Stem Cells in Drug Discovery & Toxicity Screening 2018 Agenda

Microphysiological Models for Metastatic Cancer
Roger Kamm, Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering, Massachusetts Institute of Technology (MIT), United States of America

Circulating tumor cells form metastases by reaching a distant microcirculation, undergoing transendothelial migration, entering the remote tissue and proliferating.  Microfluidic assays have been developed to visualize and quantify this process within vascular networks that recapitulate aspects of the in vivo microcirculation.  Tumor cells, with or without accompanying immune cells, are streamed into a vascular network grown in a 3D matrix, some fraction of which arrest and extravasate into the surrounding matrix. These studies provide detailed information on the ability of different tumor cell types to extravasate, the adhesion molecules they use, and the effects of various other cell types in the intravascular and extravascular spaces.  While these models are largely organ-independent, work has also begun to investigate the specificity of certain cancers to metastasize to organs such as the brain.  For this purpose, a model of the blood-brain barrier has been produced, characterized in terms of its morphology and vascular permeability, and then used it to explore extravasation and tumor formation with the brain as the target organ.

Intestine on a Chip for Basic Biology and Patient-Specific Medicine
Nancy Allbritton, Kenan Professor of Chemistry and Biomedical Engineering and Chair of the Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, United States of America

Technical advances are making it possible to create tissue microenvironments on platforms that are compatible with high-content screening strategies. We have developed microfabricated devices to enable culture of organized cellular structures which possess much of the complexity and function of intact intestinal tissue.  Stem-cell culture enables single stem cells or intestinal crypts isolated from primary small or large intestine from humans or mice to grow and persist indefinitely as organotypic structures containing all of the expected lineages of the intestinal epithelium.  Our microengineered arrays and fluidic devices build on this knowledge base to reconstruct millimeter-scale primary intestinal epithelium that closely mimics the polarized 3D in vivo microarchitecture of the intestine Chemical gradients of growth and differentiation factors as well as cytokines are readily applied across the tissues. These bioanalytical platforms are envisioned as next generation systems for assay of microbiome-, drug- and toxin-interactions with the intestinal epithelia. Finally intestinal biopsy samples can be used to populate the constructs with cells producing patient-specific tissues for personalized medicine.

Cell Fiber Technology For 3D Tissue-on-a-Chip Application
Shoji Takeuchi, Professor, Center For International Research on Integrative Biomedical Systems (CIBiS), Institute of Industrial Science, The University of Tokyo, Japan

The talk describes a 3D cell culture method using core-shell hydrogel microfibers (cell fibers). The core is filled with cells and ECM proteins, and the shell is composed of calcium alginate. Since the core diameter is about 100 microns, oxygen and nutrients can be diffused into the central area of the 3D tissue; therefore this culture system allows us to culture the tissue for a long period without central necrosis. Using this culture system, fiber-based tissues such as blood vessels, nerves, and muscles can be formed with in the core. Here, I will discuss the application of the cell fiber technology for various tissue-on-a-chip studies including cardiac tissue, neuro-muscular junctions, and vascularized skin etc.

3D Bioprinting of Soft Tissue: Translation to Clinic
Paul Gatenholm, Professor, Director of 3D Bioprinting Center, Chalmers University of Technology, Sweden; CEO, CELLHEAL AS, Norway, Sweden

3D Bioprinting has a potential to revolutionize regenerative medicine due to unique ability to place multiple cell types in predetermined position and build bottom up the microenvironment to control cellular fate processes. Adult stem cells can be harvested in operating room and combined with biopolymeric hydrogels and 3D bioprinted into desire shape. We have focused our research onto translation of 3D bioprinting technology to clinic. Together with plastic surgeons we are studying preclinical transplantation of 3D bioprinted constructs with stem cells isolated from patient in operating room. The goal is to promote wound healing and repair soft tissue. Translation includes regulatory approved cell isolation protocols and use of regulatory compliant bioinks. We have invented cell-instructive bioinks to be able to control cellular fate processes and to grow vascularized tissue which is of great interest for bringing 3D Bioprinting technology to clinic and space applications.

Industrial Adoption of Integrated Multi-Organ-Chip Solutions
Reyk Horland, CEO, TissUse GmbH, Germany

Microphysiological systems have proven to be a powerful tool for recreating human tissue- and organ-like functions at research level. This provides the basis for the establishment of qualified preclinical assays with improved predictive power. Industrial adoption of microphysiological systems and respective assays is progressing slowly due to their complexity. In the first part of the presentation examples of industrial transfer of single-organ chip and two-organ chip solutions are highlighted. The underlying universal microfluidic Multi-Organ-Chip (MOC) platform of a size of a microscopic slide integrating an on-chip micro-pump and capable to interconnect different organ equivalents will be presented. The second part of the presentation focusses on the challenges to translate a MOC-based combination of four human organ equivalents into a commercially useful tool for ADME profiling and toxicity testing of drug candidates. This four-organ tissue chip combines intestine, liver and kidney equivalents for adsorption, metabolism and excretion respectively. Furthermore, it provides an additional tissue culture compartment for a fourth organ equivalent, e.g. skin or neuronal tissue for extended toxicity testing. Issues to ensure long-term performance and industrial acceptance of such complex microphysiological systems, such as design criteria, tissue supply and on chip tissue homeostasis will be discussed.

