2016 Archived Content

3D Cell Culture: Organoid, Spheroid, and Organ-on-a-Chip Models

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Monday, October 31

7:00 am Conference Registration and Morning Coffee

Opening Plenary Session

8:00 Chairperson’s Opening Remarks

D. Lansing Taylor, Ph.D., Director, University of Pittsburgh Drug Discovery Institute & Allegheny Foundation Professor of Computational and Systems Biology, University of Pittsburgh

8:10 Phenotypic Responses to Small Molecules as a Means to Illuminate Chemistry and Biology

Stuart Schreiber, Ph.D., Director, Center for the Science of Therapeutics, Broad Institute

My lecture will focus on using: modern asymmetric synthesis in generating 3D compounds having novel (previously unknown) mechanisms of action (nMoA) in probe and therapeutics discovery, phenotypic multiplexed measurements to create performance-diverse compound libraries, and real-time biological annotation of synthetic compounds as a means to increase the potential of chemistry to impact biology and medicine. Examples will be selected from cancer and microbial therapeutics discovery.

8:35 Investigating Metastatic Breast Cancer in the Liver Niche through Quantitative Systems Pharmacology

D. Lansing Taylor, Ph.D., Director, University of Pittsburgh Drug Discovery Institute & Allegheny Foundation Professor of Computational and Systems Biology, University of Pittsburgh

We are investigating the mechanism(s) of disease progression of metastatic breast cancer (MBC) using a platform based on quantitative systems pharmacology (QSP). QSP involves an integrated and iterative application of computational and systems biology combined with experimental approaches. A key component of QSP is the development and use of disease relevant experimental models. We have developed a human, microfluidic, 4-cell liver model to explore the mechanisms of extravasation and dormancy in MBC.

9:00 A High-Content Imaging Approach to Characterize and Address Heterogeneity in an Organotypic Model of Human Alveolar Epithelium

Christophe Antczak, Ph.D., Lab Head, Center for Proteomic Chemistry, Novartis Institutes for BioMedical Research

Organoid cell models that recapitulate aspects of tissue organization/ function are of great interest for drug discovery. However, their multicell type and three-dimensional organization presents a challenge for quantitative readouts. We developed methods for confocal image analysis of a spheroid model of human alveolar epithelium that helped characterize and address its heterogeneity, intrinsic to organotypic cultures derived from pluripotent cells.

9:25 Coffee Break in the Exhibit Hall with Poster Viewing

Spheroid Models for Drug Screening

10:10 Chairperson’s Opening Remarks

Hossein Tavana, Ph.D., Associate Professor, Biomedical Engineering, University of Akron

10:15 Multi-Parametric and Molecular Analysis of Oncology Drug Screening with Aqueous Biphasic Tumor Spheroids

Hossein Tavana, Ph.D., Associate Professor, Biomedical Engineering, University of Akron

We present a robotic approach to microprint uniformly-sized tumor spheroids using an aqueous two-phase microtechnology and demonstrate high throughput screening of chemotherapeutics and molecular inhibitors against tumor spheroids of different cancer cells. We introduce a multi-parametric scoring system to rank the effectiveness of compounds and utilize protein expression studies to resolve molecular targets of effective drugs. This microtechnology will facilitate compound screening with realistic tumor models in preclinical drug discovery.

10:40 Attend Concurrent Session


11:05 Use of 3D Airway Organoids from Primary Human Airway Basal Cells in High-Throughput Screening

Marc Hild, Ph.D., Senior Investigator, Novartis Institutes for BioMedical Research

The ability of human airway basal cells to serve as progenitor cells in the conducting airway makes them an attractive target in a number of respiratory diseases associated with epithelial remodeling. We established conditions for the culture of ‘bronchospheres’, three-dimensional (3D) organoids that are derived from primary human airway basal cells. Mature bronchospheres are composed of functional multi-ciliated cells, mucin-producing goblet cells, and airway basal cells. In contrast to existing methods used for the culture of well-differentiated human airway epithelial cells, bronchospheres do not require growth on a permeable support and can be cultured in 384-well assay plates. The system provides a mechanism for investigating the regulation of basal cell fate during airway epithelial morphogenesis, as well as a basis for studying the function of the human airway epithelium in high-throughput qPCR assays.

