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SELECTBIO Conferences Bioengineering for Building Microphysiological Systems 2022

Bioengineering for Building Microphysiological Systems 2022 Agenda


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Monday, 24 October 2022

08:00

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


Session Title: Conference Opening Session -- Bioengineering to Build MPS 2022

09:00

Michael ShulerConference Chair

Building a Human Body on a Chip: An Ongoing Journey 1989-20?? — A 33-year Odyssey
Michael Shuler, Samuel B. Eckert Professor of Engineering, Cornell University, President Hesperos, Inc., United States of America

A physiologically representative, multiorgan microphysiological system (or MPS) based on human tissues may become a transformative technology to improve selection of drug candidates most likely to earn regulatory approval from clinical trials. Also, such systems can be used to test cosmetics, food ingredients, and chemicals for potential toxicity. In this talk we will explore the history of the development one type of MPS known as a "Body-on-a-Chip" as well as current and future elaborations of this technology. Current "Body-on-a-Chip" systems combine organized tissue/organ mimics with the techniques of microfabrication based on PBPK (Physiologically Based Pharmacokinetic) models. Currently these systems are "self-contained" and do require external pumps, leading to "pumpless systems" which eliminates the need for an external pump, reduces system cost and improves operational reliability. While the fluid (or blood surrogate) in these systems can be sampled directly to allow measurement of concentrations of drug, metabolites or biomarkers, they can also be interrogated in situ to determine functional responses such as electrical response, force generation, or barrier integrity. The blood surrogate can be made to be as a serum-free, chemically defined medium facilitating interpretations of responses that are more mechanistic than with serum containing media. A key advantage of this approach is that we can predict both human efficacy and toxicity of a drug or drug combination in preclinical trails, A Hesperos system has been used as the sole source of efficacy data for an IND application by Sanofi for a drug currently in a Phase 2 clinical trial and data from an Emulate system has also been used to support an IND.  For these systems to fulfill their real potential in drug development such use of these systems must become routine.  Further there are questions on human toxicity of cosmetics and other chemicals, particularly mixtures, that can be addressed with such systems.

09:45

Regina LuttgeConference Chair

Nervous System-on-a-Chip: Closing the Knowledge Gap Between in vitro and in vivo Experiments
Regina Luttge, Professor, Eindhoven University of Technology, Netherlands

Many advances in in vitro technologies to study brain cell cultures have been made by means of microfluidic Brain-on-a-Chips. However, the development of Brain-on-Chips primarily focus on the implementation of cortical cells from human stem cell source in a 3D cultured microenvironment. Instead, the objective of our EU project CONNECT is to mimic the in vivo functions of the nervous system in one connected chip system. Hence, the project brings together the knowledge accumulated among neuroscientists, stem cell experts and engineers to investigate the origins and possible treatments for Parkinson's disease in an extension of the brain-on-chip model, called nervous system-on-chip, linking tissue of the central nervous system and the enteric nervous system. In this presentation, we discuss the importance of instructive micromechanical cues next to the complexity of culture conditions in nervous system on a chip that can be simplified by selecting scaffolding materials containing instructive physical cues by design rather than ill-defined and poorly controllable biological matrices. Finally, we pinpoint on the importance to correlate findings in vitro with observations to be correlated with results from in vivo modeling.

10:30

Morning Coffee and Tea Break and Networking

11:15

Marian RaschkeKeynote Presentation

Microphysiological Systems – Why is Industry Adopting Slowly?
Marian Raschke, Head of Advanced Cellular Models, Bayer AG, Pharmaceuticals Division, Germany

Advanced cellular models and microphysiological systems (MPS) have the potential to fundamentally change the test and assessment strategies in pharma industry’s R&D which for decades relied to a great extent on animal experimentation complemented with rather simple in vitro assays. This has led the so-called “valley of death”, an evident translational gap between preclinical and clinical observations related to both safety and efficacy assessments, which ranks among the leading causes of drug failure. The ongoing transformation of the pharma industry, moving from small molecule drugs to highly diverse therapeutic modalities, including cell and gene therapy, together with increasing public and regulatory expectations for alternatives to animal testing, provides a fertile ground for MPS and other advanced cellular models. The talk will provide a general introduction of the past, present, and anticipated future role of in vitro testing in the pharma industry with focus on the application of MPS in the field of safety testing. This will be complemented by a pharma end-user perspective on opportunities and current limitations hindering a more widespread use of MPS. Moreover, recent in-house use-cases involving MPS in Investigational Toxicology will be shared to contextualize the outlined perspective.

