Abstract

Blood vessels exhibit a range of structural and functional differences, contain a range of matrices and even specialized accessory cells that align with the specific needs of the tissue in which they reside. To study and recapitulate the highly complex behavior of blood vessels, we explore the three-dimensional (3D) assembly of microvascular networks (MVNs) from multiple cells in vitro. Using a three-channel microfluidic device design we co-cultured human umbilical vein endothelial cells (HUVECs) with either normal human lung fibroblasts (NHLFs), pericytes (PCs), smooth muscle cells (SMCs), or both PCs and SMCs in 3mg/mL fibrin gels and measured their assembly dynamics, morphology, length scales, branching, and tortuosity over time. Results find that HUVECs cultured with both human SMCs and human PCs generate the smallest MVNs ~30mm in diameter that are also stable for over 2 months. Furthermore, after 21 days, these MVNs began exhibiting angiogenic activity. To our knowledge, this is the longest demonstrated stability and the first example of the generation of perfusable microvasculature enabling an initial vasculogenesis phase, a stability phase, and then subsequent angiogenesis activity.

Bio

Dr. Kara E. McCloskey, PhD, is a Founding Professor at the University of California, Merced in the Chemical and Materials Engineering (CME) Department and Fellow with the American Institute of Medical and Biomedical Engineering (AIMBE). She received her degrees in Chemical Engineering from The Ohio State University and Biomedical Engineering Department at The Cleveland Clinic Foundation and was an NIH-NRSA postdoctoral fellow at Georgia Institute of Technology. Early in her career, Dr. McCloskey was awarded a New Faculty Award from the California Institute of Regenerative Medicine (CIRM) is the Program Directors for a CIRM-funded Training Program in Undergraduate Stem Cell Engineering and Biology (TUSCEB) and the UC Merced Shared Resource Facility (SRL). She has been Founder and Chair of Graduate Program in Biological Engineering and Small-scale Technologies (BEST) and Materials and Biomaterials Science and Engineering (MBSE), and lead for a new B.S. degree in Chemical Engineering. Dr. McCloskey has participated in numerous NSF-funded research centers (CREST-CCBM, STC-CEMB, STC-EBICS and ERC-TARDISS). She is known for her work in directing and characterizing endothelial cells (EC) from embryonic stem cells (ESCs) and induced-pluripotent stem (iPS) cells. She has co-authored over 50 peer-reviewed journal articles in areas from magnetic cell separation, stem cell differentiation, and tissue assembly. She is currently focusing her efforts examining cell-material interactions for developing functional tissues.

Abstract

In this presentation, I will provide a comprehensive technical overview of the innovative organ-on-a-chip (OOC) systems currently being developed at Lawrence Livermore National Laboratory (LLNL). These advanced systems aim to replicate the complex biological functions of human organs, offering a promising alternative to traditional in vitro and in vivo models for drug testing and disease modeling. Our OOC platforms integrate various biofabrication techniques to engineer microscale environments that mimic the structural and functional properties of human tissues. Key technologies include 3D bioprinting, microfluidic fabrication, and biomaterials development. These methods allow us to create precise tissue constructs with controlled architectures, vascular networks, and cellular microenvironment.

Bio

Dr. Monica Moya is a Group Leader and biomedical engineering researcher at Lawrence Livermore National Laboratory. Currently she works as the principal investigator and as a technical lead on several bioengineering projects including 3D bioprinting of vascularized human tissues. Prior to working at Lawrence Livermore National Laboratory, she worked at UC Irvine as a National Institutes of Health (NIH) Ruth Kirschstein-NRSA Fellow. While at UC Irvine, she developed a novel microfluidic-based system of metabolically active stroma with culture medium-perfused human capillaries. Her current work focuses on developing 3D models of cerebral vasculature for studying COVID and traumatic brain injuries. Her research has resulted in over 30 peer-reviewed publications, two book chapters, and numerous national and international conference presentations.