11:30 Enjoy Lunch on Your Own


1:30 Chairperson’s Opening Remarks

Murat Cirit, Ph.D., Director, Systems Pharmacology, Massachusetts Institute of Technology

1:35 Human Physiome on a Chip: Merging Tissue Engineering and Systems Pharmacology

Murat Cirit, Ph.D., Director, Systems Pharmacology, Massachusetts Institute of Technology

In vitro models have been utilized in various stages for preclinical development. Such models have advantages such as high-throughput capability, low cost, well-controlled experimental parameters and fewer ethical concerns. The simplicity of the conventional in vitro models makes them incapable of achieving adequate physiological relevance for mimicking the human body; however, organ-on-a-chip technologies are dynamic systems that have complex three-dimensional microenvironment and intracellular communications. Hence, there is an urgent need to develop more physiologically relevant in vitro systems responsive to drugs for more reliable in vitro-in vivo translation (IVIVT) from preclinical results to clinical outcomes.

2:00 Predictive Toxicity Testing in a 3D Microphysiological Model of the Human Kidney Proximal Tubule

Edward Kelly, Ph.D., Associate Professor, Pharmaceutics, University of Washington, Seattle

The kidney proximal tubule is the primary site of drug-induced nephrotoxicity. I will describe the development of a three-dimensional flow-directed proximal tubule microphysiological system (MPS). This MPS is an ideal platform for ex vivo modeling of nephrotoxicity. Towards this goal, we have evaluated nephrotoxicity in response to exposure to multiple toxicants, including the heavy metal pollutant cadmium, the antibiotic polymyxin B and the Chinese herbal product aristolochic acid.

2:25 Recapitulating the Tumor Microenvironment for Development of Cancer Therapeutics

Jeffrey T. Borenstein, Ph.D., Laboratory Technical Staff, Biosystems and Tissue Engineering Group, Draper Labs

2:55 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Microscale Bioengineering of Chronic Diseases

Shuichi Takayama, Ph.D., Professor, Biomedical Engineering, University of Michigan

This presentation will describe microengineered culture systems that aim to recapitulate an aspect of detrimental cell-microenvironment interactions that lead to diseases. Some themes that will be discussed include microfluidic studies of tissue disorganization and extracellular matrix invasion, microscale collagen contraction assays for study of fibrosis, and micro-printed inflammatory biomaterials that modulate immune response.

4:10 Dynamic Vascularized Microtissue Models for Drug Development

Craig A. Simmons, Ph.D., Professor, Mechanical & Biomedical Engineering, University of Toronto

While microtissue and organ-on-a-chip models hold great promise to improve the efficacy and efficiency of in vitro drug testing, their incorporation into the drug development pipeline requires a balance between physiological relevance and device utility that has yet to be achieved. I will describe microfluidic platform technologies we are developing to model dynamic vascularized tissues, embodied as standard 96-well microplates to facilitate adoption.

4:35 Miniaturized 3D Cell Cultures on a Micropillar/Microwell Chip for Toxicology Assessment

Moo-Yeal Lee, Ph.D., Assistant Professor, Chemical & Biomedical Engineering, Cleveland State University

Recent advancement in “microarray bioprinting” on a micropillar/microwell chip offers new opportunities for high-throughput screening of compounds on miniaturized 3D-cultured human cells. Nanoscale human cell printing in tunable hydrogels on a robust and flexible chip platform allows us to create micro-tissues, which can be exposed to various stimuli, including compounds, enzymes, and recombinant viruses, and then stained with fluorescent dyes for high-content imaging, ultimately enhancing the predictability of compound toxicity.

5:00-6:00 Welcome Reception in the Exhibit Hall with Poster Viewing

5:45 Short Course Registration

6:00-9:00 Dinner Short Course
(SC1) Introduction to High-Content Phenotypic Screening

Separate registration required

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Tuesday, November 1

7:30 am Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee

High-Content Screening of 3D Models

8:25 Chairperson’s Remarks

Matthias Nees, Ph.D., Coordinator, HCS Lab, Turku Science Park/Finland

8:30 Supporting Phenotypic Drug Screening Efforts with 2D & 3D High-Content Analysis during Early Pharmaceutical Drug Research

