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News Article | May 10, 2017
Site: www.eurekalert.org

(BOSTON) -- The kidney - made up of about a million tiny units that work to filter blood, constantly rids the body of undesired waste products to form urine while holding back blood cells and valuable proteins, and controls the body's fluid content. Key to each of these units is a structure known the 'glomerulus', in which so-called podocyte cells wrap themselves tightly around a tuft of capillaries separated from them only by a thin membrane composed of extracellular matrix, and leaving slits between them to build an actual filtration barrier. Podocytes are also the target of many congenital or acquired kidney diseases, and they are often harmed by drugs. To build an in vitro model of the human glomerulus that could allow probing deeper into its function, as well as its vulnerabilities to disease and drug toxicities, researchers have been attempting to engineer human stem cells -- that in theory can give rise to any mature cell type -- so that they form into functional podocytes. These cell culture efforts, however, so far have failed to produce populations of mature podocytes pure enough as to be useful for modeling glomerular filtration. A team led by Donald Ingber, M.D., Ph.D., at Harvard's Wyss Institute of Biologically Inspired Engineering now reports a solution to this challenge in Nature Biomedical Engineering, which enables the differentiation of human induced pluripotent stem (iPS) cells into mature podocytes with more than 90% efficiency. Linking the differentiation process with organ-on-a-chip technology pioneered by his team, the researchers went on to engineer the first in vitro model of the human glomerulus, demonstrating effective and selective filtration of blood proteins and podocyte toxicity induced by a chemotherapy drug in vitro. Ingber is the Wyss Institute's Founding Director, 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 the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). "The development of a functional human kidney glomerulus chip opens up an entire new experimental path to investigate kidney biology, carry out highly personalized modeling of kidney diseases and drug toxicities, and the stem cell-derived kidney podocytes we developed could even offer a new injectable cell therapy approach for regenerative medicine in patients with life-threatening glomerulopathies in the future," said Ingber. Ingber's team has engineered multiple organs-on-chips that accurately mimic human tissue and organ-level physiology and that are currently being evaluated by the Food and Drug Administration (FDA) as a tool to more effectively study the effects of potential chemical and biological hazards found in foods, cosmetics or dietary supplements than existing culture systems or animal models. In 2013, his team developed an organ-on-a-chip microfluidic culture device that modeled the human kidney's proximal tubule, which is anatomically connected to the glomerulus and salvages ions from urinary fluid. Now, with the team's newly engineered human kidney glomerulus-on-a-chip, researchers also can get in vitro access to the kidney's core filtration mechanisms that are critical for drug clearance and pharmacokinetics, in addition to studying human podocytes at work. To generate almost pure populations of human podocytes in cell culture, Samira Musah, Ph.D., the study's first author and HMS Dean's Postdoctoral Fellow who is working with Ingber at the Wyss Institute, leveraged pieces of the stem cell