support in exchange for a commitment to openly share and communicate the outcomes of their research.

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    Falkor is equipped with both wet and dry lab spaces, the ROV SuBastian, echosounders, water sampling systems, and many other instruments to gather data about the ocean. Credit: Schmidt Ocean Institute.

    Vogt’s shipmates are studying the mysterious deep sea coral communities of the deep ocean, which live below 138 meters (450 feet) on seamounts which are mostly unexplored.

    The best place to find those corals is the Phoenix Islands Protected Area (PIPA), a smattering of tiny islands, atolls, coral reefs, and great swaths of their surrounding South Pacific ocean almost 3,000 miles from the nearest continent. PIPA is the largest (the size of California) and deepest (average water column depth of 4 km/2.5 mi) UNESCO World Heritage Site on Earth and, thanks to its designation as a Marine Protected Area in 2008, represents one of Earth’s last intact oceanic coral archipelago ecosystems. With over 500 species of reef fishes, 250 shallow coral species, and large numbers of sharks and other marine life, PIPA’s reefs resemble what a reef might have looked like a thousand years ago, before human activity began to severely affect oceanic communities. The team on board Falkor is conducting the first deep water biological surveys in PIPA, assessing what species of deep corals are present and any new, undescribed species, while also evaluating the effect of seawater acidification (caused by an increase in the amount of CO2 in the water) on deep coral ecosystems.

    The deep ocean is about as inhospitable to human life as outer space, so scientists largely rely on ROVs to be their eyes, legs, and hands underwater, controlling them remotely from the safety of the surface. Most ROVs used in deep-sea research were designed for use in the oil and gas industries and are built to accomplish tasks like lifting heavy weights, drilling into rock, and installing machinery. When it comes to plucking a sea cucumber off the ocean floor or snipping a piece off a delicate sea fan, however, existing ROVs are like bulls in a china shop, often crushing the samples they’re meant to be taking.

    This problem led to a collaboration between Wyss Core Faculty member Rob Wood, Ph.D. and City University of New York (CUNY) marine biologist David Gruber, Ph.D. back in 2014 that produced the first version of the soft robotic “squishy fingers,” which were successfully tested in the Red Sea in 2015. PIPA offered a unique opportunity to test the squishy fingers in more extreme conditions and evaluate a series of improvements that Vogt and other members of Wood’s lab have been making to them, such as integrating sensors into the robots’ soft bodies. “The Phoenix Islands are very unexplored. We’re looking for new species of corals that nobody has ever seen anywhere else. We don’t know what our graspers will have to pick up on a given day, so it’s a great opportunity to see how they fare against different challenges in the field.”

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    Daniel Vogt holds the ‘squishy finger’ soft robots aboard Falkor. Credit: Schmidt Ocean Institute.

    Vogt, ever the tinkerer, also brought with him something that the Red Sea voyage did not have on board: two off-the-shelf 3D printers. Taking feedback directly from the biologists and the ROV pilots about what the soft robot could and could not do, Vogt was able to print new components overnight and try them in the field the next day – something that rarely happens even on land. “It’s really a novel thing, to be able to iterate based on input in the middle of the Pacific Ocean, with no lab in sight. We noticed, for example, that the samples we tried to grasp were often on rock instead of sand, making it difficult for the soft fingers to reach underneath the sample for a good grip. In the latest iteration of the gripper, ‘fingernails’ were added to improve grasping in these situations.” The ultimate goal of building better and better underwater soft robots is to be able to conduct research on samples underwater at their natural depth and temperature, rather than bringing them up to the surface, as this will paint a more accurate picture of what is happening out of sight in the world’s oceans.

    PIPA may be somewhat insulated from the threats of warming oceans and pollution thanks to its remoteness and deep waters, but the people of Kiribati, the island nation that contains and administers PIPA, are not. The researchers visited the island of Kanton, population 25, a few days into their trip to meet the local people and learn about their lives in a country where dry land makes up less than 1% of its total area – a true oceanic nation. “The people were very nice, very welcoming. There is one ship that comes every six months to deliver supplies; everything else they get from the sea,” says Vogt (locals are allowed to fish for subsistence). “They’re also going to be one of the first nations affected by rising sea levels, because the highest point on the whole island is three meters (ten feet). They know that they live in a special place, but they’re preparing for the day when they’ll have to leave their home. The whole community has bought land on Fiji, where they’ll move once Kanton becomes uninhabitable.”

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    Daniel Vogt tests the squishy fingers on the forearm of CUNY biologist David Gruber, who spearheaded their development along with Wyss Faculty member Rob Wood. Credit: Schmidt Ocean Institute.

    Research that brings scientists from different fields together to elucidate the world’s remaining unknowns and solve its toughest problems is gaining popularity, and may be the best chance humanity has to ensure its own survival. “One of the most eye-opening part of the trip has been interacting with people from different backgrounds and seeing the scientific challenges they face, which are very different from the challenges that the mechanical and electrical engineers I’m with most of the time have to solve,” says Vogt. “I’ve been amazed by the technology that’s on Falkor related to the ROV and all the scientific tools aboard. The ROV SuBastian is one-of-a-kind, with numerous tools, cameras and sensors aboard as well as an advanced underwater positioning system. It takes a lot of engineers to create and operate something like that, and then a lot of biologists to interpret the results and analyze the 400+ samples which were collected during the cruise.”

    Vogt says he spent a lot of time listening to the biologists and the ROV pilots in order to modify the gripper’s design according to their feedback. The latest version of the gripper was fully designed and manufactured on the boat, and was used during the last dive to successfully sample a variety of sea creatures. He and Wood plan to write several papers detailing the results of his experiments in the coming months.

    “We’re very excited that what started as a conversation between a roboticist and a marine biologist at a conference three years ago has blossomed into a project that solves a significant problem in the real world, and can aid researchers in understanding and preserving our oceans’ sea life,” says Wood.

    Additional videos detailing Vogt’s voyage, including the ship’s log, can be found here.