Abstract

Three-dimensional (3D) organotypic tissue models are reshaping the landscape of biomedical research and pre-clinical testing. By addressing the inherent limitations of traditional animal models, organ-on-a-chip and Microphysiological systems are enabling more accurate investigations of complex human diseases, such as cancer. These innovative platform technologies are also significantly advancing the drug discovery process, offering scalable, high-throughput systems that streamline the assessment of drug efficacy across a broad range of compounds. In this talk, Dr. Nikkhah will present his laboratory's interdisciplinary efforts to advance organotypic tissue-on-chip platforms by integrating microfluidics, state-of-the-art biomaterials, and single-cell analyses. This research aims to develop next-generation, physiologically relevant systems for disease modeling and therapeutic testing. Special attention will be given to the lab's work in constructing tumor microenvironment (TME) models, designed to capture key stages in the metastatic process. Additionally, the seminar will briefly discuss the creation of a 3D vascularized human stem cell-derived tissue-on-chip model, a platform aimed at unraveling the mechanisms behind cardiovascular and cerebrovascular diseases.

Bio

Mehdi Nikkhah is currently an Associate Professor of Biomedical Engineering at the School of Biological and Health Systems Engineering (SBHSE), Arizona State University (ASU). He completed his postdoctoral fellowship training at Harvard Medical School and Brigham and Women’s Hospital. He received his B.S. in mechanical engineering and M.S. degree in biomedical engineering from Tehran Polytechnic University followed by Ph.D. degree in mechanical engineering from Virginia Tech. Dr. Nikkhah has published more than 80 journal articles (+11,000 citations, H-index of 48), 8 book chapters and 100 peer-reviewed conference papers and holds 10 US patents and invention disclosures.  Throughout his career, he has received numerous prestigious awards and recognitions, including the induction into the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows, National Academy of Inventors (NAI) Senior Membership, Arizona Flinn Foundation Award, ASU Biomedical Engineering Outstanding Assistant Professor Award, NSF CAREER Award, and so forth. In addition to his research endeavors, Dr. Nikkhah has been very passionate and deeply committed to educating the next generation of students and scholars, with a particular focus on minority and underrepresented groups in science and engineering. He has trained over 70 individuals, including postdoctoral fellows, PhD/MS students, and undergraduate researchers, from diverse backgrounds in his lab.

Abstract

The success rate of translating drugs from the laboratory setting to effective patient therapies is alarmingly low. To improve our understanding of tumor progression and drug efficacy, it is vital to develop preclinical tumor models that capture the intricate and dynamic characteristics of cancer. In response, we developed colorectal cancer (CRC) organoids-on-chips (OOCs) that better mimic patient-specific CRC biology and the tumor microenvironment. These 0OCs feature dual channels for epithelial and endothelial cells, and simulate in vivo mechanical forces such as fluid shear stress and peristalsis-like motions. The OOCs capture diverse patient characteristics and show transcriptomic profiles more similar to patient tissues than organoids alone. By incorporating immune cells, we also modeled immune-tumor interactions, providing deeper insights into cancer biology. This research highlights critical interactions between colorectal cancer cells and their microenvironment, offering valuable insights for drug testing and potential strategies that can prevent or delay cancer progression.

Bio

Shannon Mumenthaler, PhD, is the Chief Translational Research Officer at the Ellison Institute, where she has significant experience overseeing and developing interdisciplinary translational research programs. She also holds faculty appointments at the University of Southern California as an Associate Professor in Medicine and Biomedical Engineering. Dr. Mumenthaler specializes in quantitative cell biology, using a systems biology approach to explore the tumor microenvironment and its role in disease progression. Her multidisciplinary research program focuses on unraveling how the physical and cellular landscapes influence colorectal cancer and treatment outcomes. By developing and utilizing physiologically relevant tumor models, she creates a platform for studying cancer cell dynamics and evaluating targeted therapeutic strategies.

Abstract

Cardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.