biologists' arsenal, and merged them with snippets taken from Ingber's past research on how cells in the body respond to adhesive factors and physical forces in their tissue environments. "Our method not only uses soluble factors that guide kidney development in the embryo, but, by growing and differentiating stem cells on extracellular matrix components that are also contained in the membrane separating the glomerular blood and urinary systems, we more closely mimic the natural environment in which podocytes are induced and mature," said Musah. "We even succeeded in inducing much of this differentiation process within a channel of the microfluidic chip, where by applying cyclical motions that mimic the rhythmic deformations living glomeruli experience due to pressure pulses generated by each heart beat, we achieve even greater maturation efficiencies." The complete microfluidic system closely resembles a living, three-dimensional cross-section of the human glomerular wall. It consists of an optically clear, flexible, polymeric material the size of a computer memory chip in which two closely opposed microchannels are separated by a porous, extracellular matrix-coated membrane that corresponds to the kidney's glomerular basement membrane. In one of the membrane-facing channels, the researchers grow glomerular endothelial cells to mimic the blood microvessel compartment of glomeruli. The iPS cells are cultured on the opposite side of the membrane in the other channel that represents the glomerulus' urinary compartment, where they are induced to form a layer of mature podocytes that extend long cellular processes through the pores in the membrane and contact the underlying endothelial cells. In addition, the device's channels are rhythmically stretched and relaxed at a rate of one heart beat per second by applying cyclic suction to hollow chambers placed on either side of the cell-lined microchannels to mimic physiological deformations of the glomerular wall. "This in vitro system allows us to effectively recapitulate the filtration of small substances contained in blood into the urinary compartment while retaining large proteins in the blood compartment just like in our bodies, and we can visualize and monitor the damage inflicted by drugs that cause break-down of the filtration barrier in the kidney," said Musah. The study was also co-authored by Wyss Institute Core Faculty member George Church, Ph.D., who also is Professor of Genetics at HMS and Professor of Health Sciences and Technology at Harvard and the Massachusetts Institute of Technology (MIT), and who served as a co-mentor of Musah with Ingber. Other authors include Akiko Mammoto, M.D., Ph.D. and Tadanori Mammoto, M.D., Ph.D., who at the time of the study were Instructors in the Vascular Biology Program and Department of Surgery at Boston Children's Hospital, as well as present or past Wyss Institute researchers, including Thomas Ferrante, Sauveur Jeanty, Kristen Roberts, Seyoon Chung, Ph.D., Richard Novak, Ph.D., Miles Ingram, Tohid Fatanat-Didar, Ph.D., Sandeep Koshy, Ph.D., and James Weaver, Ph.D. Funding for the study was provided by the Defense Advanced Research Projects Agency (DARPA). Musah was supported by a HMS Dean's Postdoctoral Fellowship, Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund, UNCF-Merck Postdoctoral Fellowship, and an NIH/NIDDK Nephrology Training Grant. The Wyss Institute for Biologically Inspired Engineering at Harvard University uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité - Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology.


