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SELECTBIO Conferences 2D-to-3D Culture and Organoids 2020

2D-to-3D Culture and Organoids 2020 Agenda

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2D-to-3D Culture and Organoids 2020 | Multi-Cellular Engineered Living Systems Summit | 

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Wednesday, 19 August 2020


Conference Registration, Materials Pick-Up, Morning Coffee and Pastries

Session Title: Multi-Cellular Engineered Living Systems Summit


Roger KammConference Chair

Conference Chairperson's Welcome, Introduction and Topics Addressed
Roger Kamm, Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering, Massachusetts Institute of Technology (MIT), United States of America


Linda GriffithKeynote Presentation

Engineering Mucosal Barriers: From Organoids to Organs–on–Chips
Linda Griffith, Professor, Massachusetts Institute of Technology (MIT), United States of America

Mucosal barriers are the gateways to all internal organs, serving to transport oxygen, nutrients, and waste and at the same time performing enormous feats of protection against infection and other hazardous insults.  The explosion of interest in the human microbiome – especially but not only that in the gut – has driven new interest in building human mucosal barrier models. This talk will highlight three related themes: (i) engineering synthetic microenvironments to expand primary adult epithelial organoids and induce morphogenesis into mucosal barriers (ii) engineering microfluidic devices to create microbial-mucosal interfaces that enable chronic co-culture of the most super strict anaerobes such as Faecalibacterium prausnitzii with a colon mucosal barrier and (iii) interconnection of mucosal barriers with other tissues in systemic circuits to illuminate the role of gut-derived bacterial metabolites on function of other organ systems.  Examples will emphasize how these approaches can be used to model chronic inflammatory diseases.


Shay SokerKeynote Presentation

Tissue Organoids For Disease Modeling
Shay Soker, Professor of Regenerative Medicine and Chief Science Program Officer, Wake Forest Institute for Regenerative Medicine, United States of America

Traditional in vitro two dimensional (2D) cell cultures fail to recapitulate the microenvironment of in vivo tissues. They have three major differences from native tissue microenvironments: substrate topography, substrate stiffness, and most importantly, a 2D rather than three dimensional (3D) architecture. In contrast, 3D human tissue organoids replicate native tissue structure and function and thus are superior to traditional 2D cultures and animal models. These organoids can be studied in vitro for several weeks to allow intensive investigations. Besides their advantages in drug toxicity testing and for development of new drugs, the human tissue organoid platform serves as a model system to explore human tissue development and disease. Our recent research was focused on the use of human tissue organoids to study liver development and congenital diseases as well as other common diseases such as tissue fibrosis and cancer. Altogether our human tissue organoids system can be used for modeling of a wide verity of diseases and develop new personalized/precision medicine applications.


Morning Coffee Break and Networking


Peter ErtlKeynote Presentation

Parkinson’s-On-a-Chip: Unravelling the Complexity of Neurodegenerative Diseases Using a Chip-based Midbrain Organoid Model
Peter Ertl, Professor of Lab-on-a-Chip Systems, Vienna University of Technology, Austria

One of the main limitations in neuroscience and in the modeling and understanding of neurodegenerative diseases is the lack of advanced experimental in vitro models that truly mimic the complexity of the human brain. With its ability to emulate microarchitectures and functional characteristics of native organs in vitro, induced pluripotent stem cell technology has enabled the generation of human midbrain organoids. To improve organoid reproducibility and iPSC differentiation, we have developed a sensor-integrated organ-on-a-chip platform allowing long-term cultivation and non-invasive monitoring of hMOs under an interstitial flow regime. Our results show that dynamic cultivation of iPSC-derived hMOs maintains high cellular viabilities and dopaminergic neuron differentiation over prolonged cultivation periods of up to 50 days, while neurotransmitter release of hMOs is detected using an electrochemical sensor array.


James HickmanKeynote Presentation

Body on a Chip: Human Microscale Models for Drug Development
James Hickman, Professor, Nanoscience Technology, Chemistry, Biomolecular Science and Electrical Engineering, University of Central Florida; Chief Scientist, Hesperos, United States of America

The preclinical drug development process is inefficient at selecting drug candidates for human clinical trials, since only 11% of drug candidates selected for clinical trials exit with regulatory approval. Current technology is based on isolated human cells and animal surrogates.  We believe that a “human” multiorgan model based on physiologically based pharmacokinetics-pharmacodynamic (PBPK-PD) models that house interconnected modules with tissue mimics of various organs.  The system captures key aspects of human physiology that would potentially reduce drug attrition in clinical trials and decrease the cost of development. Integrated, multi-organ microphysiological systems (MPS) based on human tissues (also known as “body-on-a-chip”) could be important tools to improve the selection of drug candidates exiting preclinical trials for those drug most likely to earn regulatory approval from clinical trials. This methodology integrates microsystems fabrication technology and surface modifications with protein and cellular components, for initiating and maintaining self-assembly and growth into biologically, mechanically and electronically interactive functional multi-component systems.

