Microphysiological systems: From organoids to organs-on-chip

It is becoming increasingly clear that even the best in vivo models such as genetically-modified mouse models or orthotopic patient-derived xenografts cannot recapitulate the full complexity of human physiology. In addition, in vivo models do not comply with ‘3R' – Replacement, Reduction, Refinement – that the EU is pushing forward, calling for in vitro alternatives to mimic functional organs and pathologies. The past two decades have taught us that cell behavior is heavily dictated by its chemical and mechanical microenvironment together with its genetic background. This entails that cells put in culture under the right conditions display striking abilities to remodel their microenvironment and self-organize into functional units. Hence, cell-cell and cell-matrix interactions, substrate topology, chemical gradients and mechanical stimulations are crucial parameters to consider in order to understand and accurately model physiological functions. Two parallel and complementary in vitro approaches have been undertaken by researchers coming from various fields since the early 2010s: organoids and organ-on-chips, that together form the vast domain of micro-physiological systems. On the one hand, biology groups have worked on a better definition of the cellular microenvironment in terms of cell-matrix interaction and chemicals leading to three-dimensional self-organization of cells forming functional organ sub-units, called organoids (Clevers, 2016). On the other hand, organ-on-chips primarily come from the field of microfluidics, with the end-goal of imposing a well-defined topology and physico-chemical environment onto cells, to understand quantitatively the simplest design principles of organ response and function (Zhang et al., 2018). The recent interactions between these fields have led to the development of exquisite micro-physiological systems mimicking organs such as the gut (Wang et al., 2017), liver (Shintu et al., 2012), or lung (Stucki et al., 2015). The successful development and assessment of these approaches require sophisticated techniques to sense and probe – optically or electrochemically – the physiological parameters, alongside advanced three-dimensional microscopy to investigate cell architecture and topology, and biomaterial developments for proper topology and cell-matrix interaction control. The use of micro-physiological systems have led both to fundamental insights into the mechanisms of organogenesis, and is opening the door to numerous clinical applications, as exemplified by the recent NIH program launched on organ-on-chips gathering big pharma and academics (https://ncats.nih.gov/tissuechip). As research advances, our mechanistic understanding on the role of the microenvironment will require cooperation between an expanding number of fields of science. The aim of this Summer School is to gather together researchers coming from the many fields that define the new paradigm of micro-physiological systems, from theorists to experimentalists all the way to bioengineers, clinicians and researchers from pharmaceutical companies. With research, treatments and legislation moving towards a more personalized medicine and sparser use of animal models (Bredenoord, Clevers and Knoblich, 2017), the timing would be ideal to crystalize a research strategy bridging fields towards these aims.