News Article | May 18, 2017
Site: www.eurekalert.org

(BOSTON) --The human heart beats approximately 35 million times every year, effectively pumping blood into the circulation via four different heart valves. Unfortunately, in over four million people each year, these delicate tissues malfunction due to birth defects, age-related deteriorations, and infections, causing cardiac valve disease. Today, clinicians use either artificial prostheses or fixed animal and cadaver-sourced tissues to replace defective valves. While these prostheses can restore the function of the heart for a while, they are associated with adverse comorbidity and wear down and need to be replaced during invasive and expensive surgeries. Moreover, in children, implanted heart valve prostheses need to be replaced even more often as they cannot grow with the child. A team lead by Kevin Kit Parker, Ph.D. at Harvard University's Wyss Institute for Biologically Inspired Engineering recently developed a nanofiber fabrication technique to rapidly manufacture heart valves with regenerative and growth potential. In a paper published in Biomaterials, Andrew Capulli, Ph.D. and colleagues fabricated a valve-shaped nanofiber network that mimics the mechanical and chemical properties of the native valve extracellular matrix (ECM). To achieve this, the team used the Parker lab's proprietary rotary jet spinning technology - in which a rotating nozzle extrudes an ECM solution into nanofibers that wrap themselves around heart valve-shaped mandrels. "Our setup is like a very fast cotton candy machine that can spin a range of synthetic and natural occurring materials. In this study, we used a combination of synthetic polymers and ECM proteins to fabricate biocompatible JetValves that are hemodynamically competent upon implantation and support cell migration and re-population in vitro. Importantly, we can make human-sized JetValves in minutes - much faster than possible for other regenerative prostheses," said Parker. To further develop and test the clinical potential of JetValves, Parker's team collaborated with the translational team of Simon P. Hoerstrup, M.D., Ph.D., at the University of Zurich in Switzerland, which is a partner institution with the Wyss Institute. As a leader in regenerative heart prostheses, Hoerstrup and his team in Zurich have previously developed regenerative, tissue-engineered heart valves to replace mechanical and fixed-tissue heart valves. In Hoerstrup's approach, human cells directly deposit a regenerative layer of complex ECM on biodegradable scaffolds shaped as heart valves and vessels. The living cells are then eliminated from the scaffolds resulting in an "off-the-shelf" human matrix-based prostheses ready for implantation. In the paper, the cross-disciplinary team successfully implanted JetValves in sheep using a minimally invasive technique and demonstrated that the valves functioned properly in the circulation and regenerated new tissue. "In our previous studies, the cell-derived ECM-coated scaffolds could recruit cells from the receiving animal's heart and support cell proliferation, matrix remodeling, tissue regeneration, and even animal growth. While these valves are safe and effective, their manufacturing remains complex and expensive as human cells must be cultured for a long time under heavily regulated conditions. The JetValve's much faster manufacturing process can be a game-changer in this respect. If we can replicate these results in humans, this technology could have invaluable benefits in minimizing the number of pediatric re-operations," said Hoerstrup. In support of these translational efforts, the Wyss Institute for Biologically Inspired Engineering and the University of Zurich announced today a cross-institutional team effort to generate a functional heart valve replacement with the capacity for repair, regeneration, and growth. The team is also working towards a GMP-grade version of their customizable, scalable, and cost-effective manufacturing process that would enable deployment to a large patient population. In addition, the new heart valve would be compatible with minimally invasive procedures to serve both pediatric and adult patients. The project will be led jointly by Parker and Hoerstrup. Parker is a Core Faculty member of the Wyss Institute and the Tarr Family Professor of Bioengineering and Applied Physics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). Hoerstrup is Chair and Director of the University of Zurich's Institute for Regenerative Medicine (IREM), Co-Director of the recently founded Wyss Translational Center Zurich and a Wyss Institute Associate Faculty member. Since JetValves can be manufactured in all desired shapes and sizes, and take seconds to minutes to produce, the team's goal is to provide customized, ready-to-use, regenerative heart valves much faster and at much lower cost than currently possible. "Achieving the goal of minimally invasive, low-cost regenerating heart valves could have tremendous impact on patients' lives across age-, social- and geographical boundaries. Once again, our collaborative team structure that combines unique and leading expertise in bioengineering, regenerative medicine, surgical innovation and business development across the Wyss Institute and our partner institutions, makes it possible for us to advance technology development in ways not possible in a conventional academic laboratory," 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 SEAS. The Wyss Institute for Biologically Inspired Engineering at Harvard University(http://wyss. ) uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité - Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology. The University of Zurich (UZH) is a member of the League of European Research Universities and numbers among Europe's most prestigious research institutions. UZH's international standing is reflected in the many renowned academic distinctions conferred upon its members, including twelve Nobel Prizes. As Switzerland's largest university, UZH has a current enrollment of over 25,000 students and offers the most comprehensive academic program in the country. Nearly 5,000 excellent members of staff teach and perform research at one of the University's 150 departments, including over 600 professors. UZH also looks back on a rich history, having been founded in 1833 as Europe's first university to be established by a democratic political system. The mission of the Institute for Regenerative Medicine * IREM is advancing molecular life sciences into next generation bio-inspired therapy at the interface of degeneration and regeneration with a major focus on the most relevant human diseases, including neurodegeneration and cardiovascular disease. The Harvard John A. Paulson School of Engineering and Applied Sciences(http://seas. ) serves as the connector and integrator of Harvard's teaching and research efforts in engineering, applied sciences, and technology. Through collaboration with researchers from all parts of Harvard, other universities, and corporate and foundational partners, we bring discovery and innovation directly to bear on improving human life and society.