    See the full article here .

    Please help promote STEM in your local schools.

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    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 9:04 am on December 24, 2017 Permalink | Reply
    Tags: , , , , , SDC-PAINT, Visualizing single molecules in whole cells with a new spin, WYSS Institute at Harvard   

    From Wyss: “Visualizing single molecules in whole cells with a new spin” 

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    Wyss Institute

    December 12, 2017
    Benjamin Boettner

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    The researchers used their SDC-PAINT method to visualize the network of cytoskeletal microtubule filaments (green) and their proximity with two additional proteins called TOM20 (red) and HSP60 (blue). Each image shows the proteins in a different plane of the cell starting from the top, and the magnified images on the bottom compare the resolution achieved with SDC-PAINT (left) to that possible with conventional confocal microscopy (right). Credit: Florian Schueder, MPI/LMU

    Cell biologists traditionally use fluorescent dyes to label and visualize cells and the molecules within them under a microscope. With different super-resolution microscopy methods, they can even light up single molecules and see their complex interactions with one another. However, the microscopy hardware required to do this is highly specialized, expensive, and requires operators to have unique skills; hence, such microscopes are relatively rare in laboratories around the world.

    Ralf Jungmann, Ph.D., an alumnus of the Wyss Institute and currently a Professor of Biochemistry at the Ludwig Maximilian University (LMU) and the Max Planck Institute (MPI) in Germany and Wyss Institute Core Faculty member Peng Yin, Ph.D. have been developing DNA-PAINT, a powerful molecular imaging technology that involves transient DNA-DNA interactions to accurately localize fluorescent dyes with super-resolution. However, although the researchers demonstrated DNA-PAINT’s potential by visualizing single biomolecules such as proteins in fixed cells at a fixed close distance, the technology could not yet investigate molecules deep inside of cells.

    Now, Jungmann’s and Yin’s teams jointly report a solution to overcome this limitation. In their new study, they adapted DNA-PAINT technology to confocal microscopes, which are widely used by researchers in cell biology laboratories to image whole cells and thicker tissues at lower resolution. The MPI/Wyss Institute team demonstrates that the method can visualize a variety of different molecules, including combinations of different proteins, RNAs, and DNA throughout the entire depth of whole cells at super-resolution. Published in Nature Communications, the approach could open the door for detailed single-molecule localization studies in many areas of cell research.

    The DNA-PAINT approach attaches a DNA “anchor strand” to the molecule of interest. Then a dye-labeled DNA “imager strand” with a complementary sequence transiently attaches to the anchor and produces a fluorescent signal, which occurs as a defined blinking event at single molecular sites. Because this “blinking frequency” is precisely tunable, molecules that are only nanometers apart from each other can be distinguished — at the higher resolution end of super-resolution.

    “Our new approach, SDC-PAINT, integrates the versatile super-resolution capabilities of DNA-PAINT with the optical sectioning features of confocal microscopes. We thus created the means to explore the entire depth of a cell, and to visualize the molecules within it at the nanometer scale,” said Jungmann. The team mapped out the presence of different combinations of proteins within whole cells, and then went beyond that. “By diversifying our labeling approaches, we also visualized different types of individual biomolecules in the chromosome-containing nucleus, including sequences in the DNA, proteins bound to DNA or the membrane that encloses the nucleus, as well as nuclear RNAs,” adds Yin, who is also co-leader of the Wyss Institute’s Molecular Robotics Initiative, and Professor of Systems Biology at Harvard Medical School.

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    SDC-PAINT can accurately visualize the distribution of the cell’s energy-producing structures known as mitochondria by combining high-resolution fluorescence signals from a protein in their outer membranes (in red) and a protein in its interior lumen (in green). The Gif on the left shows consecutive sections taken through the cells’ 3D space at the area outlined with the small rectangle in the image on the right. Credit: Florian Schueder, MPI/LMU

    In principle, confocal microscopes use so-called pinholes to eliminate unwanted out-of-focus fluorescence from image planes above and below the focal plane. By scanning through the sample, plane after plane, researchers can gather the desired fluorescence signals emitted from molecule-bound dyes over the entire depth. Specifically, the MPI/Wyss Institute team developed the technique for “Spinning Disk Confocal” (SDC) microscopes that detect fluorescence signals from an entire plane all at once by sensing them through a rotating disc with multiple pinholes. Moreover, “to achieve 3D super-resolution, we placed an additional lens in the detection path, which allows us to archive sub-diffraction-limited resolution in the third dimension” said first author Florian Schueder, a Graduate Student working with Jungmann who also worked with Yin’s Wyss Institute team as part of his master’s thesis.

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    “This addition can be easily customized by manufacturers of SDC microscopes; so we basically implement super-resolution microscopy without complex hardware changes to microscopes that are generally available to cell biologists from all venues of biomedical research. The approach thus has the potential to democratize super-resolution imaging of whole cells and tissues,” said Jungmann.

    “With this important advance, super-resolution microscopy and DNA-PAINT could become more accessible to biomedical researchers, accelerating our insights into the function of individual molecules and the processes they control within cells,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

    Other authors on the study are past and present members of Yin’s group including Juanita Lara-Gutiérrez; Brian Beliveau, Ph.D.; Sinem Saka, Ph.D.; and Hiroshi Sasaki, Ph.D.; and Johannes Woehrstein, Maximilian Strauss, and Heinrich Grabmayr, Ph.D., who are working with Jungmann. The study was funded by grants from the Wyss Institute for Biologically Inspired Engineering at Harvard University, the German Research Foundation’s Emmy Noether Program, the European Research Council, LMU’s Center for Nanoscience, the Max Planck Society and Max Planck Foundation, the National Institutes of Health and the Office of Naval Research.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 3:28 pm on December 14, 2017 Permalink | Reply
    Tags: , , , Single-stranded DNA and RNA origami go live, WYSS Institute at Harvard   

    From Wyss: “Single-stranded DNA and RNA origami go live” 

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    Wyss Institute

    December 14, 2017
    Benjamin Boettner

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    Single-stranded origami technology is based on design rules that can be used to cross DNA strands in and out of single stranded regions to build large nanostructures. Credit: Molgraphics.