Stefan Prechtl, Ph.D., Senior Scientist, Bayer HealthCare AG

Automated imaging systems in combination with sophisticated IT infrastructure meet the needs for high-content analysis (HCA) of large data sets and can efficiently support modern pharmaceutical drug research. By evaluating, analyzing and quantifying the impact of compound treatment under physiological conditions, when it cannot be done by standard screening systems, HCA-driven approaches positively impact the lead-finding process. At Bayer Healthcare, we exploit this technology in several different therapeutic areas ranging from cell signaling via tumor metabolism to epigenetic regulation to support research projects that are aiming for the identification of novel chemical entities. Two-dimensional cell culture systems as well as three-dimensional cell culture systems are routinely used in a wide range of assay methods that are based on immunocytochemistry, reporter gene expression and live-cell imaging. Especially, three-dimensional cell culture systems enable an improved drug research support as these systems mimic the different metabolic microenvironments found in tumors under physiological conditions. A well-established and reliably running HCA facility significantly supports pharmaceutical research. Nevertheless, remarkable challenges not only pop up during the initial setup of such a complex system, they also routinely emerge whenever new assays are developed, and need to be overcome for a consistent HCA-based compound profiling support.

8:55 Fast & Curious: Combining Speed of Analysis with Physiologically Relevant, Complex Tissue Models for Informative High-Content Screening

Matthias Nees, Ph.D., Coordinator, HCS Lab, Turku Science Park/Finland

Model systems for oncology typically do not address the complex tissue architecture of clinical, solid cancers—and only few approaches aim to capture the complexity, heterogeneity and dynamics that occur in the tumor microenvironment. To facilitate this goal, ultrafast, automated image analyses are required that reconcile the needs for significant experimental throughput with an option to faithfully capture the biology of cancers in drug discovery.

9:20 High-Throughput, Open-Source Analysis of Three-Dimensional Structures Using CellProfiler
Allen Goodman, Ph.D., Senior Software Engineer, Broad Institute of Harvard and MIT

9:50 Coffee Break in the Exhibit Hall with Poster Viewing

Organoids and Organotypic Cell Culture

10:40 Chairperson’s Remarks

Shay Soker, Ph.D., Professor, Regenerative Medicine, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine

10:45 Tissue-Engineered 3D Organoids as Models of Development and Disease

Shay Soker, Ph.D., Professor, Regenerative Medicine, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine

3D human tissue organoids replicate native tissue structure and function and thus are superior to traditional 2D cultures and animal models. We are using bioengineered organoids to study liver development and congenital diseases, liver metabolism and liver cancer. Other tissue organoids are used for modeling cancer and the impact of the tumor microenvironment on tumor cell growth and drug response for future use in personalized/precision medicine.

11:10 Alzheimer’s in a Dish: Perspective and Challenges

Doo Yeon Kim, Ph.D., Assistant Professor, Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital/ Harvard Medical School

Recently, we developed a novel 3D human neural cell culture model of Alzheimer’s disease (AD) that recapitulates two key pathogenic events of AD. In this presentation, we will show our follow-up studies including: 1) 3D culture model based on single-clonal human stem cells, 2) analysis of functional deficits in our 3D AD cell models, and 3) our efforts to optimize our 3D AD models into a high-throughput AD drug screening system.

11:35 Organoid-Based High-Content Screening

Xavier Gidrol, Ph.D., Lab Director, CEA/INSERM/UGA

To analyze the phenotypic consequences of genetic perturbation in mammalian cells with drugs, RNAi or expression vectors, there are increasing needs for systematic cell-based high-content screening (HCS) approaches. Although several groups are performing HCS in human cell lines, the real challenge in translational research remains screening on a reduced number of primary cells directly obtained from patients in a microenvironment that would resemble the original tissues. While standard monolayer two-dimensional culture conditions are poor mimics of the cellular environment in situ, microfabricated systems enable three-dimensional organoid cultures and have the potential to provide biological insight not achievable before. We use microfluidics and MEMS (MicroElectroMechanical Systems) to analyze the phenotypic consequences of genetic perturbations (RNAi-based HCS) in 3D organoids. Specifically, we present a novel approach based on a flow-focusing microfluidic system that encapsulates either single prostatic or mammary cell in Matrigel beads and assay for development of organoids. We developed new imaging technology to monitor live organoids self-assembly and inter-organoids cell trafficking.

12:00 pm Close of Conference.

Stay on to attend Screening & Functional Analysis of 3D Models.

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