Bio

Dr. Arun Sharma, PhD is a stem cell biologist focusing on cardiovascular biology and space biosciences. He is an assistant professor at Cedars-Sinai and is affiliated with the Board of Governors Regenerative Medicine Institute, the Smidt Heart Institute, the Cancer Institute, and the Department of Biomedical Sciences. Research in the Sharma laboratory focuses on the applications of human induced pluripotent stem cells (hiPSCs) for modeling cardiovascular diseases outside of the body (in-vitro). The lab utilizes cutting-edge technologies including hiPSCs, genome editing, cardiac organ-on-chips, and 3D cardiac spheroids/organoids to understand the molecular mechanisms driving cardiovascular disease and heart development. For example, the Sharma laboratory employs hiPSC-derived cardiomyocytes (personalized, beating heart muscle cells) to develop novel ways to alleviate the cardiovascular damage caused by cancer drugs. The lab also studies the developmental mechanisms underlying congenital heart disease, as well as examines the impact of infections on the cardiovascular system, such as in the setting of COVID-19. Sharma also has a unique background and interest in the space biosciences and investigates means by which stem cell biology can intersect with this emerging field. In 2016, Dr. Sharma led a project that sent human stem cell-derived heart cells to the International Space Station to study the effects of microgravity on human heart function, which was the first long-duration cell culture experiment in space. He remains an internationally-recognized leader in the space biosciences field, and his laboratory studies means of harnessing microgravity to manufacture unique biomaterials. Sharma has published articles in leading scientific journals such as Science, Nature Biotechnology, Science Translational Medicine, Circulation Research, Nature Reviews, Stem Cell Reports, and Cell Stem Cell. His research has been featured in major news outlets such as Forbes Magazine, Newsweek, Science Magazine, and the Wall Street Journal. He has received numerous awards for his work, including the Forbes 30 Under 30 in Science, STAT Wunderkinds, Sartorius & Science Award in Regenerative Medicine, the American Heart Association Career Development Award, the Compelling Results Award from NASA, and the Donna and Jesse Garber Award for Cancer Research. Dr. Sharma earned his bachelor’s degree in biology from Duke University and his PhD degree in stem cell biology from Stanford University. He completed a postdoctoral research fellowship in cardiovascular genetics at Harvard Medical School. He is also an advocate for conveying science to general and scientific audiences through public speaking and social media.

Abstract

MIMETAS strives to contribute to groundbreaking therapies with unique human disease biology, revealed by robust, screenable assays in the most versatile technology platform.  By leveraging our OrganoPlate and OrganoReady platform, we have been partnering with various organizations in both academia and industry to discover and develop next generation therapeutics.  This presentation will provide an introduction about Mimetas, its product offerings, and highlight key modeling applications and read-outs produced through its collaborative research.

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Abstract

“Organ on Chip” (OOC) systems have been actively developed for nearly twenty years, and have now entered the mainstream of scientific tools to explore biology.  Our lab began with the creation of 3D perfusable vascular networks, and then extended our interests into modeling the cancer microenvironment, bone marrow, immune cell trafficking, and most recently the transport of extracellular vesicles (EVs).  This talk will review briefly some of the seminal contributions that have spurred the field of OOC, then transition into a description of some of the systems my lab has created.  The talk will end with a discussion of EVs and how OOC can provide new and impactful insights.  In brief, EVs are small (50-150 nm diameter) composite particles secreted by cells and comprised of a lipid-based membrane surrounding an aqueous core.  The membrane and core can each incorporate a wide range of molecules (e.g., proteins, nucleic acids) that can impact cellular function; thus, EVs can impact in vivo biology, but have also generated significant excitement for their potential theranostic (therapeutic and diagnostic) applications in cancer. How EVs are transported (convection, diffusion, and binding) across biological barriers including the vascular endothelium and extracellular matrix is poorly understood.  Our early work demonstrates that a subpopulation of EVs are transported across the endothelium using receptor-mediated transcytosis, and predominantly by convection (not diffusion) through the extracellular space. Examination of EV transport across biological barriers will not only enhance our understanding of the dynamic tumor microenvironment, but also provide the framework to design artificial nanovesicles as novel drug delivery vehicles.

