Although monolayer cell cultures provide valuable information in drug discovery, there is a need for physiologically relevant 3D models which can provide more predictive results for drug screening and toxicity. Cambridge Healthtech Institute’s Screening and Functional Analysis of 3D Models meeting will explore the use of 3D models to profile compound action and predict toxicity and efficacy. The meeting will cover assay development using 3D cellular models, high-content analysis and phenotypic screening of 3D models, and applications of screening 3D models for drug discovery.

Final Agenda

Arrive early and attend (Mon-Tues): 3D Cell Culture: Organoid, Spheroid & Organ-on-a-Chip Models

Tuesday, November 7

11:00 am Conference Registration

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:45 Dessert Break with Exhibit and Poster Viewing

Phenotypic Screening of 3D Models

1:25 Chairperson’s Opening Remarks

Sophie A. Lelièvre, D.V.M., Ph.D., LL.M. (Public Health), Professor, Department of Basic Medical Sciences, College of Veterinary Medicine; Associate Director, Collaborative Science, Purdue University Center for Cancer Research; Scientific Director, 3D Cell Culture Core (3D3C) Facility, Birck Nanotechnology Center, Discovery Park; Coleader, International Breast Cancer & Nutrition (IBCN); Professor of Cancer Pharmacology, West Lafayette-IU Medical School

1:30 Exploiting 3D Cell Cultures for Drug Discovery and Regenerative Medicine

Jonathan S. Dordick, Ph.D., Howard Isermann Professor of Chemical and Biological Engineering, Vice President for Research, Rensselaer Polytechnic Institute

Myriad factors (e.g., cytokines and other proteins, small molecules, and extracellular matrix components) and their combinations strongly influence cell function and fate, which has direct relevance in drug discovery, human toxicology and regenerative medicine. We have developed in vitro, 3D cellular environments that can be engineered with the capacity to emulate the in vivo cellular environment. To demonstrate the breadth of the 3D culture platforms, human neural stem cell lines are being used to elucidate factors that guide neuronal differentiation, and primary cells in vitro are being compared to identical cells engrafted into humanized mouse models. As a result, highly predictive human outcomes may be predicted.

2:00 FEATURED PRESENTATION: Translational Applications of Organ-on-a-Chip Technologies

Murat Cirit, Ph.D., Director of Translational Center of Tissue Chip Technologies, Massachusetts Institute of Technology

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

2:30 Gradient-on-a-Chip to Recreate Microenvironmental Heterogeneity and Identify Cellular Response Thresholds

Sophie A. Lelièvre, D.V.M., Ph.D., LL.M. (Public Health), Professor, Department of Basic Medical Sciences, College of Veterinary Medicine; Associate Director, Collaborative Science, Purdue University Center for Cancer Research; Scientific Director, 3D Cell Culture Core (3D3C) Facility, Birck Nanotechnology Center, Discovery Park; Coleader, International Breast Cancer & Nutrition (IBCN); Professor of Cancer Pharmacology, West Lafayette-IU Medical School

Cell exposure to chemicals traveling through the extracellular matrix depends on variable local concentrations. We designed a microfluidics-based gradient-on-a-chip for controlled delivery of a chemical gradient within the liquid bed of an open culture chamber. As proof-of-concept we used a gradient of reactive oxygen species involved in cancer progression. Preinvasive tumors displayed increasing oxidative stress and phenotypic responses, indicative of a more aggressive status, as the gradient concentration increased. The response level was influenced by matrix stiffness, a known factor in cancer progression, and tumor grade.

3:00 Microengineered 3D Hydrogels for Tissue Engineering and Surgical Applications

Nasim Annabi, Ph.D., Assistant Professor, Chemical Engineering, Northeastern University