I will describe such systems being constructed at Hesperos and at UCF that are guided in their design by a PBPK model. They are “self-contained” in that they can operate independently and do not require external pumps as is the case with man other microphysiological systems. They are “low cost”, in part, because of the simplicity and reliability of operation. They maintain a ratio of fluid (blood surrogate) to cells that is more physiologic than in many other in vitro systems allowing the observation of the effects of not only drugs but their metabolites. While systems can be sampled to measure the concentrations of drugs, metabolites, or biomarkers, they also can be interrogated in situ for functional responses such as electrical activity, force generation, or integrity of barrier function. Operation up to 28 days has been achieved allowing observation of both acute and chronic responses with serum free media. We have worked with various combinations of internal organ modules (liver, fat, neuromuscular junction, skeletal muscle, cardiac, bone marrow, blood vessels and brain) and barrier tissues (eg skin, GI tract, blood brain barrier, lung, and kidney). The use of microelectrode arrays to monitor electrically active tissues (cardiac and neuronal) and micro cantilevers (muscle) have been demonstrated. Most importantly these technical advances allow prediction of both a drug’s potential efficacy and toxicity (side-effects) in pre-clinical studies. This talk will also give results of six workshops held at NIH to explore what is needed for validation and qualification of these new systems.


Networking Lunch and Round-Table Discussions

Session Title: Organoids and 3D-Culture - Technologies and Applications

Session Chairperson: Dr. Terry Riss, Promega Corporation


Merging Human Microphysiological Systems with Quantitative Systems Pharmacology for In Vitro In Vivo Translation
Murat Cirit, CEO & Co-Founder, Javelin Biotech, United States of America

A large percentage of drug candidates fail at the clinical trial stage due to a lack of efficacy and unacceptable toxicity, primarily because of translational gap between human physiology and preclinical models including both in vitro culture and animal models. This need for more human-physiology relevant in vitro systems for preclinical efficacy and toxicity testing has led to a major effort to develop “Microphysiological Systems (MPS)”, aka tissue chips (TC) or organs on chips (OOC), based on engineered human tissue constructs.

MPSs hold promise for improving therapeutic drug approval rates by providing more physiological, human-based, in vitro assays for preclinical drug development activities compared to traditional in vitro and animal models. The full impact of MPS technologies to bridge the gap preclinical and clinical gap will be realized only when robust approaches for in vitro–in vivo (MPS-to-human) translation are developed and utilized.


Albert FolchKeynote Presentation

Microfluidics For Interrogating Intact Tumor Biopsies
Albert Folch, Professor of Bioengineering, University of Washington, United States of America

The intricate microarchitecture of tissues – the “tissue microenvironment” – is a strong determinant of tissue function. Microfluidics offers an invaluable tool to precisely stimulate, manipulate, and analyze the tissue microenvironment in live tissues and engineer mass transport around and into small tissue volumes. Such control is critical in clinical studies, especially where tissue samples are scarce (e.g. tumor biopsies), in analytical sensors, where testing smaller amounts of analytes results in faster, more portable sensors, and in biological experiments, where accurate control of the cellular microenvironment is needed (e.g. organ-on-a-chip). Microfluidics also provides inexpensive multiplexing strategies to address the pressing need to test large quantities of drugs and reagents on a single biopsy specimen, increasing testing accuracy, relevance, and speed while reducing overall diagnostic cost. I will discuss the development of our platforms for cancer diagnostics that allow for multiplexed functional drug testing on live, intact tissues in various formats: 1) tumor slices; 2) core needle biopsies; and 3) cuboids (precision-sliced tumor fragments that retain viability and the tumor microenvironment for several days). These platforms are currently under commercial development by startup OncoFluidics.


Ex Vivo Immuno-Oncology Dynamic Environment For Tumor Biopsies
Jeffrey Borenstein, Group Leader, Synthetic Biology, Draper, United States of America

We present the design, construction and testing of a microfluidic perfused tumor microenvironment platform capable of evaluating the efficacy of immune checkpoint inhibitors with circulating immune cells in mouse and human tumor biopsy fragments.