    Like genetic DNA (and RNA) in nature, these engineered nanotechnological devices are also made up of strands that are comprised of the four bases known in shorthand as A, C, T, and G. Regions within those strands can spontaneously fold and bind to each other via short complementary base sequences in which As from one sequence specifically bind to Ts from another sequence, and Cs to Gs. Researchers at the Wyss Institute of Biologically Inspired Engineering and elsewhere have used these features to design self-assembling nanostructures such as scaffolded DNA origami and DNA bricks with ever-growing sizes and complexities that are becoming useful for diverse applications. However, the translation of these structures into medical and industrial applications is still challenging, partially because these multi-stranded systems are prone to local defects due to missing stands. In addition, they self-assemble from hundreds to thousands of individual DNA sequences that each need to be verified and tested for high-precision applications, and whose expensive synthesis often produces undesired side products.

    Now, a novel approach published in Science by a collaborative team of researchers from the Wyss Institute, Arizona State University, and Autodesk for the first time enables the design of complex single-stranded DNA and RNA origami that can autonomously fold into diverse, stable, user-defined structures. In contrast to the synthesis of multi-stranded nanostructures, these entirely new types of origami are folded from one single strand, which can be replicated in living cells, allowing their potential low-cost production at large scales and with high purities, opening entirely new opportunities for diverse applications such as drug delivery and nanofabrication.

    Earlier generations of larger-sized origami are composed of a central scaffold strand whose folding and stability requires more than two hundred short staple strands that bridge distant parts of the scaffold and fix them in space. “In contrast to traditional scaffolded origamis, which are assembled from hundreds of components, our new approach allows us to reliably design and synthesize stable single-stranded and self-folding origami,” said Wyss Institute Core Faculty member and corresponding author Peng Yin, Ph.D. “Our fundamentally new approach relies on single-strand folding, rather than multi-component assembly, to produce large nanostructures. This, together with the ability to basically clone and multiply the single component strand in bacteria, presents a game-changing advance in DNA nanotechnology that greatly enhances single-stranded origami’s potential for real-world applications.” Yin is also co-lead of the Wyss Institute’s Molecular Robotics Initiative and Professor of Systems Biology at Harvard Medical School (HMS).

    To first enable the production of single-stranded and stable DNA-based origami with distinct folding patterns, the team had to overcome several challenges. In a large DNA strand that goes through a complex folding process, many sequences need to accurately pair up with sequences that are far away from each other. If this process does not happen in an orderly and precise fashion, the strand gets tangled and forms unspecific knots along the way, rendering it useless. “To avoid this problem, we identified new design rules that we can use to cross DNA strands between different double-stranded regions and developed a web-based automated design tool that allows researchers to integrate many of these events into a folding path leading up to a large knot-free nanocomplex,” said Dongran Han, Ph.D., the study’s first author and a Postdoctoral Fellow on Yin’s team.

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    This schematic shows how a single strand of DNA can be programmed to self-fold into a large nanostructure, like, for example, that of a heart. The Wyss Institute researchers used atomic force microscopy to visualize the heart-shaped and a variety of other nanostructures, which can inexpensively and consistently be multiplied using bacteria as nanofactories. Credit: Wyss Institute at Harvard University.

    The largest DNA origami structures created previously were assembled by synthesizing all their constituent sequences individually in vitro and by mixing them together. As a key feature of the new design process, the single-strandedness of the DNA origami allowed the researchers to introduce DNA sequences stably into E. coli bacteria to inexpensively and accurately replicate them with every cell division. “This could greatly facilitate the development of single-stranded origami for high-precision nanotech like drug delivery vehicles, for example, as only a single easy-to-produce molecule needs to be validated and approved,” said Han.

    Finally, the team also adapted single-stranded origami technology to RNA, which as a different nucleic acid material offers certain advantages including, for example, even higher production levels in bacteria, and usefulness for potential intra-cellular and therapeutic RNA applications. Translating the approach to RNA also scales up the size and complexity of synthetic RNA structures 10-fold compared to previous structures made from RNA.

    Their proof-of-concept analysis also proved that protruding DNA loops can be precisely positioned and be used as handles for the attachment of functional proteins. In future developments, single-stranded origami could thus be potentially functionalized by attaching enzymes, fluorescent probes, metal particles, or drugs either to their surfaces or within cavities inside. This could effectively convert single-stranded origami into nanofactories, light-sensing and emitting optical devices, or drug delivery vehicles.

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    In this disc-shaped single-stranded DNA origami, visualized with atomic force microscopy, individual protruding hairpins have been introduced at positions that together compose a “smiley face” and that can be functionalized with useful molecules and activities. Credit: Wyss Institute at Harvard University

    “This new advance by the Wyss Institute’s Molecular Robotics Initiative transforms an exciting laboratory research methodology into a potentially transformative technology that can be manufactured at large scale by leveraging the biological machinery of living cells. This work opens a path by which DNA nanotechnology and origami approaches may be translated into products that meet real-world challenges,” said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).

    The results announced today establish DNA nanotechnology as a viable alternative approach for applications that have the potential to benefit all of us and the Nation as a whole,” said Jim Kurose, Assistant Director of the National Science Foundation’s (NSF) Directorate for Computer and Information Science and Engineering (CISE). “We are delighted this work was supported by NSF’s Expeditions in Computing program, which has, over the last decade funded large teams of researchers to pursue ambitious, fundamental research agendas that help define and shape the future of computer and information science and engineering, and impact our national competitiveness.