Tissue engineering is an interdisciplinary field aimed at maintaining, restoring and enhancing the normal function of organs and tissues through the use of live cells, and by incorporating concepts from engineering, biological sciences and medicine. One of the central themes in the field of tissue engineering is the development of tissue constructs that mimic the three-dimensional (3D) architecture of native tissues. To date, tissue engineering has been successfully implemented in the engineering of several types of tissues including bone, cartilage, and vascular systems. Despite the significant progress in this field, many challenges still remain, which hinder the development of fully functional tissue construct. Micro- and nanoscale technologies have been shown to hold great potential to address the current challenges in tissue engineering. These technologies have immensely benefited the fields of experimental biology and medicine, and have allowed the design of complex biomaterials that can be used for cell-based studies. Our research is focused on merging micro/nanofabrication techniques with advanced protein-based biomaterials for tissue engineering applications. Our group has been actively involved in engineering novel cell-laden elastomeric biomaterials with unique physical properties by using recombinant protein technologies. We use these elastomers as 3D matrices for various soft tissue engineering applications. In addition, we utilize them as highly elastic and adhesive hydrogels for wound closure after different surgical procedures. Our work encompasses a wide range of scientific subjects, from materials science to biology. In this presentation, I will outline our work in the development of microscale hydrogels to modulate cell-microenvironment interactions for tissue engineering applications. I will also highlight some of the clinical applications of our engineered biomaterials as surgical sealants and tissue adhesives.

3:30 Refreshment Break with Exhibit and Poster Viewing

4:10 Nonlinear Optical Microscopic Imaging for Non-Invasive and Label-Free Screening of Viability and Function in 3D Engineered Tissues

Mary-Ann Mycek, Ph.D., Associate Professor & Associate Chair, Biomedical Engineering; Faculty Member, Applied Physics Program; Core Member, Comprehensive Cancer Center, University of Michigan

Label-free nonlinear optical microscopic imaging with quantitative image analysis non-invasively screened viability and function in engineered tissues in 3D. In situ optical measures of living tissue morphology and function could serve as quality control criteria for engineered tissues prior to implantation in patients, a critical regulatory requirement in regenerative medicine. Applications to engineered oral mucosa and skeletal muscle will be discussed.

4:40 A 3D ex vivo Orthotopic Xenograft Screening Platform to Identify Novel Drug and Drug Target Candidates for Brain Cancers

Shawn D Hingtgen, Ph.D., Assistant Professor, Clinical Assistant Professor, Molecular Pharmaceutics, University of North Carolina Chapel Hill

In preclinical development of brain cancer therapeutics, it has become increasingly apparent that conventional, 2D cell culture models (i.e., brain cancer cell lines propagated in plastic) diverge substantially from primary tumors in genomic as well as phenotypic characteristics. To address this, we are developing a novel 3D bona fide brain tissue-based, high-content and high-context assay platform for the identification and validation of new brain cancer drug and drug target candidates.

5:10 Engineered Assembly of Stem Cell-Derived Human Tissues for Discovery and Therapy

William L. Murphy, Ph.D., Harvey D. Spangler Professor, Biomedical Engineering and Orthopedics; Co-Director, Stem Cell and Regenerative Medicine Center; Director, Human MAPs Center, University of Wisconsin

The next generation of high throughput cell-based assay formats will require a broadly applicable set of tools for human tissue assembly and analysis. To address these needs, we have recently focused on: i) generating iPS-derived cells that properly represent the diverse phenotypic characteristics of developing or mature human somatic cells; ii) assembling engineered organoids that are robust and reproducible; iii) translating engineered organoids to microscale systems for high throughput screening; iv) combining genomic analyses with bioinformatics to gain insights into engineered organoid assembly and the pathways influenced by drugs and toxins; and v) assembling cellular constructs that can be efficiently delivered in therapeutic applications. This talk will emphasize recent studies on engineered assembly of 3-dimensional “cellular scaffolds” and engineered vascular, neural, and hepatic organoids. The talk will also introduce the use of our engineered organoids to develop models of developmental disorders, degenerative diseases, and infectious disease effects.

5:40 Close of Day

Wednesday, November 8

7:30 am Breakfast Breakout Roundtable Discussions

 

7:30 am Breakfast Breakout Roundtable Discussions

Concurrent breakout discussion groups are interactive, guided discussions hosted by a facilitator to discuss some of the key issues presented earlier in the day’s sessions. Delegates will join a table of interest and become an active part of the discussion at hand. To get the most out of this interactive session and format please come prepared to share examples from your work, vet some ideas with your peers, be a part of group interrogation and problem solving, and, most importantly, participate in active idea sharing.

