Inadequate representation of the human tissue environment during a preclinical screen can result in inaccurate predictions of compound effects. Thus, pharmaceutical investigators are searching for preclinical models that closely resemble original tissue for predicting clinical outcome. Three-dimensional cell culture recapitulates normal and pathological tissue architectures that provide physiologically relevant models to study normal development, disease, and drug response. However, challenges remain for screening as researchers must procure large numbers of identical 3D cell cultures, develop assays and obtain fast, automated readouts from these more complex assays. Join cell biologists, tissue engineers, assay developers, screening managers and drug developers at Cambridge Healthtech Institute’s Third Annual 3D Cellular Models: Engineering Predictive Preclinical Screening Models conference as they discuss strategies that accelerate the identification of novel therapeutic leads.

Final Agenda

Wednesday, June 14

11:00 am Registration

12:00 pm Bridging Luncheon Presentation: 3D Bioprinted Tissue Models for Predictive Toxicology and Disease Modeling

Jeff Irelan, Ph.D., Director, Scientific Applications, Tissue Operations, Organovo

Translation of preclinical data to clinical outcomes remains a challenge in drug development. Organovo’s ExVive™ 3D Bioprinted Human Liver and Kidney Tissues are positioned to bridge the gap by providing tissue-like responses in vitro through spatially-controlled, automated deposition of cells. Multicellular tissues preserve native cellular interactions for assessment of biological responses at the biochemical, transcriptional, and histological levels. Examples of toxicological applications and capacity for disease modeling will be discussed.

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing

1:30 PLENARY KEYNOTE SESSION

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

3D MODELS: STEM CELL SOURCES

4:15 Chairperson’s Opening Remarks

Claudia McGinnis, Ph.D., Principal Scientist & Group Leader, Pharma Research and Early Development, Pharmaceutical Sciences, Mechanistic Safety, Roche Innovation Center Basel

4:25 Stem Cell-Derived Kidney Models for Drug Discovery

Piyush Bajaj, Ph.D., Senior Scientist, Drug Safety R&D, Investigative Toxicology Group, Pfizer

I discuss the current state of in vitro kidney models in support of drug discovery. Advances in both 2D and 3D models – specifically using organoid-based culture and organ-on-a-chip technologies – will be presented. Finally, we highlight ongoing efforts to leverage pluripotent stem cells to develop a physiologically relevant in vitro human kidney model that has been characterized in terms of drug transporter function and sensitivity to known nephrotoxicants.

4:55 Modeling Neurological Diseases Using Human-Induced Pluripotent Stem Cells

Shawn Je, Ph.D., Assistant Professor, Program in Neuroscience and Behavioral Disorders, Duke-National University of Singapore Medical School

The ability to make functional neural cells from human pluripotent stem cells (hPSCs) provides a unique opportunity to study human brain development and neurological disorders. I present recent findings from our laboratory – 1) the direct induction and functional maturation of forebrain glutamatergic and GABAergic neurons from hPSCs, 2) the generation of midbrain-like organoids from hPSCs, and 3) their utilities in modeling human neurological disorders.

  5:25 Overcoming Barriers to High Throughput Single Cell Clonal Culture

Michael Hiatt, Scientist, Research & Development, STEMCELL Technologies, Inc.

Traditional methods of deriving clonal cultures offer a choice between low-throughput techniques, or more rapid methods that may sacrifice true clonality. Ensuring clonality in 3D sphere-forming assays is particularly challenging. We will present a novel workflow for high-throughput clone derivation in non-adherent 3D cultures. This method is ideally suited to gene editing or cancer sphere-forming assay applications.

5:40 Nortis’ Organ-on-Chip Technology: Human Tissue Microenvironments for Basic Research, Drug Toxicology & Efficacy Testing

Henning Mann, Ph.D., Scientific Director, Nortis, Inc.

The Nortis system is a novel, commercially available technology allowing to recapitulate units of human organs in microfluidic chips, providing in-vivo like cues to guide tissue architecture and function. Developed organ models include vasculature, kidney and liver models for toxicology studies, blood-brain barrier models for drug transport studies, and vascularized tumor/tissue microenvironment models for drug efficacy studies. Our aim is to substantially improve in-vitro predictability of clinical outcome.

5:55 Automated 3D Stem Cell Profiling of Drug Candidates for Identification of Developmental Toxicity

Claudia McGinnis, Ph.D., Principal Scientist & Group Leader, Pharma Research and Early Development, Pharmaceutical Sciences, Mechanistic Safety, Roche Innovation Center Basel

Embryonic stem cells, and their ability to differentiate in vitro, are an essential 3D model for in vitro developmental toxicity approaches. We routinely use this approach to profile our early drug candidates to deprioritize compounds with the highest risk of in vivo findings. We have recently fully automated this 3D assay, which proved to be a highly challenging project, and this presentation will cover the most important milestones and results from this effort.

6:25 Close of Day

6:30 Dinner Short Course Registration

Thursday, June 15

7:00 am Registration Open and Morning Coffee

7:30 Interactive Breakout Discussion Groups with Continental Breakfast

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants.