News Article | May 18, 2017
Site: www.prnewswire.com

A team lead by Kevin Kit Parker, Ph.D. at Harvard University's Wyss Institute for Biologically Inspired Engineering recently developed a nanofiber fabrication technique to rapidly manufacture heart valves with regenerative and growth potential. In a paper published in Biomaterials, Andrew Capulli, Ph.D. and colleagues fabricated a valve-shaped nanofiber network that mimics the mechanical and chemical properties of the native valve extracellular matrix (ECM). To achieve this, the team used the Parker lab's proprietary rotary jet spinning technology – in which a rotating nozzle extrudes an ECM solution into nanofibers that wrap themselves around heart valve-shaped mandrels. "Our setup is like a very fast cotton candy machine that can spin a range of synthetic and natural occurring materials. In this study, we used a combination of synthetic polymers and ECM proteins to fabricate biocompatible JetValves that are hemodynamically competent upon implantation and support cell migration and re-population in vitro. Importantly, we can make human-sized JetValves in minutes – much faster than possible for other regenerative prostheses," said Parker. To further develop and test the clinical potential of JetValves, Parker's team collaborated with the translational team of Simon P. Hoerstrup, M.D., Ph.D., at the University of Zurich in Switzerland, which is a partner institution with the Wyss Institute. As a leader in regenerative heart prostheses, Hoerstrup and his team in Zurich have previously developed regenerative, tissue-engineered heart valves to replace mechanical and fixed-tissue heart valves. In Hoerstrup's approach, human cells directly deposit a regenerative layer of complex ECM on biodegradable scaffolds shaped as heart valves and vessels. The living cells are then eliminated from the scaffolds resulting in an "off-the-shelf" human matrix-based prostheses ready for implantation. In the paper, the cross-disciplinary team successfully implanted JetValves in sheep using a minimally invasive technique and demonstrated that the valves functioned properly in the circulation and regenerated new tissue. "In our previous studies, the cell-derived ECM-coated scaffolds could recruit cells from the receiving animal's heart and support cell proliferation, matrix remodeling, tissue regeneration, and even animal growth. While these valves are safe and effective, their manufacturing remains complex and expensive as human cells must be cultured for a long time under heavily regulated conditions. The JetValve's much faster manufacturing process can be a game-changer in this respect. If we can replicate these results in humans, this technology could have invaluable benefits in minimizing the number of pediatric re-operations," said Hoerstrup. In support of these translational efforts, the Wyss Institute for Biologically Inspired Engineering and the University of Zurich announced today a cross-institutional team effort to generate a functional heart valve replacement with the capacity for repair, regeneration, and growth. The team is also working towards a GMP-grade version of their customizable, scalable, and cost-effective manufacturing process that would enable deployment to a large patient population. In addition, the new heart valve would be compatible with minimally invasive procedures to serve both pediatric and adult patients. The project will be led jointly by Parker and Hoerstrup. Parker is a Core Faculty member of the Wyss Institute and the Tarr Family Professor of Bioengineering and Applied Physics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). Hoerstrup is Chair and Director of the University of Zurich's Institute for Regenerative Medicine (IREM), Co-Director of the recently founded Wyss Translational Center Zurich and a Wyss Institute Associate Faculty member. Since JetValves can be manufactured in all desired shapes and sizes, and take seconds to minutes to produce, the team's goal is to provide customized, ready-to-use, regenerative heart valves much faster and at much lower cost than currently possible. "Achieving the goal of minimally invasive, low-cost regenerating heart valves could have tremendous impact on patients' lives across age-, social- and geographical boundaries. Once again, our collaborative team structure that combines unique and leading expertise in bioengineering, regenerative medicine, surgical innovation and business development across the Wyss Institute and our partner institutions, makes it possible for us to advance technology development in ways not possible in a conventional academic laboratory," 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 SEAS. The Wyss Institute for Biologically Inspired Engineering at Harvard University(http://wyss.harvard.edu) uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana–Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité – Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology. University of Zurich The University of Zurich (UZH) is a member of the League of European Research Universities and numbers among Europe's most prestigious research institutions. UZH's international standing is reflected in the many renowned academic distinctions conferred upon its members, including twelve Nobel Prizes. As Switzerland's largest university, UZH has a current enrollment of over 25,000 students and offers the most comprehensive academic program in the country. Nearly 5,000 excellent members of staff teach and perform research at one of the University's 150 departments, including over 600 professors. UZH also looks back on a rich history, having been founded in 1833 as Europe's first university to be established by a democratic political system. The mission of the Institute for Regenerative Medicine • IREM is advancing molecular life sciences into next generation bio-inspired therapy at the interface of degeneration and regeneration with a major focus on the most relevant human diseases, including neurodegeneration and cardiovascular disease. The Harvard John A. Paulson School of Engineering and Applied Sciences(http://seas.harvard.edu) serves as the connector and integrator of Harvard's teaching and research efforts in engineering, applied sciences, and technology. Through collaboration with researchers from all parts of Harvard, other universities, and corporate and foundational partners, we bring discovery and innovation directly to bear on improving human life and society. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/engineering-heart-valves-for-the-many-300459641.html