Table 1: The Art of Choosing Appropriate 3D Cell Culture Models

Moderator: Sophie A. Lelièvre, D.V.M., Ph.D., LL.M. (public health), Professor, Department of Basic Medical Sciences, College of Veterinary Medicine; Associate Director, Collaborative Science, Purdue University Center for Cancer Research; Scientific Director, 3D Cell Culture Core (3D3C) Facility, Birck Nanotechnology Center, Discovery Park; Coleader, International Breast Cancer & Nutrition (IBCN); Professor of Cancer Pharmacology, West Lafayette-IU Medical School

  • When are organs-on-a-chip better suited than standard 3D cell cultures to address a biological question?
  • What is the importance of the cell model and of the culture medium for 3D culture compared to classical (2D) cell culture?
  • Is there a real advantage of using 3D bioprinting to design and build 3D culture models?

Table 2: Mimicking Tumor Immunosuppression in a Dish - Use of Cell Culture Models for Immuno-oncology

Moderator: Jakub Swiercz, Head of In Vitro Pharmacology & Screening, iTeos Therapeutics SA

  • What are current challenges to overcome?
  • Can one model mimic multiple immunosuppression mechanisms
  • 2D vs 3D models for compound screening in IO

Table 3: Multi-Organ Organ-on-a-Chip Models

Moderator: James J. Hickman, Ph.D., Professor, Nanoscience Technology, Chemistry, Biomolecular Science, and Electrical Engineering, University of Central Florida

Table 4: Toxicity Screening in 3D Models

Moderator: Matt Wagoner, Associate Director, Mechanistic and Investigative Toxicology, Takeda Pharmaceuticals

  • The devil’s in the details | Quantitative considerations for toxicity screening
  • The Valley-dation of Death | Building a bridge between academic innovation and the high-confidence assays needed by industry

Table 5: Screening Complex Biological Models

Moderator: Andreas Vogt, Ph.D., Associate Professor, Department of Computational and Systems Biology, University of Pittsburgh Drug Discovery Institute

  • Are complexity and heterogeneity obstacles or opportunities? Should we abandon a good model just because it is difficult to analyze and standardize? What influences that decision?
  • How much assay development is needed? How much is enough?
  • Are canonical measures of assay performance appropriate for complex systems? What are the alternatives?
 

Translational Applications of 3D Models

8:25 Chairperson’s Remarks

Christopher C.W. Hughes, Ph.D., Professor & Francisco J. Ayala Chair, Department of Molecular Biology and Biochemistry; Professor, Biomedical Engineering; Director, Edwards Lifesciences Center for Advanced Cardiovascular Technology; UC Irvine

8:30 Breakout Roundtable Report-Outs


9:00 FEATURED PRESENTATION: Complex 3D in vitro Models for AstraZeneca Drug Development Projects

Kristin Fabre, Ph.D., Microphysiological Systems Lead, Drug Safety & Metabolism, AstraZeneca

Failure for a drug to meet drug safety and efficacy standards is the primary causes for drug attrition. Therefore, more physiologically relevant models that more accurately represent patients are needed. Currently, there are numerous technologies that aim to address these issues and could significantly impact the drug development process. Examples of how industry could use these complex in vitro platforms, including microphysiological systems, will be highlighted.

9:30 Body-on-a-Chip: Recreating Vascularized Micro-Environments in vitro

Christopher C.W. Hughes, Ph.D., Professor & Francisco J. Ayala Chair, Department of Molecular Biology and Biochemistry; Professor, Biomedical Engineering; Director, Edwards Lifesciences Center for Advanced Cardiovascular Technology; UC Irvine

We have developed several versions of the Vascularized Micro-Organ (VMO), incorporating, for example, cardiomyocytes, pancreatic islets, and neural cells. We have also developed the Vascularized Micro-Tumor (VMT) platform that provides unprecedented opportunities to study drug responses of tumors in a more natural environment than a plastic dish. The basics of the platform have been developed and its utility has been established as we have incorporated cells from several tumor types within the VMT platform, including colon, breast, melanoma, prostate and glioma, and shown its effectiveness for drug screening. The VMT platform provides a new and superior way to screen drugs for efficacy and toxicity.