Applications of Microfluidic Systems for Drug Discovery and Validation

Moderator: Mohammad F. Kiani, Ph.D., FAHA, Professor, Mechanical Engineering, Bioengineering, and Radiation Oncology, Temple University

• Developing microfluidic systems with representative architecture/microenvironment
• Validating data from microfluidic systems against in vivo data
• Validating data from microfluidic systems against human data
• Endpoint assays/real-time visualization
• Use of microfluidic data to gain FDA approval

Use of Organ-on-a-Chip Technologies for Drug Discovery

Moderator: Piyush Bajaj, Ph.D., Senior Scientist, Drug Safety R&D, Investigative Toxicology Group, Pfizer

• Use of iPS or genetically modified cell lines in organ-on-a-chip devices vs. primary cells
• Making the platforms more compatible for drug discovery – increasing the throughput, reducing the footprint
• Costs involved in the fabrication and the feasibility of using these technologies for compound screening
• Robustness, reproducibility, ease of use of these systems by other scientists

Identify the Requirements that Would Determine Quantitatively Whether an MPS Is Superior to Existing in vitro and Animal Assays

Moderator: John P. Wikswo, Ph.D., Founding Director, Vanderbilt Institute for Integrative Biosystems Research and Education and Gordon A. Cain University Professor, Vanderbilt University

• How extensive a transcriptomic and proteomic comparison is required?
• Would the addition of metabolomics and phospho-proteomics inform the validation of MPS assays and extend their utilization?
• How might weighted gene co-expression network analysis, as has been done for rat and mouse liver and rat hepatocytes-in-a-dish, be used to validate MPS models?
• Should the known genetic differences amongst the various BXD recombinant inbred murine strains be used to create diverse mouse-on-chip MPS systems?

3D MODELS: MICROENGINEERED CHIPS

8:35 Chairperson’s Remarks

Jose A. Lebron, Ph.D., Executive Director, Investigative Laboratory Sciences, Safety Assessment & Laboratory Animal Resources, Merck & Co., Inc.

8:45 KEYNOTE PRESENTATION: The Need for Analytical Chemistry and Multi-Omics for Understanding the Physiology and Pathology of 3D Cellular Models: Examples from the Neurovascular Unit/Blood-Brain Barrier

John P. Wikswo, Ph.D., Founding Director, Vanderbilt Institute for Integrative Biosystems Research and Education and Gordon A. Cain University Professor, Vanderbilt University

We review how validation of a microphysiological system (MPS) as an effective recapitulation of the organ it models could affect the design, operation, and testing of organ chips. We consider how MPS validation would benefit from a mouse-on-a-chip, for example by allowing a proteomic, transcriptomic, and metabolomic comparison of a mouse brain with both transwell and microfluidic neurovascular units. These tools can then be applied to assess disease models.

9:15 Bioprinted Renal Tubules on Perfusable Chips

Kimberly Homan, Ph.D., Research Associate, Lewis Research Group, Wyss Institute for Biologically Inspired Engineering, Harvard University

Three-dimensional models of kidney tissue that recapitulate human responses are needed for drug screening, disease modeling, and, ultimately, kidney organ engineering. We present a bioprinting method for creating functional 3D human renal proximal tubules in vitro. This in vitro model system allows customization by printing perfusable vasculature and multiple cell types in predefined locations, enabling both drug screening and drug toxicity mechanistic studies at user-defined levels of complexity.

9:45 A Microfluidic Model of Transport Tissues for 96-Well Format Screening of Therapeutics

Joseph Charest, Ph.D., Program Manager, Biomedical Solutions, Draper

Preclinical screening for therapeutics will become more predictive when in vitro models express organ- or tissue-specific function. Our model uses controlled microfluidic fluid flow, cell-substrate topography, and cell-cell cues to guide cells to form tissue with organ-specific function. A 96-well format scales the model to high levels of throughput and integrated electrical traces provide near real-time data collection of barrier function.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 Instrumented Cardiac Microphysiological Devices Fabricated by Multimaterial 3D Printing

Johan Ulrik Lind, Ph.D., Research Associate, Disease Biophysics Group, John A. Paulson School of Engineering and Applied Sciences, Wyss Institute for Biologically Inspired Engineering, Harvard University

Microphysiological systems promise to accelerate biomedical research by providing accurate in vitro models of human tissue. However, device instrumentation and fabrication remain severe obstacles. Here, we present a multimaterial 3D printing methodology for fabricating cardiac microphysiological devices with built-in sensors. The platform allows non-invasive and scalable readouts of the contractile stress and beat rate of multiple cardiac microtissues, to support higher throughput drug dose response studies, and long-term experiments. March 2017 Speaker Interview

11:30 KEYNOTE PRESENTATION: The NIH Tissue Chips for Drug Screening Program: Improving Health through Smarter Science

Danilo A. Tagle, Ph.D., MS, Associate Director, Special Initiatives, Office of the Director, National Center for Advancing Translational Sciences (NCATS), NIH

Tissues-on-chips involves the development of 3D platforms engineered to support living human tissues and cells, and are designed as accurate models of the structure and function of human organs, such as the lung, liver and heart. Researchers can use these models to predict whether a candidate drug, vaccine or biologic agent is safe or toxic in humans in a faster and more effective way than current methods.

