Microphysiological Systems 2023: A Deep Dive into Technologies & Applications Agenda

Making Microphysiological Systems (MPS) Useful
Michael Shuler, Samuel B. Eckert Professor of Engineering, Cornell University, President Hesperos, Inc., United States of America

We will discuss briefly some of the origins and history of multiorgan  MPS development as well as current applications of the technology. The differences between multiorgan (e.g., "body-on-a chip") and single organ models will be discussed. Examples of current uses will be described including the use of MPS data to gain FDA approval for clinical trials.  Current "Body-on-a-Chip" systems combine organized tissue/organ mimics with the techniques of microfabrication based on PBPK (Physiologically Based?Pharmacokinetic) models. These systems are "self-contained" and do not require external pumps, leading to "pumpless systems" which reduce system cost and improve?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. We have constructed models of barrier tissues and have integrated them into a multiorgan system.  A key advantage of this "Body-on-a-Chip" 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?demonstrating that these systems are beginning to have direct commercial impact as well as helping companies evaluate drug leads.

An Outlook Towards Adoption of MPS in Drug Development
Jason Ekert, Head US Discovery Translational Technology, UCB Pharma, United States of America

• Outline where there are opportunities/challenges to implement MPS into the drug discovery pipeline
• Report on the use and uptake of MPS across the pharma industry plus where there is an opportunity when applicable to use animal MPS models.
• Provide examples of where MPS have been utilized in disease modeling and pharmacology to progress molecules in early drug discovery.
• Conclude on where there remains gaps and a future outlook for MPS in drug discovery.

The Impact of Integrated Multi-Organ-Chip Systems in Substance Testing: Progress and Future Outlook
Reyk Horland, CEO, TissUse GmbH, Germany

Microphysiological systems (MPS) are complex cell culture models, which mimic an organ, or defined parts of an organ, in aspects of structure and function. MPS typically consist of several cell types, which are spatially and functionally organized similar to their organization in a normal organ. Integrated microfluidic MPS in particular have proven to be a powerful tool for recreating human tissue- and organ-like functions at research level, providing the basis for the establishment of qualified preclinical assays with improved predictive power. However, industrial adoption of microphysiological systems and respective assays is progressing slowly due to their complexity. In the first part of the presentation examples of established single-organ chip, two-organ and four-organ chip solutions are highlighted. The underlying universal microfluidic Multi-Organ-Chip (MOC) platform of a size of a microscopic slide integrating an on-chip micro-pump and capable to interconnect different organ equivalents will be presented. Issues to ensure long-term performance and industrial acceptance of MPS, such as design criteria, tissue supply and on chip tissue homeostasis will be discussed. The second part of the presentation focusses on the establishment of automated MOC-based assays as a robust tool for safety and efficacy testing of drug candidates. These automated assays will allow for increased throughput and higher inter-laboratory reproducibility thus eventually enabling broad industrial implementation. Finally, an outlook will be given on how these automated systems can be used for on-chip clinical trials as well as personalized medicine testing.

Human-on-a-Chip Systems as Pre-Clinical Models for Neurological Diseases and Disorders
James Hickman, Professor, Nanoscience Technology, Chemistry, Biomolecular Science and Electrical Engineering, University of Central Florida; Chief Scientist, Hesperos, United States of America