Afternoon Coffee Break in the Exhibit Hall


Modeling Immune Mediated Beta Cell Destruction in Human Type 1 Diabetes with Organoids
Matthias von Herrath, Vice President and Senior Medical Officer, Novo Nordisk, Professor, La Jolla Institute, United States of America

In the past 15 years we have been studying the pathology of human type 1 diabetes with access to donor pancreata through the human pancreatic organ donor consortium (nPOD). These studies have led to several findings, for example that certain cytokines are generated by beta cells themselves, sometimes under stress, and also that there are probably key factors that render beta cells susceptible to immune attacks. Mechanistically, the importance and meaning of these observations needs to be addressed in a suitable and easily manipulable in vitro system consisting of human islets and immune cells. We have built such a system in collaboration with the company InSphero and will discuss emerging findings.


Roger KammKeynote Presentation

Vascular Networks on a Chip and Their Applications
Roger Kamm, Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering, Massachusetts Institute of Technology (MIT), United States of America

Due to the capacity of vascular endothelial cells to self-assemble into 3D vascular networks in a conducive hydrogel, it is now possible to grow microvasculature within microfluidic chips comparable to in vivo capillary beds in both morphology and function.  These systems have numerous applications including vascularized organs-on-chip, studies of transport across the vascular endothelium, and models of disease.  This presentation will focus on the growth of these networks and quantitative analysis of their morphology and transport properties.  Results will be discussed showing networks grown from several different sources of endothelial cells that stabilize over 4-7 days, and can then be maintained in some cases for periods of over one month.  Various accessory cells are used, including fibroblasts, pericytes and mesenchymal stem cells, and these contribute to changes in matrix composition and mechanics over time. Examples will be used to illustrate some of the potential applications of these vascularized models, selected from metastatic cancer, the blood-brain barrier, and cerebral amyloid angiopathy.


Networking Reception with Beer and Wine in the Exhibit Hall -- Meet Exhibitors and Network with Colleagues


Close of Day 1 of the Conference

Thursday, 20 August 2020


Morning Coffee and Pastries in the Exhibit Hall

Session Title: Emerging Themes in Organoids and Organs-on-Chips


Selecting and Validating Fit-for-Purpose Assays to Interrogate 3D Culture Models
Terry Riss, Global Strategic Marketing Manager Cell Health, Promega Corporation, United States of America

There is a rapid expansion in the use of 3D cell culture model systems ranging from individual scaffold-free spheroids to multiple organoids designed to represent a human-on-a-chip. Researchers soon become aware the spectrum of 3D models have vastly different culture requirements and there is no “one size fits all” approach. Selecting a 3D culture model that is “fit for purpose” often involves compromises considering sample throughput, complexity, physiological relevance, cost and limitations in the available assay technologies. I will describe an overview of factors to consider when designing an appropriate 3D culture model and stress the importance of considering limitations of assay methods to interrogate relatively large 3D structures.


Modeling Cancer Prevention In Breast Organoids
Jennifer Rosenbluth, Instructor in Medicine, Dana-Farber Cancer Institute, United States of America

Mammary organoids can be used to preserve complex lineages in long-term culture.  Using mass cytometry to profile cell states in patient-derived breast organoids, we identify a cell population that is expanded in the breast tissue of BRCA1/2 mutation carriers.  This approach is being extended to model early stages of cancer development as well as aggressive breast cancer subtypes.


CELLINK3D Bioprinting for Cancer Research
Shubhankar Nath, Senior Oncology Scientist, CELLINK

The presentation will discuss recent advancements in the area of cancer model development utilizing 3D bioprinting technologies. Physiologically relevant 3D cancer models are critical for drug discoveries. These 3D cancer models predict the outcome of in vivo experiments that 2D models often fail. The use of 3D cell culture, aided by CELLINK’s bioprinting technologies, affords the use of multicellular constructs in the presence of tissue-specific extracellular matrix to better mimic the in vivo milieu. These cancer models are also used to study the interactions between cancer cells and their microenvironment to develop mechanism-informed therapies.