News Article | May 18, 2017
Site: phys.org

Today, clinicians use either artificial prostheses or fixed animal and cadaver-sourced tissues to replace defective valves. While these prostheses can restore the function of the heart for a while, they are associated with adverse comorbidity and wear down and need to be replaced during invasive and expensive surgeries. Moreover, in children, implanted heart valve prostheses need to be replaced even more often as they cannot grow with the child. A team lead by Kevin Kit Parker, Ph.D. at Harvard University's Wyss Institute for Biologically Inspired Engineering recently developed a nanofiber fabrication technique to rapidly manufacture heart valves with regenerative and growth potential. In a paper published in Biomaterials, Andrew Capulli, Ph.D. and colleagues fabricated a valve-shaped nanofiber network that mimics the mechanical and chemical properties of the native valve extracellular matrix (ECM). To achieve this, the team used the Parker lab's proprietary rotary jet spinning technology - in which a rotating nozzle extrudes an ECM solution into nanofibers that wrap themselves around heart valve-shaped mandrels. "Our setup is like a very fast cotton candy machine that can spin a range of synthetic and natural occurring materials. In this study, we used a combination of synthetic polymers and ECM proteins to fabricate biocompatible JetValves that are hemodynamically competent upon implantation and support cell migration and re-population in vitro. Importantly, we can make human-sized JetValves in minutes - much faster than possible for other regenerative prostheses," said Parker. To further develop and test the clinical potential of JetValves, Parker's team collaborated with the translational team of Simon P. Hoerstrup, M.D., Ph.D., at the University of Zurich in Switzerland, which is a partner institution with the Wyss Institute. As a leader in regenerative heart prostheses, Hoerstrup and his team in Zurich have previously developed regenerative, tissue-engineered heart valves to replace mechanical and fixed-tissue heart valves. In Hoerstrup's approach, human cells directly deposit a regenerative layer of complex ECM on biodegradable scaffolds shaped as heart valves and vessels. The living cells are then eliminated from the scaffolds resulting in an "off-the-shelf" human matrix-based prostheses ready for implantation. In the paper, the cross-disciplinary team successfully implanted JetValves in sheep using a minimally invasive technique and demonstrated that the valves functioned properly in the circulation and regenerated new tissue. "In our previous studies, the cell-derived ECM-coated scaffolds could recruit cells from the receiving animal's heart and support cell proliferation, matrix remodeling, tissue regeneration, and even animal growth. While these valves are safe and effective, their manufacturing remains complex and expensive as human cells must be cultured for a long time under heavily regulated conditions. The JetValve's much faster manufacturing process can be a game-changer in this respect. If we can replicate these results in humans, this technology could have invaluable benefits in minimizing the number of pediatric re-operations," said Hoerstrup. In support of these translational efforts, the Wyss Institute for Biologically Inspired Engineering and the University of Zurich announced today a cross-institutional team effort to generate a functional heart valve replacement with the capacity for repair, regeneration, and growth. The team is also working towards a GMP-grade version of their customizable, scalable, and cost-effective manufacturing process that would enable deployment to a large patient population. In addition, the new heart valve would be compatible with minimally invasive procedures to serve both pediatric and adult patients. The project will be led jointly by Parker and Hoerstrup. Parker is a Core Faculty member of the Wyss Institute and the Tarr Family Professor of Bioengineering and Applied Physics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). Hoerstrup is Chair and Director of the University of Zurich's Institute for Regenerative Medicine (IREM), Co-Director of the recently founded Wyss Translational Center Zurich and a Wyss Institute Associate Faculty member. Since JetValves can be manufactured in all desired shapes and sizes, and take seconds to minutes to produce, the team's goal is to provide customized, ready-to-use, regenerative heart valves much faster and at much lower cost than currently possible. "Achieving the goal of minimally invasive, low-cost regenerating heart valves could have tremendous impact on patients' lives across age-, social- and geographical boundaries. Once again, our collaborative team structure that combines unique and leading expertise in bioengineering, regenerative medicine, surgical innovation and business development across the Wyss Institute and our partner institutions, makes it possible for us to advance technology development in ways not possible in a conventional academic laboratory," 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 SEAS. Explore further: Clinical study offers new hope for patients with congenital heart disease More information: Andrew K. Capulli et al, JetValve: Rapid manufacturing of biohybrid scaffolds for biomimetic heart valve replacement, Biomaterials (2017). DOI: 10.1016/j.biomaterials.2017.04.033


News Article | May 23, 2017
Site: www.eurekalert.org

(BOSTON) 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 today 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. The Wyss Institute for Biologically Inspired Engineering at Harvard University (http://wyss. ) uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité - Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology.

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