Organ-On-Chip in Development: Towards a Roadmap for Organs-On-Chip Doi:10.14573/Altex.1908271
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Meeting Report Organ-on-Chip in Development: Towards a Roadmap for Organs-on-Chip doi:10.14573/altex.1908271 1 Introduction other hazard risks of various substances under increasingly strin- gent regulatory requirements (Marx et al., 2016). Organ-on-Chip is considered a potentially game-changing tech- Organ-on-Chip (OoC) is increasingly regarded as a potential- nology born from the convergence of tissue engineering and mi- ly game-changing technology for these problems (Bahinski et al., crofluidic technology. Organ-on-Chip devices (OoCs) are ex- 2015) and able to meet the needs of different stakeholders (Mid- pected to offer effective solutions to persisting problems in drug delkamp et al., 2016). In spite of its promise (Zhang and Radis- development and personalized disease treatments. This report sur- ic, 2017), pharma has nevertheless remained cautious to invest veys the current landscape in research, development, application, in this new technology, presently awaiting evidence of its add- and market opportunities for OoCs towards establishing a glob- ed cost-benefit value and whether it could represent a feasible al and multi-stakeholder OoC ecosystem. Based on panel discus- route to precision medicine and improved patient stratification. It sions held at the Vision Workshop (Stuttgart, 23 May 2018) orga- is thus necessary to bridge the gap between the potential of OoC nized by the EU ORCHID consortium, as well as on additional systems and their worldwide acceptance. Defining the putative bibliometric study, market analysis, and expert interviews con- benefits of OoCs and how these can be proven and achieved is the ducted within the EU ORCHID project, we outline perceived un- preamble for an OoC roadmap – which is one of the aims of the met needs, key challenges, barriers, and perspectives of the field. ORCHID project. We finally propose recommendations towards the definition of a The Horizon 2020 FET-Open project Organ-on-Chip In De- comprehensive roadmap that could render OoCs realistic models velopment (ORCHID) started in 2017 with the goal of creating of human (patho)physiology in the near future. a roadmap for OoC technology and of building a network of ac- ademic, research, industrial, and regulatory institutions to move 1.1 The healthcare challenge and the OoC roadmap OoCs from laboratories into general use to benefit the citizens A critical problem in the development of effective disease treat- of Europe and beyond. The ORCHID Consortium is a collabo- ments is the paucity of adequate model systems to identify drug ration between 7 partner organizations from 6 European coun- targets, screen toxicity, predict clinical drug efficacy, and ascertain tries – namely: Leiden University Medical Center (coordina- the effects of active substances in humans (Marx et al., 2016). Tra- tor, The Netherlands), Institute for Human Organ and Disease ditional animal models (McGonigle and Ruggeri, 2014; Smirno- Model Technologies (hDMT, The Netherlands), Delft Univer- va et al., 2018) or conventional cell cultures (Pampalonie et al., sity of Technology (TU Delft, The Netherlands), Commissar- 2007; Watson et al., 2017) often do not accurately mimic human iat à l’Energie Atomique et aux Energies Alternatives (CEA, physiology and thus tend to poorly recapitulate human disease France), imec (Belgium), Fraunhofer Institute for Interfacial pathophysiology or accurately predict in vivo responses to med- Engineering and Biotechnology (Fraunhofer IGB, Germany), ical treatments. This is a major cause of late drug failures in clin- and University of Zaragoza (Spain) – and engages an interna- ical trials, high costs of new drugs, and lack of medication for tional advisory board of world-renowned experts from the OoC some diseases (Marx et al., 2016). In addition, translational issues field1. As part of the project, these and other experts were asked (McGonigle and Ruggeri, 2014; Smirnova et al., 2018) and ethi- to share their views on the state-of-the-art, unmet needs, chal- cal questions raised by animal use increase the pressure to mini- lenges, and barriers of the field. The results of the expert inter- mize animal experimentation. For these reasons, the pharmaceu- views (refer to Section A.2 of Appendix2 for the full list of in- tical industry is looking for new ways to improve the drug devel- terviewees and experts that contributed to ORCHID), togeth- opment process (Esch et al., 2015), assess drug toxicity (Ewart et er with the results of bibliographical, bibliometric, and market al., 2018), and identify effective and personalized treatments; bio- analyses of OoC technology (see the Appendix2 for a descrip- medical researchers require better systems to model