Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology.

BACKGROUND: Conventional preclinical models often miss drug toxicities, meaning the harm these drugs pose to humans is only realized in clinical trials or when they make it to market. This has caused the pharmaceutical industry to waste considerable time and resources developing drugs destined to fail. Organ-on-a-Chip technology has the potential improve success in drug development pipelines, as it can recapitulate organ-level pathophysiology and clinical responses; however, systematic and quantitative evaluations of Organ-Chips' predictive value have not yet been reported. METHODS: 870 Liver-Chips were analyzed to determine their ability to predict drug-induced liver injury caused by small molecules identified as benchmarks by the Innovation and Quality consortium, who has published guidelines defining criteria for qualifying preclinical models. An economic analysis was also performed to measure the value Liver-Chips could offer if they were broadly adopted in supporting toxicity-related decisions as part of preclinical development workflows. RESULTS: Here, we show that the Liver-Chip met the qualification guidelines across a blinded set of 27 known hepatotoxic and non-toxic drugs with a sensitivity of 87% and a specificity of 100%. We also show that this level of performance could generate over $3 billion annually for the pharmaceutical industry through increased small-molecule R&D productivity. CONCLUSIONS: The results of this study show how incorporating predictive Organ-Chips into drug development workflows could substantially improve drug discovery and development, allowing manufacturers to bring safer, more effective medicines to market in less time and at lower costs.

Drug development is lengthy and costly, as it relies on laboratory models that fail to predict human reactions to potential drugs. Because of this, toxic drugs sometimes go on to harm humans when they reach clinical trials or once they are in the marketplace. Organ-on-a-Chip technology involves growing cells on small devices to mimic organs of the body, such as the liver. Organ-Chips could potentially help identify toxicities earlier, but there is limited research into how well they predict these effects compared to conventional models. In this study, we analyzed 870 Liver-Chips to determine how well they predict drug-induced liver injury, a common cause of drug failure, and found that Liver-Chips outperformed conventional models. These results suggest that widespread acceptance of Organ-Chips could decrease drug attrition, help minimize harm to patients, and generate billions in revenue for the pharmaceutical industry.

Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development

The first microfluidic microphysiological systems (MPS) entered the academic scene more than 15 years ago and were considered an enabling technology to human (patho)biology in vitro and, therefore, provide alternative approaches to laboratory animals in pharmaceutical drug development and academic research. Nowadays, the field generates more than a thousand scientific publications per year. Despite the MPS hype in academia and by platform providers, which says this technology is about to reshape the entire in vitro culture landscape in basic and applied research, MPS approaches have neither been widely adopted by the pharmaceutical industry yet nor reached regulated drug authorization processes at all. Here, 46 leading experts from all stakeholders - academia, MPS supplier industry, pharmaceutical and consumer products industries, and leading regulatory agencies - worldwide have analyzed existing challenges and hurdles along the MPS-based assay life cycle in a second workshop of this kind in June 2019. They identified that the level of qualification of MPS-based assays for a given context of use and a communication gap between stakeholders are the major challenges for industrial adoption by end-users. Finally, a regulatory acceptance dilemma exists against that background. This t4 report elaborates on these findings in detail and summarizes solutions how to overcome the roadblocks. It provides recommendations and a roadmap towards regulatory accepted MPS-based models and assays for patients' benefit and further laboratory animal reduction in drug development. Finally, experts highlighted the potential of MPS-based human disease models to feedback into laboratory animal replacement in basic life science research.

Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium.

The vascular endothelium and shear stress are critical determinants of physiological hemostasis and platelet function in vivo, yet current diagnostic and monitoring devices do not fully incorporate endothelial function under flow in their assessment and, therefore, they can be unreliable and inaccurate. It is challenging to include the endothelium in assays for clinical laboratories or point-of-care settings because living cell cultures are not sufficiently robust. Here, we describe a microfluidic device that is lined by a human endothelium that is chemically fixed, but still retains its ability to modulate hemostasis under continuous flow in vitro even after few days of storage. This device lined with a fixed endothelium supports formation of platelet-rich thrombi in the presence of physiological shear, similar to a living arterial vessel. We demonstrate the potential clinical value of this device by showing that thrombus formation and platelet function can be measured within minutes using a small volume (0.5 mL) of whole blood taken from subjects receiving antiplatelet medications. The inclusion of a fixed endothelial microvessel will lead to biomimetic analytical devices that can potentially be used for diagnostics and point-of-care applications.

Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment.

Kidney toxicity is one of the most frequent adverse events reported during drug development. The lack of accurate predictive cell culture models and the unreliability of animal studies have created a need for better approaches to recapitulate kidney function in vitro. Here, we describe a microfluidic device lined by living human kidney epithelial cells exposed to fluidic flow that mimics key functions of the human kidney proximal tubule. Primary kidney epithelial cells isolated from human proximal tubule are cultured on the upper surface of an extracellular matrix-coated, porous, polyester membrane that splits the main channel of the device into two adjacent channels, thereby creating an apical 'luminal' channel and a basal 'interstitial' space. Exposure of the epithelial monolayer to an apical fluid shear stress (0.2 dyne cm(-2)) that mimics that found in living kidney tubules results in enhanced epithelial cell polarization and primary cilia formation compared to traditional Transwell culture systems. The cells also exhibited significantly greater albumin transport, glucose reabsorption, and brush border alkaline phosphatase activity. Importantly, cisplatin toxicity and Pgp efflux transporter activity measured on-chip more closely mimic the in vivo responses than results obtained with cells maintained under conventional culture conditions. While past studies have analyzed kidney tubular cells cultured under flow conditions in vitro, this is the first report of a toxicity study using primary human kidney proximal tubular epithelial cells in a microfluidic 'organ-on-a-chip' microdevice. The in vivo-like pathophysiology observed in this system suggests that it might serve as a useful tool for evaluating human-relevant renal toxicity in preclinical safety studies.

Tissue engineering and developmental biology: going biomimetic.

This article contains the collective views expressed at the first session of the workshop "Tissue Engineering--The Next Generation," which was devoted to the interactions between developmental biology and tissue engineering. Donald Ingber discussed the chasms between developmental biology and tissue engineering from the perspective of a cell biologist who has had interest in tissue engineering since its early days. Van C. Mow shared a historical perspective on the development of tissue engineering as one of the first engineers involved in the field. David Butler offered an assessment of functional tissue engineering, a new area he helped establish and promote. Laura Niklason discussed how to be more effective in developing cellular therapies for large numbers of patients. Johnny Huard described his approach to tissue engineering, based on the use of muscle-derived cells. Jeremy Mao focused on cell homing and cell density in the context of native development and relevance to tissue engineering. Ioannis Yannas proposed a set of "rules" in organ regeneration. Collectively, the faculty expressed a remarkable level of enthusiasm for bridging the gaps between developmental biology and tissue engineering and offered new ideas on how to facilitate the interaction between the two fields.