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It is recognized that in vitro toxicology studies are complex. Organotypic culture models (OCMs)—tissue models that mimic in vivo tissue architecture through interactions of heterotypic cell types and extracellular matrices—are increasingly being explored for prediction of organ-specific toxicity. As these models become more widely used for chemical and drug toxicity testing, there is a corresponding need to establish standardized testing conditions, endpoint analyses and acceptance criteria. Cambridge Healthtech Institute’s Inaugural Organotypic Culture Models for Toxicology meeting addresses the balanced approach between sample throughput and biological relevance, providing better in vitro tools to replace animal testing and predict human risk assessment.
Sunday, November 16
5:00 pm Short Course Registration and Main Conference Pre-Registration
Monday, November 17
7:00 am Conference Registration and Morning Coffee
8:15 Welcome and Chairperson’s Opening Remarks
Jonathan Garlick, D.D.S, Ph.D., Tufts University
KICKOFF KEYNOTE PRESENTATION
8:25 Personalized Reading and Writing of Organs
George Church, Ph.D., Professor, Genetics, Harvard Medical School; Professor, Health Sciences and Technology, Harvard and MIT; Founding Core Faculty Member, Platform Lead, Synthetic Biology, Wyss Institute for Biologically Inspired Engineering, Harvard University
We need better systems for testing small molecule, protein and nucleic acid therapeutics—ideally personalized organs, as can be achieved via iPSC, ePSC or SCNT-ESCs. One or more variants of unknown significance can be tested for a causal role by using CRISPR genome editing and a variety of simple cell types and complex organs and systems derived by epigenomic reprogramming. This engineering system is especially useful in leveraging the world’s only open-access (with very well-characterized -omic and medical data) human subjects (personalgenomes.org). The faithfulness of the organ system models, as well as their drug responses, can be checked using fluorescent in situ sequencing (FISSEQ).
William Proctor, Ph.D., Genentech
9:05 A Human Kidney Microphysiological System
Jonathan Himmelfarb, M.D., Director, Kidney Research Institute; Joseph W. Eschbach Endowed Chair in Kidney Research; Professor, Medicine, Division of Nephrology, University of Washington
We have designed, implemented and tested a tissue-engineered human kidney microphysiological system. The system is developed to fully evaluate uptake, metabolism and elimination of xenobiotics in a human tissue-derived, in vitro 3-dimensional system that accurately reflects human physiology. The microphysiological system can be used to predict disposition kinetics of xenobiotics and also assess the response to kidney injury inflicted by endogenous and exogenous toxicants.
9:35 Mini-Kidneys Derived from Human Stem Cells
Juan Carlos Izpisua Belmonte, Ph.D., Roger Guillemin Chair and Professor, Gene Expression Laboratories, Salk Institute for Biological Sciences
Human pluripotent stem cells hold great promise for the modeling of disease and toxicology studies upon directed differentiation. The kidney represents an architecturally complex organ responsible for blood toxin clearance. Here we discuss how derivation of functional renal structures in vitro can open unprecedented opportunities for the modeling of kidney disease and general toxicology studies.
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
10:30 Engineering Macroscale 3D Human Cardiac Tissue from hPSCs
Kareen Coulombe, Ph.D., Assistant Professor, Engineering, School of Engineering, Brown University
Regenerating the heart post-injury requires a large, muscular implant contributing contractile force to aid the heart’s pumping action. We are developing 3D engineered tissues of various geometries using cardiomyocytes derived from human pluripotent stem cells to study tissue architecture, cellular phenotype, passive and active mechanical properties and regeneration in a rat model of myocardial infarction. We focus on vascularization and contractility in vivo and design tissues in vitro for translational applications, including toxicology testing.
11:00 Screening Drug-Induced Arrhythmia Events Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Andrew S. Lee, Ph.D., Co-Founder and CSO, Stem Cell Theranostics
Cardiotoxicity is a leading cause of drug attrition during pharmaceutical development and of market withdrawal due to safety concerns. Recent advances in induced pluripotent stem cell (iPSC) technology have allowed the generation of cardiomyocytes that can be used to model drug-induced cardiotoxicity. We describe a novel iPSC platform that utilizes patient-specific cardiomyocytes for personalized prediction of cardiac drug toxicity in patient subpopulations with a history of cardiovascular disease.