One of the primary limitations in drug discovery and toxicology research is the lack of good model systems between the single cell level and animal or human systems. This is especially true for neurodegenerative diseases such as ALS and Alzheimer’s as well as spinal cord injury. In addition, with the banning of animals for toxicology testing in many industries body-on-a-chip systems to replace animals with human mimics is essential for product development and safety testing. Our research focus is on the establishment of functional in vitro systems to address this deficit where we seek to create organs and subsystems to model motor control, muscle function, myelination and cognitive function, as well as cardiac and liver subsystems. The idea is to integrate 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. Specific embodiments of this technology are the creation of a functional human NMJ system to understand ALS and a long-term potentiation (LTP) for AD utilizing clinically relevant functional readouts. We have investigated four mutations found in ALS patients; SOD1, FUS, TDP43 and C9ORF72. The models have demonstrated variations of the disease phenotype compared to WT for NMJ stability and functional dynamics. We have also demonstrated the LTP model can reproduce ABeta pathology and tauopathy in human cortical neurons and demonstrated how AD therapeutics can recover these effects Examples will be given of some of the other human-on-a-chip systems being developed for CNS and PNS disease applications as well as the results  Sanofi has used as efficacy data from one of our models to file the first IND only from MPS data that has enabled a clinical trial (#NCT04658472).

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

We have developed pumpless multi-organ cell culture systems that can be used to co-culture interconnected human tissues to probe inter-organ interactions and secondary drug toxicities. Short connections among organ-chambers and pumpless operation using gravity-driven flow enable us to reduce the amount of liquid typically needed to operate the microfluidic cell culture systems. The devices can be operated with near-physiological amounts of recirculating blood surrogate (cell culture medium). We demonstrate the systems with heart and liver tissues scaled at 1/75,000. Our approach allows us to reduce the dilution of recirculating drug metabolites that cause acute toxicity and long-term 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.

Calcific Aortic Valve Disease on a Chip
Gretchen Mahler, Professor of Biomedical Engineering, Binghamton University, United States of America

The development of calcific aortic valve disease (CAVD) is an active process and ranges from mild valve thickening (aortic sclerosis) to severe leaflet calcification (aortic stenosis). Early CAVD is characterized by the infiltration of immune cells into the extracellular matrix (ECM), reorganization of the ECM, and the deposition of oxidized low-density lipoproteins (oxLDLs), while late CAVD includes severe calcification, collagen disorganization, and the deposition of glycosaminoglycans (GAGs) in the fibrosa layer. In the United States, the prevalence of moderate to severe calcific aortic stenosis in patients =75 years old is 2.8% and is projected to more than double by 2050. Current treatments for CAVD include surgical valve replacement and/or minimal drug interventions tailored to other cardiovascular diseases. Advances in valve disease research have relied on animals and static cell cultures, but engineered, dynamic models may help to further the understanding of CAVD onset and progression. We have created a microfluidic model of the aortic valve fibrosa that includes a dynamic, 3D culture environment, physiologically relevant extracellular matrix, and aortic valve and immune cells that remain viable for up to 21 days. Our previous work demonstrated that the addition of GAGs, particularly chondroitin sulfate, to 3D collagen I hydrogels promoted endothelial to mesenchymal transformation and calcification in a static cell culture. Our results show that after 14 days in dynamic culture both low (1 dyne/cm2) and high (20 dyne/cm2) shear stress induce significant calcifications in the microfluidic model, that the addition of GAGs to the 3D matrix only slightly advances pathogenesis, and that the presence of endothelial cells results in more significant calcification. SEM/EDX was used to analyze chemical composition, composition distribution, and composition concentration of the static or dynamic cell culture samples that formed calcified nodules. Our microfluidic device-derived calcifications are primarily composed of octacalcium phosphates (Ca/P = 1.33), while human valve calcifications are primarily composed of hydroxyapatite. These results were generated without osteogenic medium. The addition of 50 µg/mL oxLdLs to the collagen I ECM in the microfluidic device resulted in hydroxyapatite nodules forming within two days at high (20 dyne/cm2) shear rates, and differentiation of monocytes toward M1 macrophages. No other dynamic in vitro models have reported the natural development of hydroxyapatites. Given that CAVD has no targeted medical therapies, the creation of a physiologically relevant model of the aortic valve fibrosa may lead to contributions in preclinical studies for new therapeutic interventions.

Title to be Confirmed.
Matthias von Herrath, Vice President and Senior Medical Officer, Novo Nordisk, Professor, La Jolla Institute, United States of America