12:00

Advanced Disease Modeling Utilizing Human Stem Cell-derived Cells
Verena Schwach, Assistant Professor, Applied Stem Cell Technologies, University of Twente, Netherlands

Cardiovascular diseases are one of the major causes of mortality and morbidity worldwide. However, current disease models are often not predictive enough because of species differences or lacking complexity. It is of major importance to create models able to predict the effect and toxicity of novel drugs and understand underlying disease models. We differentiate human pluripotent stem cells towards a variety of cells, which provides us with an unlimited source of human cells for 3D tissue engineering and disease modeling. Together with state-of-the-art CRISPR/Cas genome editing, we also generate in vitro models inherited disease.

12:30

Networking Lunch in the Exhibit Hall -- Meet Exhibitors and Engage Over Lunch

14:00

James HickmanKeynote Presentation

Title to be Confirmed.
James Hickman, Professor, Nanoscience Technology, Chemistry, Biomolecular Science and Electrical Engineering, University of Central Florida; Chief Scientist, Hesperos, United States of America

14:45

Human Adherent Cortical Brain Organoids in a Multiwell Format
Femke de Vrij, Associate Professor, Erasmus Medical Center, Netherlands

Recent developments in induced pluripotent stem cell technology offer the unique opportunity to implement lineage-specific human cellular models suitable for drug development applications. Here, we expand on our platform for adherent cortical organoids that resemble the human frontal cortex during early development. The resulting 3D MICro-brains model the essence of cortical structure formation in a miniature format that is literally about 1-millionth the size of a normal human brain. The platform contains all relevant brain cell types: functional neurons and glial cell types in layered radial structures, including astrocytes, myelinating oligodendrocytes and microglia. This advanced 3D MICro-brain platform is amenable to high-throughput analyses for toxicity testing and screening purposes aimed at discovery of pathophysiological mechanisms and therapeutic compound testing for neurodevelopmental and psychiatric disorders.

15:15

High Throughput Phenotypic Screening with Organ on a Chip
Henriëtte Lanz, Director, Model Development, MIMETAS BV, Netherlands

Organ-on-a-Chip is a powerful technology driving physiological relevance by utilizing microfluidic techniques. The technology is expected to impact drug development and ultimately replace or reduce animal testing. Since most platform technologies are either based on single chips or small numbers of chips in dedicated surroundings, application for Organ-on-a-chip is largely envisioned in pre-clinical testing, such as preclinical safety, pharmacology, or pharmacokinetics. Thus far it was thought that with the advanced complexity of models prevents use in drug discovery studies. The OrganoPlate is an exception to this rule, as it comprises 40 to 96 chips. The microtiter plate footprint renders it fully compatible with automated imaging and robotic handling. In fact, Kane et al. reported automation of the platform for long term maintenance of dopaminergic neurons in a Parkinson’s Disease study. High throughput screening applications utilizing Organ-on-a-Chip technology, however have thus far not been reported. Here we report a 1500+ compound screen on a 3D angiogenic sprouting assay. We utilized a newly developed platform, the OrganoPlate 3-lane 64, which comprises 64 chips underneath a microtiter plate. Similar to other versions of the OrganoPlate platform, it utilizes surface tension techniques to stratify extracellular matrix gels and tissue layers and employs passive leveling between reservoirs for inducing flow. Each chip comprises a gel lane and is flanked by two perfusion lanes. Human Umbilical Vein Endothelial Cell (HUVEC) microvessels were grown against a collagen gel according to previously reported protocols. The effect of a small molecule protein kinase inhibitor library of over 1500 compounds was assessed on the angiogenic sprouting behavior of the vessels. The microvessels were exposed to an optimized cocktail of angiogenic factors in conjunction with the compound utilizing automated liquid handling. Readouts including sprout length, sprout and microvessel morphological changes were used. Cultures were imaged using a high content device (Molecular Devices, ImageXpress Micro Confocal). The screen yielded a limited number of hits that either enhanced or inhibited angiogenic capacity. The OrganoPlate 3-lane 64 showed considerable benefit over its predecessor, the OrganoPlate 3-lane 40, not only due to the increased density of chips, but also its 8-well pipette pitch for functionally similar inlets and outlets. This is the first time that Organ-on-a-Chip is reported to be utilized in a large library screen, opening up the route towards early drug screening on tissue models of unrivaled physiological relevance.