Bio

Steven C. George, M.D., Ph.D. is the Edward Teller Distinguished Professor and Chair of the Department of Biomedical Engineering at the University of California, Davis. He received his bachelors degree in chemical engineering in 1987 from Northwestern University, M.D. from the University of Missouri School of Medicine in 1991, and Ph.D. from the University of Washington in chemical engineering in 1995.  He was on the faculty at the University of California, Irvine for 19 years (1995-2014) where he pursued a range of research interests including pulmonary gas exchange, lung mechanics, vascularizing engineered tissues, and microphysiological systems (“organ-on-a-chip”). The NIH FIRST award in 1998 and the CAREER and Presidential Early Career Award for Scientists and Engineers (PECASE) from the National Science Foundation in 1999 have previously recognized his work.  While at UCI, he served as the William J. Link Professor and founding Chair of the Department of Biomedical Engineering (2002-2009), the founding Director of the Edwards Lifesciences Center for Advanced Cardiovascular Technology (2009-2014), and was the founding PI on a T32 predoctoral training grant from the National Heart Lung and Blood Institute entitled “Cardiovascular Applied Research and Entrepreneurship” (CARE).  In 2014 he transitioned to become the Elvera and William Stuckenberg Professor and Chair of Biomedical Engineering at Washington University in St. Louis, and in 2017 moved to the UC Davis.  He became Chair of the department in January 2019.  He was elected a fellow in the American Institute of Medical and Biological Engineering (AIMBE) in 2007, a fellow of the Biomedical Engineering Society in 2017, a fellow of the International Academy for Medical and Biological Engineering (IAMBE) in 2021, has published more than 160 peer-reviewed manuscripts, and has co-founded an early and active start-up company (Aracari Biosciences in 2019).  His work is currently funded by grants from the NIH that focus on creating microfluidic models of the pancreas, bone marrow, cancer, and immune microenvironments to address questions related to immune cell and extracellular vesicle trafficking.

Abstract

The Blood-Brain Barrier (BBB) is a crucial biological barrier that regulates the interface between blood circulation and the central nervous system (CNS), serving both as a physical and metabolic barrier. In vitro models of the human BBB are essential for advancing drug development and studying neurovascular pathology. SynVivo has created a physiologically relevant 3D human BBB-on-a-Chip model utilizing primary and iPSC-derived cells to replicate key components of the BBB. This model demonstrates barrier integrity comparable to in vivo conditions and significantly surpasses the performance of static models, such as Transwell BBB systems. Flow-based models exhibit enhanced expression of tight junction proteins and transporters, leading to improved barrier tightness. Our findings indicate that SynBBB effectively mimics the physiological characteristics of the in vivo BBB, providing a more predictive platform for evaluating the transport of biotherapeutics across the barrier. This presentation will explore the SynBBB model's applications in assessing drug permeability—from small molecules to biologics—as well as its role in studies of neuroinflammation and receptor-mediated transcytosis. Additionally, we will discuss a blood-brain-tumor barrier model designed to evaluate CAR-T cytotoxicity and neurotoxicity.

Bio

Dr Gwen Fewell is a neuroscientist by training and has spent the last 15 years in product development and commercialization at start-up, mid-size to large life science research tools companies. She is the President & CEO at SynVivo, an Organ-on-Chip company with proprietary microfluidic based 3D Tissue and Organ-on-Chip models for drug development and personalized medicine applications.

Dr Fewell earned an M.S in Neurophysiology from University of Mumbai and a PhD in Neuroscience at Florida State University. She performed postdoctoral studies at Children's Hospital, Cincinnati exploring the genetic role of homeobox genes in brain development and later studied the genetics of pediatric medulloblastoma in the Department of NeuroOncology at MD Anderson Cancer Center in Houston, TX.

Dr Fewell has a wealth of experience driving commercial strategy at both startup and large companies. Previously she led global product marketing of the RNAi and Gene Expression portfolio at Thermo Scientific Genomics and was Director of Product Marketing at Open Biosystems (acquired by Thermo Fisher Scientific) where she led product management and marketing teams with responsibility for commercializing new gene modulation products including the first vector-based RNAi whole genome product on the market. She has spent her career working with teams that are on the leading edge of innovation and technology within the life sciences to accelerate research and innovation in health and medicine. and commercial operations and currently serves on the Board of Directors. Dr Fewell was awarded the 2014 State of Alabama Innovation Award for Outstanding Woman in Innovation. She currently also serves on the Board of Directors at BioAlabama whose mission is to connect the bioscience ecosystem in Alabama.