    Besides Yin and Han, the study includes corresponding authors Hao Yan, Ph.D., and Fei Zhang, Ph.D., Director and Assistant Professor at the Biodesign Center for Molecular Design and Biomimetics at Arizona State University, Tempe, respectively, and Byoungkwon An, Ph.D., Principle Research Scientist at Autodesk Research, San Francisco; Shuoxing Jiang, Ph.D., Xiaodong Qi, and Yan Liu, Ph.D., Assistant Professor from the Biodesign Institute; Cameron Myhrvold, Ph.D., Bei Wang, and Mingjie Dai, Ph.D., past and present members of Yin’s team at the Wyss Institute; and Maxwell Bates, who worked with An. The study was funded by the Office of Naval Research, the Army Research Office, the National Science Foundation’s Expeditions in Computing program, and the Wyss Institute for Biologically Inspired Engineering.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 10:19 am on November 29, 2017 Permalink | Reply
    Tags: Artificial muscle-like actuators are one of the most important grand challenges in all of engineering, Artificial muscles give soft robots superpowers, , Origami-inspired muscles are both soft and strong and can be made for less than $1, , WYSS Institute at Harvard   

    From Paulson: “Artificial muscles give soft robots superpowers” 

    Harvard School of Engineering and Applied Sciences
    John A Paulson School of Engineering and Applied Sciences

    November 27, 2017

    Lindsay Brownell
    The Wyss Institute for Biologically Inspired Engineering at Harvard University
    lindsay.brownell@wyss.harvard.edu
    (617) 432-8266

    Leah Burrows
    The Harvard John A. Paulson School of Engineering and Applied Sciences
    lburrows@seas.harvard.edu
    (617) 496-1351

    Multimedia contact
    Seth Kroll
    seth.kroll@wyss.harvard.edu
    (617) 432-7758)

    Origami-inspired muscles are both soft and strong, and can be made for less than $1.

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    Origami-inspired artificial muscles are capable of lifting up to 1,000 times their own weight, simply by applying air or water pressure. (Image courtesy of the Wyss Institute for Biologically Inspired Engineering)

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    The movement and shape of the artificial muscles is defined by the shape of their internal “skeleton” – in this case, made of notched blocks of foam. (Image courtesy of the Wyss Institute for Biologically Inspired Engineering)

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    The zig-zag pattern of this muscle’s interior “skeleton” allows the muscle to contract down to a fraction of its original width. (Image courtesy of the Wyss Institute for Biologically Inspired Engineering)

    Soft robotics has made leaps and bounds over the last decade as researchers around the world have experimented with different materials and designs to allow once rigid, jerky machines to bend and flex in ways that mimic and can interact more naturally with living organisms. However, increased flexibility and dexterity has a trade-off of reduced strength, as softer materials are generally not as strong or resilient as inflexible ones, which limits their use.

    Now, researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), the Wyss Institute at Harvard University and MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) have created origami-inspired artificial muscles that add strength to soft robots, allowing them to lift objects that are up to 1,000 times their own weight using only air or water pressure. The study will be published this week in Proceedings of the National Academy of Sciences (PNAS).

    “We were very surprised by how strong the actuators [aka, “muscles”] were. We expected they’d have a higher maximum functional weight than ordinary soft robots, but we didn’t expect a thousand-fold increase. It’s like giving these robots superpowers,” said Daniela Rus, the Andrew and Erna Viterbi Professor of Electrical Engineering and Computer Science at MIT and one of the senior authors of the paper.

    “Artificial muscle-like actuators are one of the most important grand challenges in all of engineering,” said Robert J. Wood, corresponding author of the paper and the Charles River Professor of Engineering and Applied Sciences at the SEAS. “Now that we have created actuators with properties similar to natural muscle, we can imagine building almost any robot for almost any task.” Wood is also a Founding Core Faculty member of the Wyss Institute.

    Each artificial muscle consists of an inner skeleton that can be made of various materials, such as a metal coil or a sheet of plastic folded into a certain pattern, surrounded by air or fluid and sealed inside a plastic or textile bag that serves as the skin. A vacuum applied to the inside of the bag initiates the muscle’s movement by causing the skin to collapse onto the skeleton, creating tension that drives the motion. No other power source or human input is required to direct the muscle’s movement; it is determined entirely by the shape and composition of the skeleton.

    “One of the key aspects of these muscles is that they’re programmable, in the sense that designing how the skeleton folds defines how the whole structure moves. You essentially get that motion for free, without the need for a control system,” said first author Shuguang Li, a Postdoctoral Fellow at the Wyss Institute and MIT CSAIL. This approach allows the muscles to be very compact and simple, and thus more appropriate for mobile or body-mounted systems that cannot accommodate large or heavy machinery.

    “When creating robots, one always has to ask, ‘Where is the intelligence – is it in the body, or in the brain?’” said Rus. “Incorporating intelligence into the body (via specific folding patterns, in the case of our actuators) has the potential to simplify the algorithms needed to direct the robot to achieve its goal. All these actuators have the same simple on/off switch, which their bodies then translate into a broad range of motions.”

    The team constructed dozens of muscles using materials ranging from metal springs to packing foam to sheets of plastic, and experimented with different skeleton shapes to create muscles that can contract down to 10 percent of their original size, lift a delicate flower off the ground, and twist into a coil, all simply by sucking the air out of them.

    Not only can the artificial muscles move in many ways, they do so with impressive resilience. They can generate about six times more force per unit area than mammalian skeletal muscle can, and are also lightweight; a 2.6-gram muscle can lift a 3-kilogram object, which is the equivalent of a mallard duck lifting a car. Additionally, a single muscle can be constructed within ten minutes using materials that cost less than $1, making them cheap and easy to test and iterate.

    These muscles can be powered by a vacuum, a feature that makes them safer than most of the other artificial muscles currently being tested. “A lot of the applications of soft robots are human-centric, so of course it’s important to think about safety,” said Daniel Vogt, co-author of the paper and Research Engineer at the Wyss Institute. “Vacuum-based muscles have a lower risk of rupture, failure, and damage, and they don’t expand when they’re operating, so you can integrate them into closer-fitting robots on the human body.”