15:45

Afternoon Coffee and Tea Break in the Exhibit Hall

16:30

Development of Pumpless Single-Organ and Multi-Organ Microphysiological Devices
Mandy Esch, Project Leader, National Institute of Standards and Technology (NIST), United States of America

We developed several pumpless microphysiological cell culture systems that can be used to co-culture interconnected human tissues with near-physiological amounts of recirculating blood surrogate (cell culture medium). Our GI-tract – liver system can simulate the oral uptake and first pass metabolism of drugs, and our two-organ and four-organ systems can be used to detect primary and secondary drug toxicities. Short channel connections and pumpless operation using gravity enabled us to reduce the amount of liquid needed to operate the systems. We demonstrate the systems with tissues scaled at 1/73,000 and cultured under drug exposure for 24 h. Our approach allows us to reduce the dilution of recirculating drug metabolites that cause acute toxicity. Better predictions of drug toxicity and efficacy with in vitro systems are needed, since clinical trials with humans often do not reproduce the results seen with animal models.

17:00

Uwe MarxKeynote Presentation

Title to be Confirmed.
Uwe Marx, CSO & Founder, TissUse GmbH, Germany

Tuesday, 25 October 2022

08:00

Morning Coffee, Tea and Networking in the Exhibit Hall

09:00

Biomimetic Biohybrid Synapses
Claudia Lubrano, Post doc, Juelich Forshcungszentrum, Germany

Synaptic plasticity is at the base of learning and memory capabilities of the human brain and lately recent studies reported a strong correlation between synaptic dysfunction and neurodegenerative diseases. Unfortunately, the complexity of the brain and the nervous system prevents the investigation of mechanisms underlying cognitive impairment, and for this reason the possibility to inhibit neurodegeneration at the early stage of disease is still far from being concrete. In this scenario, in vitro platforms have attracted significant interest as they could provide simplified biomimetic models of neuronal systems and allow for the investigation of synaptic dysfunctions in neurodegeneration. In this context, organic electrochemical transistors (OECTs) have recently emerged as neuromorphic devices that exhibit synaptic plasticity and adaptive behavior as biological neuronal cells. Furthermore, the recent implementation of supported lipid bilayers (SLBs) on conductive polymers and OECTs lead to the development of a new class of bionsensors able to mimic cells native environment. Here, we present a biomimetic in vitro platform which displays a neuronal membrane outer architecture and is able to recapitulate the same functionalities of neurons (i.e., neurotransmitter-mediated synaptic plasticity). In detail, we engineered a biohybrid platform where dopamine directly secreted from cells is able to modulate the conductance of an OECT on the short and long-time scale mimicking synaptic potentiation of biological systems. Furthermore, we investigated the role of an artificial biomembrane on the neuromorphic functionalities of the OECT exploiting the SLB ionic barrier behavior to enhance the plasticity behavior of the device. We expect that such biomembrane-based organic neuromorphic transistor could represent a first step towards the implementation of fully biomimetic in vitro systems, which resemble composition and functionalities of neuronal networks and as such, could contribute to unwind the complex mechanisms underlying neurodegeneration and synaptic plasticity loss.

09:30

Building Complex Neuronal Networks on Chips to Understand Neurodevelopmental Disorders
Nael Nadif Kasri, Professor Medical Neurosciences for Neurodevelopmental Disorders, Radboud University Medical Center Nijmegen, Netherlands

Recent progress in human genetics has led to the identification of hundreds of genes associated with neurodevelopmental disorders (NDDs). Despite considerable progress in elucidating the genetic architecture of NDDs, a major gap exists between the genetic findings and deciphering the pathophysiology of NDDs. Induced pluripotent stem cell technology allow us to generate all cell types present in the brain, in vitro, in a patient-specific manner. However, for most NDDs we currently do no know the exact cellular loci of disease, i.e. which cell type is contributing to the pathophysiology. In this talk I will explain our strategy to disentangle the cell type-specific contribution to neuronal network phenotypes in the context of NDDs. We generate composite cultures consisting of well-defined cell types differentiated on micro-electrode arrays (MEA) to probe for neuronal network activity during development. In addition, we combine MEA recordings with transcriptomics within the same experiment (MEA-Seq) to identify molecular pathways that underlie specific neuronal network phenotypes observed in ASD subtypes. Our data indicate that MEA-Seq is a robust and sensitive method to perform genotype-phenotype analyses, which can serve as a powerful platform to identify functional points of convergence between NDD genes and be used for high-throughput drug screening assays.