Making 3D Possible: Large-Scale Organoid Production Using Bioprocess Design
Victoria Marsh Durban, Lead Scientist, Cellesce Limited, United Kingdom

While it is increasingly appreciated that 2D cell models poorly represent physiological drug responses, 3D alternatives have not yet replaced their widespread use. Organoid technology has the potential to transform drug discovery, improving the predictiveness of efficacy and toxicity assays, and therefore reducing the use of animal models in the drug discovery pipeline. Although organoid models are recognised as a superior in vitro tool, the production of organoids is currently a time consuming, highly manual process. Moreover, the small batch sizes achieved and substantial variability of manual batch production significantly limits the reproducibility of organoid-based assays. These issues preclude the use of organoids in the medium-to-high throughput formats required for early drug discovery. Cellesce has developed proprietary bioprocessing systems for the expansion of organoids at scale, with the long-term goal of positioning organoid technology as a cost-effective and accurate alternative to 2D cell models in drug discovery. Using our first-generation bioprocess, “CXP1”, we have successfully shown that breast and colorectal cancer-derived organoids grown in bioreactors are comparable to those grown according to traditional manual methods. Bioprocessed organoids are size standardised, produced in sufficient quantities to allow for drug screening in high-throughput formats, and are available in frozen format suitable for use ‘off the shelf’.


Morning Coffee Break and Networking in the Exhibit Hall


Organoids: A Patient In the Lab
René Overmeer, Assay Development & Screening Manager, Hubrecht Organoid Technology (HUB), Netherlands

Organoids such as IPSC derived brain organoids (Lancaster et al Nature 2013) or our adults epithelial stem cell derived organoids (Sato et al., Nature 2009, 2011) are proving to be a major breakthrough in preclinical models. The new patient like models are fundamental change in the way drug discovery and development can be performed. The development of the HUB Organoids started in the lab of Hans Clevers with the discovery of the identity of adult stem cells in human epithelial tissues such as intestine and liver (Barker et al., Nature 2007; Huch et al., Nature 2013). With the identification of these stem cells, we were able to develop a culture system that allowed for the virtually unlimited, genetically and phenotypically stable expansion of the epithelial cells from most, if not all, epithelial animal and human tissues, both from healthy and diseased tissue (Sato et al., Nature 2009, 2011; Gastroenterology 2011; Huch et al., Nature 2013, Cell 2015; Boj et al., Cell 2015). We have now generated HUB organoid models from most epithelial organs. Recently, we and others have demonstrated that the in vitro response of organoids correlates with the clinical outcome of the patient from which the organoid was derived (Dekkers et al., Sci Trans Med 2016; Sachs et al., Cell 2018; Vlachogiannis et al., Science 2018). In addition, we have developed a coculture system using HUB Organoids and the immune system to study this interaction and drugs that target the role of the immune system in cancer and other diseases. We have recently developed new models to study intestinal and lung barrier function and transport of the epithelium of these organs. These experiments show how organoids can be used to study mechanism that underly barrier function disruption in IBD or COPD. Furthermore, we have developed new models to study the interaction between immune system and epithelium. The combination of the new coculture models and assay development to study the epithelium allows us new insights into disease mechanisms and drug treatment strategies.


InSphero AGModeling and Imaging the Immune Response in 3D Cell-based Assays
Jan Lichtenberg, CEO & Co-Founder, InSphero AG

The immune system plays an important role in disease progression for a variety of indications. Still, the vast majority of in-vitro cell-based assays neglects the immune system. The complexity of sourcing matched donor material, differentiating between different cell types in assay readouts and handling the dynamics of these systems imposes difficult hurdles in implementation.

We present two examples of human in-vitro 3D microtissue assays including PBMCs to model the immune response in oncology and T1 diabetes applications. Live-cell, high-content imaging is used as primary readout to assess the dynamics of the immune response. Image analysis of the 3D microtissues allows for the generation of robust quantified data on immune cell penetration and target-cell viability.


Scientific BioprocessingReal-Time Sensing of pH and Dissolved Oxygen in Microfluidics Devices
Jake Boy, Application Scientist, Scientific Bioprocessing

Real-time sensing of critical cell culture parameters continues to be a major challenge in tissue/organ-on-a-chip systems. While electrochemical probes have been used for decades in large bioreactor systems, use of these probes in microfluidics systems is prohibitive due to form factor challenges. Optical sensor technologies have enabled non-invasive, real-time sensing that can be tailored to a wide range of custom microfluidic bioreactor systems. In this presentation, we describe application examples that utilize pH and dissolved oxygen sensors developed with state-of-the-art fluorescence technology. The sensors support long-term cultures in the order of weeks that are typical for engineered tissue and organ model development and can be used either for monitoring or for monitoring and control through closed loop feedback.