12:00 pm Making It Biologically Relevant with RAFT™ 3D Cell Culture System

Theresa D’Souza, Ph.D., Section Manager, Cell Biology Research & Technology, Lonza Walkersville, Inc.

The environmental cues cells are experiencing in a three-dimensional (3D) cell culture environment bring them closer to their in vivo state compared to two-dimensional (2D) culturing surfaces. RAFT™ 3D Cell Culture system allows the creation of tissue-like structures with cells growing within or on top of a compressed, high-density collagen scaffold.

12:15 3D-Culture Using Elplasia Microplates

Gonzalo Castillo, Ph.D., Consultant to Elplasia Life Science of Kuraray Co. Ltd., BioEnsis

The use of 3D-cell culture models has been growing steadily in the last few years, because they closely resemble the natural cellular environment. Pharmacology utilizing 3D- cultures allow for more accurate in vitro to in vivo predictions, thereby preventing costly expenditures in downstream development. Elplasia microplates offer a complete flexible solution that allows for scalable relevant 3D cultures.

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:00 Session Break

3D MODELS: TAKING SCREENING INTO THE THIRD DIMENSION

1:30 Chairperson’s Remarks

Mohammad F. Kiani, Ph.D., FAHA, Professor, Mechanical Engineering, Bioengineering, and Radiation Oncology, Temple University

1:35 A Biomimetic Microfluid Assay for Rapid Screening of Anti-Inflammatory Drugs

Mohammad F. Kiani, Ph.D., FAHA, Professor, Mechanical Engineering, Bioengineering, and Radiation Oncology, Temple University

There is an urgent need for rapid screening of anti-inflammatory drugs before they are tested in human trials. We have developed and validated a novel biomimetic microfluidic assay (bMFA) that reproduces the entire leukocyte adhesion cascade in a physiologically realistic 3D environment and validated it directly against a mouse model of inflammation. We have used bMFA to rapidly screen the potentially therapeutic effects of a novel drug for treating sepsis.

2:05 3D Liver Spheroids for High-Throughput Drug-Drug Interaction Screening

Noushin Dianat, Ph.D., Bioengineering Team Leader, Colloids & Divided Materials Lab, ESPCI Paris

Persisting failures in clinical validation of promising drug candidates due to safety issues reflect the inefficiency of traditional 2D mono-layer models. In order to study DILI due to drug-drug interaction (DDI), we have developed a high-throughput technology of miniaturized 3D spheroid fabrication with primary human hepatocytes. 3D micro-livers were then treated with a panel of drugs and drug-drug interaction risk was evaluated.

2:35 Coffee and Dessert Break in the Exhibit Hall. Last Chance for Poster Viewing.

3:20 A 3D Self-Assembled Neural Spheroid Model for Capillary-Like Network Formation

Diane Hoffman-Kim, Ph.D., Associate Professor, Medical Science and Engineering, Brown University

In vitro models of the specialized neurovascular environment are imperative for advancing understanding of healthy and pathological states, and for developing therapeutics. We have developed a spheroid model to study the formation of capillary-like networks in a three-dimensional environment that incorporates both neuronal and glial cell types, and does not require exogenous vasculogenic growth factors.

3:50 Current and Future Impact of Advanced 2D and 3D Tissue Models on Improving Safety Testing in Early Drug Development

Jose A. Lebron, Ph.D., Executive Director, Investigative Laboratory Sciences, Safety Assessment & Laboratory Animal Resources, Merck & Co., Inc.

Despite multiple advances, preclinical de-risking efforts do not always predict clinical outcomes. Emerging in vitro technologies promise to fill some of these de-risking gaps. We characterized two in vitro hepatocyte co-culture models – Organovo’s 3D BioPrinted ExVive™ Human Liver and Ascendance’s Hepatopac® micropatterned hepatocyte-fibroblast models. We review the results of these evaluations and provide perspective on what additional models are needed and how future use of in vitro systems could look.

4:20 Organ in a Drop: A 3D Cellular Model Constructed by Droplet-Based Microfluidics

Dong Chen, Ph.D., Professor, Institute of Process Equipment, College of Energy Engineering, Zhejiang University

Developing a 3D model of a human organ that consists of multiple cells embedded in a 3D scaffold and expresses improved functions is practically important for drug developments. We show that droplet-based microfluidics is a powerful technique to construct a 3D cellular model of an organ in a drop, with precise spatial control of different cells in the 3D microenvironment.

4:50 Development of a Human Skin Explant Culture System as an Alternative to Animal Testing

Apostolos Pappas, Ph.D., Research Manager and Fellow, Emerging Science and Innovation, Johnson & Johnson Consumer, Inc.

The talk is around the development of a 3D skin explant system which allows testing of compounds/technologies that could affect all layers of skin (epidermis, dermis, subcutaneous).

5:20 Close of Conference