    “In addition to their muscle-like properties, these soft actuators are highly scalable. We have built them at sizes ranging from a few millimeters up to a meter, and their performance holds up across the board,” said Wood. This feature means that the muscles can be used in numerous applications at multiple scales, such as miniature surgical devices, wearable robotic exoskeletons, transformable architecture, deep-sea manipulators for research or construction, and large deployable structures for space exploration.

    The team was even able to construct the muscles out of the water-soluble polymer PVA, which opens the possibility of robots that can perform tasks in natural settings with minimal environmental impact, as well as ingestible robots that move to the proper place in the body and then dissolve to release a drug. “The possibilities really are limitless. But the very next thing I would like to build with these muscles is an elephant robot with a trunk that can manipulate the world in ways that are as flexible and powerful as you see in real elephants,” said Rus.

    This research was funded by the Defense Advanced Research Projects Agency (DARPA), the National Science Foundation (NSF), and the Wyss Institute for Biologically Inspired Engineering.

    See the full article here .

    Please help promote STEM in your local schools.

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    Stem Education Coalition

    Through research and scholarship, the Harvard School of Engineering and Applied Sciences (SEAS) will create collaborative bridges across Harvard and educate the next generation of global leaders. By harnessing the power of engineering and applied sciences we will address the greatest challenges facing our society.

    Specifically, that means that SEAS will provide to all Harvard College students an introduction to and familiarity with engineering and technology as this is essential knowledge in the 21st century.

    Moreover, our concentrators will be immersed in the liberal arts environment and be able to understand the societal context for their problem solving, capable of working seamlessly withothers, including those in the arts, the sciences, and the professional schools. They will focus on the fundamental engineering and applied science disciplines for the 21st century; as we will not teach legacy 20th century engineering disciplines.

    Instead, our curriculum will be rigorous but inviting to students, and be infused with active learning, interdisciplinary research, entrepreneurship and engineering design experiences. For our concentrators and graduate students, we will educate “T-shaped” individuals – with depth in one discipline but capable of working seamlessly with others, including arts, humanities, natural science and social science.

    To address current and future societal challenges, knowledge from fundamental science, art, and the humanities must all be linked through the application of engineering principles with the professions of law, medicine, public policy, design and business practice.

    In other words, solving important issues requires a multidisciplinary approach.

    With the combined strengths of SEAS, the Faculty of Arts and Sciences, and the professional schools, Harvard is ideally positioned to both broadly educate the next generation of leaders who understand the complexities of technology and society and to use its intellectual resources and innovative thinking to meet the challenges of the 21st century.

    Ultimately, we will provide to our graduates a rigorous quantitative liberal arts education that is an excellent launching point for any career and profession.

     
  • richardmitnick 10:24 am on October 9, 2017 Permalink | Reply
    Tags: , , , WYSS Institute at Harvard   

    From Wyss: “Just add water: Biomolecular manufacturing ‘on-the-go’” 

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    The portable biomolecular manufacturing method, developed by Wyss Institute Core Faculty member James Collins and his team, can produce a broad range of biomolecules, including vaccines, antimicrobial peptides and antibody conjugates, without power or refrigeration. The team envisions that the method’s freeze-dried components could be carried in portable kits (such as the mock kit pictured here) for use in the field anywhere in the world. Credit: Wyss Institute at Harvard University

    September 22, 2016 [From a reference in a current article in social media.]
    No writer credit

    Wyss Institute team unveils a low-cost, portable method to manufacture biomolecules for a wide range of vaccines, other therapies as well as diagnostics.

    Even amidst all the celebrated advances of modern medicine, basic life-saving interventions are still not reaching massive numbers of people who live in our planet’s most remote and non-industrialized locations. The World Health Organization states that one half of the global population lives in rural areas. And according to UNICEF, last year nearly 20 million infants globally did not receive what we would consider to be basic vaccinations required for a child’s health.

    These daunting statistics are largely due to the logistical challenge of transporting vaccines and other biomolecules used in diagnostics and therapy, which conventionally require a “cold chain” of refrigeration from the time of synthesis to the time of administration. In remote areas lacking power or established transport routes, modern medicine often cannot reach those who may need it urgently.

    A team of researchers at Harvard’s Wyss Institute for Biologically Inspired Engineering has been working toward a paradigm-shifting goal: a molecular manufacturing method that can produce a broad range of biomolecules, including vaccines, antimicrobial peptides and antibody conjugates, anywhere in the world, without power or refrigeration.

    Now, in a new paper published September 22 in Cell journal, the team has unveiled what they set out to deliver, a “just add water” portable method that affordably, rapidly, and precisely generates compounds that could be administered as therapies or used in experiments and diagnostics.

    “The ability to synthesize and administer biomolecular compounds, anywhere, could undoubtedly shift the reach of medicine and science across the world,” said Wyss Core Faculty member James Collins, Ph.D., senior author on the study, who is also Professor of Medical Engineering & Science and Professor of Biological Engineering at the Massachusetts Institute of Technology (MIT)’s Department of Biological Engineering. “Our goal is make biomolecular manufacturing accessible wherever it could improve lives.”

    The approach, called “portable biomolecular manufacturing” by Collins’ team, which also included Neel Joshi, Ph.D., a Wyss Core Faculty member and Associate Professor of Chemical and Biological Engineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS), hinges on the idea that freeze-dried pellets containing “molecular machinery” can be mixed and matched to achieve a wide variety of end-products. By simply adding water, this molecular machinery can be set in motion.

    Compounds manufactured using the method could be administered in several ways to a patient, including injection, oral doses or topical applications. As described in the study, a vaccine against diphtheria was synthesized using the method and shown to successfully induce an antibody response against the pathogen in mice.