Human Pluripotent Stem Cell-derived Cardiomyocytes/Neurons on 3D Micro-Tissue Devices for Matured and Functional Cell Products in Drug Discovery and Screening
Norio Nakatsuji, Chief Advisor, Stem Cell & Device Laboratory, Inc. (SCAD); Professor Emeritus, Kyoto University, Japan

Human pluripotent stem (PS) cells, including ES and iPS cells, are promising sources of various model cells for drug discovery and toxicology screening.  However, there are important (but still unsatisfactory) needs of more matured and functional cells with reliable and low-cost production from human iPS or ES cells. We developed a method of robust and low-cost cytokine-free differentiation of cardiomyocytes from human ES/iPS cells by combination of small chemical compounds.  We also developed low-cost and labor-saving methods for construction of 3D multi-cellular devices with aligned nanofibers for more matured and functional cell device products. Our human iPSC-derived cardiomyocytes or neurons seeded on nanofiber scaffolds form 3D multi-layered structures (Micro-Tissues), which show matured and stable cell/tissue functions. Our Micro-Tissue devices are easy to handle and useful for drug screening and toxicology assays.

Multi-MPS Interactions for Chronic Inflammatory Disease: A Scaling Challenge
Linda Griffith, Professor, Massachusetts Institute of Technology (MIT), United States of America

The pioneering work of Shuler and colleagues over 20 year ago demonstrated the potential for using interconnected MPS for pharmacology and toxicology applications by showing metabolic conversion of a compound in one MPS and downstream effects on a second MPS.  As the role of immunological contributions to drug safety have become more appreciated, the need for more complex immunologically-competent MPS has grown.  This has driven development of more complex MPS that are also potentially valuable for modeling inflammatory diseases. This talk will address technical challenges in modeling complex diseases with  “organs on chips” approaches include the need for relatively large tissue masses and organ-organ cross talk to capture systemic effects, as well as new ways of thinking about scaling to capture multiple different functionalities from drug clearance to cytokine signaling crosstalk. An example of how gut-liver interactions can be parsed at these levels will be featured, along with new approaches for culturing complex 3D tissues with synthetic extracellular matrix and higher-order multi-organ interactions involving immunology.

Incorporating Human Relevant Stem-Cell Derived Cardiomyocytes in Drug Safety Studies: Inspirations and Future Aspirational Goals
Gary Gintant, Senior Research Fellow, Abbvie, United States of America

New applications for human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM’s) continue to challenge users to define best uses for these cells and best practices for more comprehensive drug safety assessments.  This presentation will discuss evolving uses for hiPSC-CMs involving inspirational cellular models and aspirational objectives in support of industrial in vitro cardiac safety screening and evaluations.

Polymers that Control Cells
Mark Bradley, Professor of Therapeutic Innovation, Precision Healthcare University Research Institute, Queen Mary University of London, United Kingdom

The focus of the Bradley group is the application of the tools of chemistry to allow the manipulation, control and understanding of specific biological processes and functions and to address specific biological questions, problems and needs. One piece of work which forms the basis of my talk is polymer microarray technology which has been developed in the Bradley group for over 15 years. For example my group was the first to use polymer microarray technology to discover new polymers that prevent bacterial adhesion (see J. Mater. Chem., 2011, 21, 96).  In my talk I will introduce polymer microarray technology; including our inkjet mediated fabrication methodologies (which allows over 7,000 different substrates to be made on a single glass slide) and describe how this approach has been used in a large number of stem cell based applications.

Human-on-a-chip Systems For Use in Efficacy and Toxicological Investigations in Pre-clinical Drug Discovery Utilizing Stem Cell-derived Disease Models
James Hickman, Professor, Nanoscience Technology, Chemistry, Biomolecular Science and Electrical Engineering, University of Central Florida; Chief Scientist, Hesperos, United States of America

The utilization of multi-organ human-on-a-chip or body-on-a-chip systems for toxicology and efficacy, which ultimately should lead to personalized medicine applications, is a topic that has received much attention recently for drug discovery and subsequent regulatory approval. The considerable attrition-rate of drug candidates at all stages of development to a significant extent arises from the poor predictive nature of preclinical models for efficacy and toxicity, especially the inability to translate efficacy between preclinical and clinical situations. Systems capable of directly measuring organ function, biomarker release, and most importantly the synergistic interactions between organs, especially the generation of liver metabolites would be ideal. Our human-on-a-chip systems utilize function based cell models that accurately capture and predict multi organ complexity in response to administered compound within correctly scaled and physiologically relevant platforms. Our group, in collaboration with Dr. Michael Shuler from Cornell University, has been constructing these systems with up to 6 organs and have demonstrated long-term (>28 days) evaluation of drugs and compounds, that have shown similar response to results seen from clinical data or reports in the literature. Application of these systems for stem cell derived disease models of ALS and Alzheimer’s will be presented.  Cardiac and skeletal muscle mechanistic toxicity and PDPK modeling will also be addressed. Additionally, this talk will give results of six workshops held at NIH to explore what is needed for validation and qualification of these new systems.