10:00

3D VESSELS-ON-CHIP TO MODEL VASCULAR DISEASE AND BEYOND
Valeria Orlova, , Leiden University Medical Center, Netherlands

Small vessel diseases are the leading cause of disability and death worldwide. The major challenge is that they are multisystem disorders affecting different organs, such as the brain, heart and kidney.  They have been difficult to model in vitro because high-quality vascular cells are difficult to derive from patients and the local organ microenvironment which is difficult to mimic often contributes to the disease. For this reason, human induced pluripotent stem cells (hiPSCs) have become attractive sources of patient- and organ-specific cells. We use hiPSCs to re-create blood vessels on microfluidic chips that recapitulate micro- and macrovascular networks and the local microenvironment. We developed efficient protocols to differentiate hiPSCs towards ECs, pericytes/vSMCs, and inflammatory cells (monocytes and pro- and anti-inflammatory macrophages).  We have demonstrated that both micro- (10-50 µm) and macro-scale (250-300 µm) perfusable 3D vessels composed of hiPSC-derived endothelial cells, pericytes/vSMCs, and other non-vascular components, such as hiPSC- derived astrocytes, can be generated inside the microfluidic devices. Recently we also developed a microphysiological system that behaves as a human “mini-heart” using cardiomyocytes, endothelial cells, and cardiac fibroblasts all derived from hiPSCs. These mini-hearts can be produced just 5000 cells and without specialized equipment.  They thus represent a low-cost, low tech platform for cardiac drug discovery and disease modeling. Using isogenic patient hiPSC lines and 3D vessels-on-chip, we recapitulated the phenotype of a genetic vascular disease called hereditary hemorrhagic telangiectasia (HHT). This patient-based hiPSC model serves as proof of principle that vascular diseases can be modeled using patient-specific hiPSCs in 3D microfluidic chips and used to identify new target cells and possible pathways for therapy.

10:30

Mid-Morning Coffee, Tea and Networking in the Exhibit Hall

11:00

Olivier FreyKeynote Presentation

Emulating Organ-Organ Interaction Using Scalable Microfluidics and Multi-Cellular Spheroids
Olivier Frey, Vice President Technologies and Platforms, InSphero AG, Switzerland

Over the past years, we have developed the different technical and biological components ultimately merging into a scalable microfluidic multi-organ platform applicable for a broad spectrum of pre-clinical studies. An example we are currently advancing is a microphysiological 3D human liver – islet microtissue platform, that enables direct liver – pancreas crosstalk and a better understanding of metabolic diseases. We use 3D spheroids as biological organ models. They have become one of the most frequently used 3D cell culture systems in research and pharmaceutical industry, mainly due to their reasonable balance between physiological relevance and experimental complexity. The liver model consists of a primary Hepatocyte – Kupffer – Stellate cell triple-culture with preserved metabolic and inflammatory function over at least four weeks. Islet microtissues comprise all endocrine cells at physiological ratio and remain glucose responsive over the same duration. Both models are combined in microfluidic culturing device enabling interconnecting of up to ten 3D spherical microtissues. The microfluidic platform meets the requirements for scalability through the use of an injection-molding mass-fabrication process and a gravity-driven tubeless flow concept, which enables parallelization. Large-scale multi-tissue experiments are enabled with a fast and reliable method for loading of quality-controlled spheroids using a fully automated robotic pick-and place-transfer.

11:45

Title to be Confirmed.
Bas WM van Balkom, Assistant Professor, University Medical Center Utrecht, Netherlands

12:15

Networking Lunch

14:00

Round Table Discussion Focusing on Microphysiological Systems: Technology Trends and Adoption by the Pharma Industry -- Chaired by Professor Mike Shuler and Professor Regina Luttge


Add to Calendar ▼2022-10-24 00:00:002022-10-25 00:00:00Europe/LondonBioengineering for Building Microphysiological Systems 2022Bioengineering for Building Microphysiological Systems 2022 in Rotterdam, The NetherlandsRotterdam, The NetherlandsSELECTBIOenquiries@selectbiosciences.com