    Subsequently, the team envisions that the method could be employed to create batches of tetanus or flu shots routinely manufactured in remote clinics. Vaccines against emerging infectious disease outbreaks could quickly be mobilized in the field to contain spiraling epidemics. Episodes of food poisoning could be dosed orally with the production of neutralizing antibodies produced on the spot. Flesh wounds susceptible to infection could be applied with topical antimicrobial peptides generated on demand. In these manners, the team’s approach could be leveraged to design a vast number of different lifesaving measures.

    The approach is built upon work described in a seminal 2014 paper also published in Cell, when the team demonstrated that transcription and translation machinery could function in vitro, without being inside living cells, inside freeze-dried slips of ordinary paper embedded with synthetic gene networks.

    Building off that work, the novel manufacturing method employs two types of freeze-dried pellets containing different kinds of components. The first kind of pellet contains the cell-free “machinery” that will synthesize the end product. The second kind contains DNA instructions that will tell the “machinery” what compound to manufacture. When the two types of pellets are combined and rehydrated with water, the biomolecular manufacturing process is triggered. The second type of pellet can be customized to produce a wide range of final products.

    Since they are freeze-dried, the pellets are extremely stable and safe for long-term storage at room temperature for up to and potentially beyond one year.

    “This approach could — with very little training — put therapeutics and diagnostic tools in the hands of clinicians working in remote areas without power,” said Keith Pardee, Ph.D., a co-first author on the study who was a Wyss Research Scientist and is now an Assistant Professor in the Leslie Dan Faculty of Pharmacy at the University of Toronto. “Currently, distribution of life-saving doses of protein-based preventative and interventional medicines are often restricted by access to an uninterrupted chain of cold refrigeration, which many areas of the world lack.”

    The cost of the approach, at roughly three cents per microliter, could also give access to biomolecular manufacturing to researchers and educators who lack access to wet labs and other sophisticated equipment, impacting basic science beyond the immediately apparent promise in clinical applications.

    “Synthetic biology has been harnessed to increase efficiency of manufacturing of biological products for medical and energy applications in the past, however, this new breakthrough utterly changes the application landscape,” said Wyss Core Faculty member Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s SEAS. “It’s really exciting because this new biomolecular manufacturing technology potentially offers a way to solve the cold chain problem that still restricts delivery of vaccines and other important medical treatments to patients in the most far-flung corners of the world who need them the most.”

    In addition to Collins, Joshi, and Pardee, additional authors on the study include: Shimyn Slomovic, co-first author, Institute for Medical Engineering & Science (IMES) at MIT; Peter Nguyen, co-first author, Wyss Institute; Jeong Wook Lee, co-first author, IMES at MIT, Wyss Institute; Nina Donghia, co-author, Wyss Institute; Devin Burrill, co-author, Wyss Institute; Tom Ferrante, co-author, Wyss Institute; Fern McSorley, co-author, University of Ottawa; Yoshikazu Furata, co-author, IMES at MIT; Michael Lewandowski, co-author, Wyss Institute; and Christopher Boddy, co-author, University of Ottawa.

    See the full article here .

    Please help promote STEM in your local schools.

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    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 11:36 am on June 15, 2017 Permalink | Reply
    Tags: , , , Low-energy ultrasound waves to trigger the dispersal of chemotherapy-containing sustained-release nanoparticles precisely at tumor sites, , , WYSS Institute at Harvard   

    From Wyss: “A mechanical trigger for toxic tumor therapy” 

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    June 15, 2017
    Lindsay Brownell

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    An electron microscope image of a hollow, roughly spherical nanoparticle aggregate (NPA), consisting of nanoparticles loaded with chemotherapy drugs. Credit: Wyss Institute at Harvard University

    Cells in nearly any part of the body can become cancerous and transform into tumors. Some, like skin cancer, are relatively accessible to treatment via surgery or radiation, which minimizes damage to healthy cells; others, like pancreatic cancer, are deep in the body and can only be reached by flooding the bloodstream with cell-killing chemotherapies that, ideally, shrink tumors by accumulating in their ill-formed blood and lymph vessels in higher amounts than in vessels of healthy tissues. To improve the low efficacy and toxic side effects of chemotherapies that rely on this passive accumulation, a team of researchers at the Wyss Institute at Harvard University, Boston Children’s Hospital, and Harvard Medical School has developed a new drug delivery platform that uses safe, low-energy ultrasound waves to trigger the dispersal of chemotherapy-containing sustained-release nanoparticles precisely at tumor sites, resulting in a two-fold increase in targeting efficacy and a dramatic reduction in both tumor size and drug-related toxicity in mouse models of breast cancer. This research was recently published in Biomaterials.

    “We essentially have an external activation method that can localize drug delivery anywhere you want it, which is much more effective than just injecting a bunch of nanoparticles,” says co-first author Netanel Korin, Ph.D., former Wyss Technology Development Fellow and current Assistant Professor at the Israel Institute of Technology.

    The key to this new method is the creation of nanoparticle aggregates (NPAs), which are tiny structures consisting of drug-containing nanoparticles surrounded by a supportive matrix, akin to the berries suspended in a blueberry muffin. Like chefs trying to craft the perfect pastry, the researchers experimented with a variety of nanoparticle sizes and nanoparticle-to-matrix ratios to create NPAs that are stable enough to remain intact when injected, but also finely tuned to break apart when disrupted with low-energy ultrasound waves, freeing the nanoparticles that then release their drug payloads over time, like blueberries slowly leaking their juice.

    To test whether the NPAs worked as designed, the team first exposed mouse breast cancer cells to either loose nanoparticles, intact NPAs, or NPAs that had been treated with ultrasound. The ultrasound-treated NPAs and loose nanoparticles both showed greater tumor internalization than the intact NPAs, showing that the ultrasound waves effectively broke up the NPAs to allow the nanoparticles to infiltrate cancer cells.

    Next, the researchers repeated the experiments with nanoparticles containing doxorubicin (a common chemotherapy drug used to treat a variety of cancers) and found that the NPAs resulted in a comparable level of cancer cell death, demonstrating that NPA encapsulation did not negatively impact the efficacy of the drug.