diseases to tion of the analytical methodology), were combined with the in- improve understanding of their mechanism and etiology; and cos- sights and conclusions of the ORCHID Vision Workshop, held metics, chemical, food and other industries are in need of physi- in Stuttgart on May 23, 2018. The goal of the workshop was to ologically relevant human models to determine toxicological and define the pillars of a European OoC roadmap, including the 1 https://www.h2020-orchid.eu 2 doi:10.14573/altex.1908271s 650 ALTEX 36(4), 2019 MEETING REPORTS Fig. 1: Simplified synopsis of the OoC value chain, according to the ORCHID analyses definition of specific goals and their feasibility for concrete de- ervoir. In either case, the coupling mimics in vivo physiological ployment of the OoC technology. coupling and provides appropriate cell-to-fluid volume ratios and This paper outlines the results of the Vision workshop and of flow distributions to create realisticin vitro models of subsystems ORCHID’s updated analyses, discussions among experts, con- of the human body (Ronaldson-Bouchard and Vunjak-Novakov- clusions and recommendations, with a view to creating a road- ic, 2018). Human(-body)-on-Chip (HoC) systems go beyond this map fostering a thriving global OoC ecosystem. An early draft of and aim to emulate whole organismal physiology by integrating this document3 was released at the International OoC Symposium many relevant single-organ models (Marx et al., 2016). (IOOCS, Eindhoven, the Netherlands, 8-9 November 2018). The As implied by these definitions, OoC technology is poised on present version features extended content and reference list, and converging advances in tissue engineering, semiconductor and discloses the full list of contributing experts (see Appendix2). polymer microfabrication, and human cell sourcing. The associ- ated value chain emerging from the ORCHID analyses (Fig. 1) 1.2 Organ-on-Chip: Definition, key features, highlights the need for multidisciplinary approaches to imple- and value chain ment OoCs and for facilitating dialogue between academic and According to the interviewed experts, and as ratified during the industrial developers as well as stakeholders such as clinicians, ORCHID workshop, an OoC can be defined as “a fit-for-purpose patients, regulators and different end-users. All these disciplines microfluidic device, containing living engineered organ substruc- are represented in the ORCHID Consortium. tures in a controlled microenvironment, that recapitulates one or more aspects of the organ’s dynamics, functionality and (patho) physiological response in vivo under real-time monitoring”. 2 State-of-the-art OoCs can be classified into two types with complementary goals and distinct complexity: (i) single-organ systems, emulat- 2.1 An internationally expanding field of research ing key functions of single tissues or organs, and (ii) multi-organ The OoC field emerged from the convergence of microflu- platforms, combining multiple OoCs to reproduce the systemic idics and tissue engineering research. Whereas in the ear- interaction and response of several organ models within a single ly 2000’s, patents and publications in the field mainly focused system. Multi-OoCs link individual OoCs through tubing or mi- on microfluidics and associated fabrication techniques, more crofluidic channels (Vernetti et al., 2017), often coated with en- recently advances in stem cell biology, combined with de- dothelial cells or with functional coupling provided by transfer of cades of fundamental biological studies in cell signaling and effluent from one organ’s effluent reservoir to another’s input res- biomechanics, have accelerated the development of OoCs. 3 http://www.hdmt.technology/download/?id=9618 (accessed 18.09.2019) ALTEX 36(4), 2019 651 MEETING REPORTS The ORCHID bibliometric approach reflected this increas- clinicians, and end users, from both academia and industry. ing activity by finding evidence for a rise in both dedicat- Originating in the USA, which pioneered the development of ed patents and publications with a compound annual growth customized cellular microenvironments to capture the structur- rate (CAGR) of +46% over the last ten years (123 patents al complexity of organs, this worldwide interest is increasingly and publications in 2007, compared to at least 390 in 2017) engaging Europe, which has a strong track record in tissue engi- (Fig. 2a). Such continuous growth, driven by the huge market neering and microfluidics, and for which OoCs could represent potential, was made possible by the concomitant diffusion of a new growth opportunity (Fig. 2b,c). The Asia-Pacific region multidisciplinary approaches supported by improved dialogue (APAC) also contributes substantially to the field with both es- between developers such as biologists (cell culture, physiology),