Networking Lunch in the Exhibit Hall


Recreating Kidney Organogenesis in vitro with Human Pluripotent Stem Cells
Ryuji Morizane, Assistant Professor, Harvard Medical School; Visiting Scholar, Wyss Institute, United States of America

We have developed an efficient, chemically defined protocol for differentiating human pluripotent stem cells into multipotent nephron progenitor cells (NPCs) that can form kidney organoids. By recapitulating metanephric kidney development in vitro we generate SIX2+SALL1+WT1+PAX2+ NPCs with 80-90% efficiency within 8-9 days of differentiation. NPCs form kidney organoids containing epithelial nephron-like structures expressing markers of podocytes, proximal tubules, loops of Henle and distal nephrons in an organized, continuous arrangement that resembles the nephron in vivo. The organoids express genes reflecting many transporters seen in adult metanephric-derived kidney, enabling assessment of transporter-mediated drug nephrotoxicity. Stromal cells are also generated with the presence of PDGFRBeta+ fibroblasts/pericytes, and CD31+ endothelial cells. This kidney differentiation system can be used to study mechanisms of human kidney development. Repetitive injury to tubular cells causes interstitial fibroblast expansion with characteristics of myofibroblasts, indicating kidney organoids can be used to model kidney fibrosis in vitro. Polycystic kidney disease (PKD) patient-derived organoids exhibit cystic phenotypes. Hence the generated kidney organoids are effective tools to study genetic disorders of the kidney as well as mechanisms of kidney injury and fibrosis. Microphysiological platforms in vitro facilitate kidney organoid vascularization and maturation, which may lead to the development of functional bioengineered kidneys in the future.


High-Throughput Brain Organoids Reveal Human Neurogenesis-Relevant Transcriptional Profiles
Milos Kostic, Researcher, Novartis Institutes for BioMedical Research, United States of America

Recent breakthroughs in 3D brain organoid systems show that they can recapitulate aspects of human neurogenesis, such as cytoarchitecture, cell type heterogeneity, lineage progression and gene expression that are absent in 2D models. These properties mark them as attractive model system to study neurodevelopmental disorders. However, brain organoid research suffers from the lack of rigorous quality control for heterogeneity. To address this, we developed a high-throughput platform to generate organoids from multiple stem cell lines. We will present comprehensive quality control of brain organoids using single cell RNA sequencing (scRNA-seq) coupled with immunohistochemistry analysis.


Afternoon Coffee Break and Networking


Exploring the Utility of iPSC-derived 3D Cortical Spheroids in the Detection of CNS Toxicity
Qin Wang, Scientist, Drug Safety Research & Evaluation, Takeda Pharmaceuticals, Inc., United States of America

Drug-induced Central Nervous System (CNS) toxicity is a common safety attrition for project failure during discovery and development phases due to low concordance rates between animal models and human, absence of clear biomarkers, and a lack of predictive assays. To address the challenge, we validated a high throughput human iPSC-derived 3D microBrain model with a diverse set of pharmaceuticals. We measured drug-induced changes in neuronal viability and Ca channel function. MicroBrain exposure and analyses were rooted in therapeutic exposure to predict clinical drug-induced seizures and/or neurodegeneration. We found that this high throughput model has very low false positive rate in the prediction of drug-induced neurotoxicity. This assay has the potential to be used as a predictive assay to detect neurotoxicity hazard identification in early drug discovery.


Phenotypic Machine Learning in High Content Imaging Screening with Organoids
Yu-Chi Chen, Scientist, Bioprinting Group, NCATS, United States of America

In the last few years, there has been a fast increase in the use of 3D cellular models as physiological relevant assays for drug discovery and development.  The use of U-bottom plates has been widely used for growing 3D spheroids because they facilitate spheroid formation in a scalable and reproducible manner to enable large scale compound screening.  However, the U-bottom shape of the wells in these plates limits the use of high-resolution imaging (>20X) and high-content screening mainly due to light diffraction.  Therefore, the assays used for screening with spheroids have mostly been restricted to simple readouts such as cell viability using standard well-based assays, or high content assays measuring total fluorescence intensity.  As more complex spheroids and organoids models are developed for disease modeling, there is an increased need to be able to quantitate the effects of compounds in different cell types, sub-cellular biomarkers and phenotypes within these 3D systems.  Here we will discuss the development of a 1536-well 3D HCS assay platform that enables the generation of high-resolution sub-cellular images coupled with a Phenotypic machine learning and 3D segmentation analysis within 3D spheroids that enables the implementation of 3D High Resolution Imaging Screening.


Close of Day 2 of the Conference

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