11:30 Micro- and Nanotechnologies for 3D Cardiac Tissue Constructs with Functionalized Nanoparticles
Su-Ryon Shin, Ph.D., Instructor, Medicine, Harvard Medical School
The development of highly organized and functional 3D complex constructs in vitro is important in tissue engineering. In particular, heart muscles are dense quasi-lamellar and highly vascularized tissues in which functional syncytia of the cardiomyocytes are tightly interconnected with gap junctions. To address these challenges, we are developing a novel approach that combines nanoparticles and microfabrication techniques to create dense and highly organized 3D cardiac tissue constructs with biomimetic electrophysiological function.
12:15 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:30 Chairperson’s Remarks
Rosemarie Hunziker, Ph.D., Director, Tissue Engineering and Regenerative Medicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health
1:35 2D Versus 3D: When to Make the Switch
Christopher S. Chen, M.D., Ph.D., Professor, Biomedical Engineering, Boston University and Wyss Institute for Biologically Inspired Engineering, Harvard University
The structure, mechanics and dimensionality of an extracellular matrix have fundamental effects on the phenotype of mammalian cells. This presentation examines how these physical cues can drive cell signaling and function, and how we can use these insights to develop in vitro cultures that better mimic in vivo biology for both discovery and development applications.
2:05 Human iPSC-Derived Tissues in Complex Organotypic Culture Systems for Predictve Toxicity Assessment
David Mann, Ph.D., Product Manager, Cellular Dynamics International
Stem cell technology affords a limitless, consistent supply of tissues, including: cardiomyocytes, hepatocytes, neurons, and endothelial cells. Bioengineered culture systems add complexity via dimensionality, scaffolding, flow, and co-culture. Coupling iPSC-derived tissues with organotypic culture systems synergizes to advances predictive in vitro toxicity.
2:35 Organotypic Three-Dimensional Tissue Models
Heike Walles, Ph.D., Chair and Head, Regenerative Therapies, Tissue Engineering and Regenerative Medicine and Fraunhofer IGB Project Group, University Hospital Würzburg
Our group has been committed to the development of alternative human test systems that reflect the body’s complex characteristics. We have succeeded in building up skin equivalents that can be extended by other cells. Moreover, we have established a trachea and an intestine tissue model as different tumor model systems. To ensure culture conditions that are similar to the cells’ natural environment in the body, specific bioreactor systems have been developed.
3:05 Refreshment Break in the Exhibit Hall with Poster Viewing
3:45 Organs-on-Chips to Screen for Drug Efficacy and Toxicity
Kristin Fabre, Ph.D., Scientific Program Manager, NCATS, National Institutes of Health
The Microphysiological Systems Program, comprised of an MPS Consortium of academic and government entities, aims to bioengineer platforms (or chips) that mimic human organ systems. These platforms help predict efficacy and toxicity of candidate compounds faster, cheaper and with fewer animal models than current methods. The project’s goal is to incorporate human iPSC-derived cell sources (inducible pluripotent stem cells) into corresponding organ modules and create an integrated Human-on-a-Chip to study drug response within human bodies.
4:30 Organs-on-Chips: Highly Functional Microphysiological Systems to Predict Human Physiology and Pathobiology
Geraldine A. Hamilton, Ph.D., Senior Staff Scientist, Wyss Institute for Biologically Inspired Engineering, Harvard University
This presentation focuses on our novel biomimetic microsystem technologies and their potential application in predicting efficacy, safety and mechanism of action for new drugs, chemicals and cosmetics. Human organs-on-chips provide exciting new approaches to attack fundamental questions in biology and develop smart in vitro surrogates. This technology also offers a more human-relevant alternative to current animal-based approaches for disease model development.