    Finally, to see whether the NPAs performed well compared with loose nanoparticles in vivo, both formulations were injected intravenously into mice with breast cancer tumors. Ultrasound-treated NPAs delivered nearly five times the amount of nanoparticles to the tumor site as intact NPAs, while loose nanoparticles delivered two to three times that amount. When the nanoparticles were loaded with doxorubicin, tumors in mice that received NPAs and ultrasound shrank by nearly half compared with those in mice that received loose nanoparticles. Crucially, by using NPAs, the researchers were able to cut tumor size in half using one-tenth of the dose of doxorubicin usually required, reducing the number of mouse deaths due to drug toxicity from 40% to 0%.

    “Locking nanoparticles up in NPAs permits precise delivery of an army of nanoparticles from each single NPA directly to the tumor in response to ultrasound, and this greatly minimizes the dilution of these nanoparticles in the bloodstream,” says Anne-Laure Papa, Ph.D., co-first author and Postdoctoral Fellow at the Wyss Institute. “Additionally, our ultrasound-triggered NPAs displayed distribution patterns throughout the body similar to the FDA-approved PLGA polymer nanoparticles, so we expect the NPAs to be comparably safe.”

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    How ultrasound-sensitive NPAs work: 1. Intact NPAs are introduced into the bloodstream. 2. Ultrasound waves are applied to the site of the tumor. 3. NPAs break apart in response to ultrasound, releasing nanoparticles that deliver their drug payload directly to the tumor. Credit: Wyss Institute at Harvard University

    NPAs were also shown to limit the “burst release” commonly observed in nanoparticle drug delivery, in which a significant number of them break open and release their drug soon after injection, causing an adverse response around the site of injection and reducing the amount of the drug that gets to the tumor. When applied to cancer cells in vitro, loose nanoparticles released 25% of their drug payload within five minutes of being administered, while the nanoparticles contained within intact NPAs released just 1.8% of their drug. When ultrasound was applied, an additional 65% of the drug was released from the NPAs compared with loose nanoparticles, which only released an additional 11%.

    The team says additional research could further improve the performance of ultrasound-sensitive NPAs, making the platform an attractive option for safer, more effective chemotherapy delivery. It could be made even more powerful through combination with other tumor-targeting strategies such as using peptides that home to the tumor microenvironment to further guide cancer drugs to their targets. “We hope that in the future our triggered accumulation technique can be combined with such targeting strategies to produce even more potent treatment effects,” says Papa.

    “This approach offers a novel solution to the pervasive problem of delivering a high concentration of an intravenous drug to a very specific area while sparing the rest of the body,” says senior author and Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at Harvard SEAS. “By using localized ultrasound to selectively deploy sustained-release nanoparticles loaded with high drug concentrations, we have created a non-invasive way to safely and effectively deliver chemotherapy only where and when it’s needed.”

    Mathumai Kanapathipillai, Ph.D., who also co-first authored the paper as a Research Scientist at the Wyss Institute, is currently an Assistant Professor of Mechanical Engineering at University of Michigan-Dearborn. Other contributing authors include Robert Mannix, Ph.D., Oktay Uzun, Ph.D., Christopher Johnson, Deen Bhatta, and Garry Cuneo from the Wyss Institute; and Akiko Mammoto, M.D., Ph.D., Tadanori Mammoto, M.D., Ph.D., and Amanda Jiang from the Vascular Biology Program and Department of Surgery at Boston Children’s Hospital and HMS.

    This research was supported by the US Army Medical Research and Materiel Command under DoD Breast Cancer Innovator Award No. W81XWH-08-1-0659, DoD grant No. W81WXH-10-1-0565, and DoD Breast Cancer Breakthrough Award No. W81XWH-15-1-0305. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

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    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 2:01 pm on May 27, 2017 Permalink | Reply
    Tags: , Bioelectricity is a new weapon to fight dangerous infection, , WYSS Institute at Harvard   

    From Wyss: “Bioelectricity is a new weapon to fight dangerous infection” 

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    May 26, 2017
    Kim Thurler, Tufts University

    Drugs already approved for other uses in people help frogs survive deadly E. coli by changing their cells’ electrical charge.

    Changing the natural electrical signaling that exists in cells outside the nervous system can improve resistance to life-threatening bacterial infections, according to new research from Tufts University biologists. The researchers found that administering drugs, including those already used in humans for other purposes, to make the cell interior more negatively charged strengthens tadpoles’ innate immune response to E. coli infection and injury. This reveals a novel aspect of the immune system – regulation by non-neural bioelectricity – and suggests a new approach for clinical applications in human medicine. The study is published online May 26, 2017, in npj Regenerative Medicine, a Nature Research journal.

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    How bioelectricity strengthens the innate immune response (Credit: Jean-Francois Pare/Tufts University)

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
  • richardmitnick 5:03 am on May 23, 2017 Permalink | Reply
    Tags: , , Pulmonary Thrombosis-on-a-Chip provides new avenue for drug development, WYSS Institute at Harvard   

    From Wyss: “Pulmonary Thrombosis-on-a-Chip provides new avenue for drug development” 

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    May 22, 2017
    Lindsay Brownell

    Model of blood clot formation in the lung allows for unprecedented study of human blood responses to organ-level injury and inflammation in vitro

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    An image of a thrombus (blood clot) formed on endothelial tissue in the pulmonary-thrombosis-on-a-chip, demonstrating the characteristic “teardrop” shape observed in vivo. Credit: Wyss Institute at Harvard University

    The average human pair of lungs is permeated by a network of about 164 feet of blood vessels (roughly the width of a football field), including microscopic blood capillaries, which facilitate the diffusion of oxygen into the bloodstream in exchange for carbon dioxide. Damage to any of those vessels can cause a blood clot, or thrombus, to form, which can cause or exacerbate a number of lung diseases, including pneumonia, acute lung injury and acute chest syndrome. The use of some drugs is also limited by their propensity to promote clot formation in lung vessels. Developing and testing drugs to treat or prevent pulmonary thrombosis is difficult because the complex interplay between the many different cell types in the lung hampers efforts to tease out the exact causes of clot formation. A new study conducted by members of the Wyss Institute at Harvard University, Emulate Inc., and Janssen Pharmaceutical Research and Development, published this week in the journal Clinical Pharmacology and Therapeutics, is the first to successfully recreate a human pulmonary thrombosis within an organ-level model of the lung in vitro.