10:00 Networking Coffee Break

Toxicity Testing and 3D Models

10:30 Chairperson’s Remarks

Christopher C.W. Hughes, Ph.D., Professor & Francisco J. Ayala Chair, Department of Molecular Biology and Biochemistry; Professor, Biomedical Engineering; Director, Edwards Lifesciences Center for Advanced Cardiovascular Technology; UC Irvine

10:35 Applications and Limitations of Advanced Cell Culture Models in Toxicology

Matt Wagoner, Associate Director, Mechanistic and Investigative Toxicology, Takeda Pharmaceuticals

Advanced cell culture systems have significantly improved our ability to recapitulate key aspects of mammalian physiology. While some technologies like spheroids and organoids have already begun to impact how we de-risk toxicities preclinically, others have had a more modest impact. Here we will highlight the areas of toxicology most amenable to impact from 3D cell culture, and potential solutions to the challenges of organ-on-a-chip technology.

11:05 A Human Kidney-on-a-Chip for Disease Modeling and Toxicity Testing

Jonathan Himmelfarb, M.D., Professor of Medicine; Director, Kidney Research Institute; Co-Director, Center for Dialysis Innovation, Joseph W. Eschbach MD Endowed Chair for Kidney Research, Department of Medicine, Division of Nephrology, University of Washington

This talk will review recent developments in the use of 3D microphysiological systems (human kidney-on-a-chip) in drug and environmental nephrotoxicity. The audience will understand recent developments in the use of 3D microphysiological systems (human kidney-on-a-chip) in kidney disease models and understand the critical importance of the kidney microvasculature in kidney injury and disease modeling.

11:35 Functional Multi-Organ Human Models for Preclinical Efficacy and Toxicity Evaluations of Therapeutic Candidates

James J. Hickman, Ph.D., Professor, Nanoscience Technology, Chemistry, Biomolecular Science, and Electrical Engineering, University of Central Florida

Our research focus is on the establishment of high content, functional in vitro systems to mimic organs and subsystems to model motor control, muscle function, metabolism, barrier function, cognitive function, cardiac subsystems and disease models such as cancer and neurological deficits. The idea is to integrate microsystems fabrication technology and surface modifications with protein and cellular components, to fabricate mechanically and electronically interactive functional multi-component systems. A pumpless platform is used to circulate the serum-free medium in the multi-organ systems to understand systemic effects of drugs and other metabolites. Examples will be given of some of the more advanced body-on-a-chip systems being developed as well as the results of six workshops held at NIH to explore what is needed for validation and qualification of these systems.

12:05 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:50 Session Break

iPSC Technology Use in 3D Models

1:35 Organ-on-Chip Models of Neurological Disease Using iPSC Technology

Samuel Sances, Ph.D., Postdoctoral Researcher, Clive Svendsen Laboratory, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center

We have developed novel ways to introduce iPSC-derived neural and endothelial tissues into human patient-specific microengineered chips. These systems can mature neurons faster and provide a novel blood-brain barrier to establish the effects of neuroactive drugs. Data will be shown from our attempts to model a number of neurological diseases using these systems, and have developed a panel of functional and molecular assays for pathogenesis, biomarker, and therapy discovery.

2:05 Patient-Specific 3D Engineered Ocular Tissue to Identify Mechanism of AMD Onset and Progression

Kapil Bharti, Earl Stadtman Tenure-Track Investigator, Head Unit on Ocular and Stem Cell Translational Research, NIH, NEI

We have combined bioprinting, tissue engineering, and induced pluripotent stem (iPS) cell technology to develop a 3D in vitro model of RPE/“choroid” as an in vitro model to study age-related macular degeneration, a disease that affects these two tissues. This 3D RPE/choroid construct is currently being combined with 3D retina derived from the same iPS cells to develop the entire back of the eye tissue relevant for AMD pathogenesis. This work provides a platform to discover disease initiating pathways and the possibility of identifying potential therapeutic drugs for wet-AMD.

2:35 Close of Conference

 

Arrive early and attend (Mon-Tues): 3D Cell Culture: Organoid, Spheroid & Organ-on-a-Chip Models