5:15 Welcome Reception in the Exhibit Hall with Poster Viewing
6:15 Short Course Registration
Tuesday, November 18
8:00 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
James J. Hickman, Ph.D., University of Central Florida
8:35 iPSC-Derived Hepatic Model Systems for Investigating Mechanisms of IDILI
Jingtao Lu, Ph.D., Research Scientist, National Exposure Research Laboratory, Environmental Protection Agency
Induced pluripotent stem cell-derived hepatocytes (iHC) were assessed as a drug-induced liver injury model. iHCs were comparable to primary human hepatocytes (pHH) in architecture, gene expression profiles, CYP activities and sensitivities to multiple model hepatotoxins. In the study of isoniazid (INH)-induced idiosyncratic liver injury (IDILI), iHCs showed pHH-like sensitivity towards INH-mediated cytotoxicity, protein adduction and mitochondrial toxicity. Combined results support iHCs as a promising new hepatic model to investigate IDILI mechanisms.
9:05 Biomimiks as Chemosynthetic Livers
Mukund S. Chorghade, Ph.D., CSO, Empiriko Corporation
Our proprietary technology mimics metabolism of chemical entities for pharmaceuticals, enables prediction of metabolism patterns and introduces new paradigms for drug discovery and drug-drug interactions. Our catalysts provide speed, stability and scalability. We predict structures of metabolites, prepare them on scale and elucidate chemical structures. Comprehensive safety evaluation enables complete metabolism studies, confirmation of structure and quantitative measures of toxicity. This is an animal-free platform for safety-relevant metabolites.
9:35 Three-Dimensional Human Small Intestine Models for ADME-Tox Studies
Jiajie Yu, Ph.D., Research Scientist, Linda Griffith Laboratory, Biological Engineering, Massachusetts Institute of Technology
In vitro cell-based human small intestine models have been widely used in drug preclinical development. However, these traditional models could provide misleading results due to their relatively poor recapitulation of small intestine physiology. This presentation focuses on recent breakthroughs of developing more physiological in vitro human small intestine models as well as their impacts on preclinical ADME-Tox studies.
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Evaluation of Spherical 3D Liver Microtissues for Assessing Cytotoxicity of Small and Large Molecules
William Proctor, Ph.D., Scientist, Investigative Toxicology, Safety Assessment, Genentech
Drug-induced liver injury is a major cause of clinical attrition. Spherical liver microtissues provide a stable 3D co-culture model to assess cytotoxicity over treatment durations not achievable with conventional hepatocyte cultures. Accordingly, this model is a promising tool for evaluating hepatotoxicity risk for both small and molecules and antibody-drug conjugates.
11:15 Body-on-a-Chip Systems for Toxicological Evaluations
James J. Hickman, Ph.D., Professor, NanoScience Technology, Chemistry, Biomolecular Science and Electrical Engineering, University of Central Florida
Replacing animals in toxicology and drug discovery with integrated functional organ constructs in a serum-free defined system composed of human cells will greatly reduce the cost and increase the relevance of these studies. Furthermore, utilizing functional human models in both 2D and 3D systems will facilitate both acute and chronic compound evaluations for toxicological applications that are not currently possible in vitro.
CLOSING KEYNOTE PRESENTATION
11:45 Scaling and Systems Biology for Integrating Multiple Organs-on-a-Chip
John P. Wikswo, Ph.D., Founding Director, Vanderbilt Institute for Integrative Biosystems Research and Education and Gordon A. Cain University Professor, Vanderbilt University
Determination of the toxicity of drugs, consumer products and industrial chemicals will benefit from quantitative systems approaches to pharmacology and toxicology. By supporting heterogeneous cell populations and complex 3D extracellular matrices, tissue-engineered organs-on-chips and human organ constructs provide in vitro organotypic culture models for tissue-scale toxicology that are more realistic than static, planar, monolayer, immortal monocultures. Properly coupled, they create a new class of in vitro microphysiological systems models. Dr. Wikswo was recently published in Experimental Biology and Medicine, a Sage Publication, on The relevance and potential roles of microphysical systems in biology and medicine.
12:30 pm Close of Engineering Functional 3D Models and Organotypic Culture Models for Toxicology Conferences