    “It’s very difficult to distill out specific mechanisms inside an animal, and a lot of work in toxicology or drug discovery fails when it goes to human clinical trials,” says co-first author Abhishek Jain, Ph.D., former Wyss Institute Postdoctoral Fellow and current Assistant Professor of Biomedical Engineering at Texas A&M University. “In vitro models like our Thrombosis-on-a-Chip are made from the ground-up, so you can build them to be exactly as complex as you need for the problem you want to study.”

    To meet this challenge, the team used Organ-on-a-Chip (Organ Chip) technology developed at the Wyss Institute, which involves engineering microfluidic culture devices with two parallel channels separated by a porous extracellular-matrix-coated membrane. The key innovation in this new design relative to a previously described Lung-on-a-Chip is that the upper surface of the porous membrane is lined by primary human alveolar epithelial cells, and all sides of the lower vascular channel are coated with a layer of lung microvascular endothelium to accurately mimic human lung capillaries. Because thrombosis is perpetrated by platelets and other cells, the team perfused whole human blood through the lower endothelium-lined channel of the chip for the first time, while air was introduced into the upper channel. When an inflammatory stimulus was applied to the endothelial cells followed by perfusing whole blood, platelets clumped and formed blood clots on the surface of the endothelium in a characteristic teardrop shape that has been observed in living animals, but never before in vitro.

    “This is the first time we’re seeing clots form with the same dynamics and morphology that you see in vivo, which is a major step forward in studying and eventually treating blood clots that cause many life-threatening diseases.” says Donald Ingber, M.D., Ph.D., senior author of the study and the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s School of Engineering and Applied Sciences (SEAS).

    The team further tested the chip’s functionality by replicating an inflammatory lung injury that originates in the lung’s airways – the most likely source of a pathogen or other damaging substance. They introduced lipopolysaccharide endotoxin (LPS), an inflammatory chemical found on the surface of certain types of bacteria and is known to induce clot formation in vivo, into both the upper and lower channels of the chip. They were surprised to find that LPS had no effect on blood clot formation when they added it directly to the endothelium-lined blood channel; but, when added to the air channel, it induced the air-facing epithelium to trigger a cascade of cytokines, a class of inflammatory signaling molecules that initiate blood clot formation, in the underlying endothelium. “Epithelial cells are the guardians of the airways – they need to be sensitive to airborne pathogens and then signal the danger to the rest of the body,” says co-author Riccardo Barrile, Ph.D., also a former Wyss Institute Postdoctoral Fellow and current principal investigator at Emulate, Inc. “This study demonstrated that information travels from the epithelium to the endothelium, but I was surprised to see that the entire system is so well-connected.”

    In addition to facilitating the discovery of crucial insights into the mechanism of how lung injury promotes blood clot formation, the Thrombosis-on-a-Chip allows for the testing of potential drugs on an organ-level system in vitro, an approach that has become highly attractive to pharmaceutical companies. Working with Robert Flaumenhaft, M.D., Ph.D., Associate Professor of Hematology at HMS and Beth Israel Deaconess Medical Center, the team introduced parmodulin-2 (PM2), an inflammation inhibitor, into the vascular channel of the device, and found that it significantly decreased the number of clots on the vessel wall following the addition of LPS to the airway channel. This confirmation of drug activity, as well as the insight that LPS causes thrombosis only by acting directly on the epithelium, would have been very difficult to achieve in vivo, as blood flow and individual cellular compartments cannot be controlled individually as they can in Organ Chips.

    The team plans to continue their pulmonary thrombosis work by introducing mechanical forces that imitate breathing to the Chip and analyzing the role that immune cells such as neutrophils play in blood clot formation. “By including whole blood, we’re reaching a new standard of complexity and precision for mimicking a human body in both health and disease,” says Barrile. “This study affirms that we are recapitulating organ-level responses to lung injury, emphasizing that this is a true Organ-on-a-Chip, not just a tissue-on-a-chip,” adds Ingber.

    Andries D. van der Meer, Ph.D., former Senior Research Fellow at the Wyss Institute and current Assistant Professor at the MIRA Institute for Biomedical Technology and Technical Medicine, was the third co-author of this study. Additional authors include Akiko Mammoto, M.D., Ph.D., Instructor in the Vascular Biology Program at Boston Children’s Hospital and HMS; Tadanori Mammoto, M.D., Ph.D., Instructor in Surgery at Boston Children’s Hospital and HMS; Karen De Ceunynck, Ph.D., Postdoctoral Research Fellow at Beth Israel Deaconess Medical Center and HMS; Omozuanvbo Aisiku, Ph.D., former Postdoctoral Research Fellow at Beth Israel Deaconess Medical Center and HMS, currently a Scientist at Instrumentation Laboratory; Monicah A. Otieno, Ph.D., Senior Research Investigator at Bristol-Myers Squibb; Calvert S. Louden, D.V.M., Ph.D., Senior Director at Johnson & Johnson Pharmaceuticals; and Geraldine A. Hamilton, Ph.D., President and Chief Scientific Officer of Emulate, Inc.

    This work was funded by DARPA contract N66001-11-1-4180, HR0011-13-C-0025, Janssen Pharmaceuticals, and the Wyss Institute for Biologically Inspired Engineering at Harvard University. Ingber and Hamilton are founders and hold equity in Emulate, Inc, and Ingber chairs its scientific advisory board; van der Meer serves as a scientific consultant to the company.

    See the full article here .

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

     
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