Abstract 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 to 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&amp;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. 

/pdf/performance-assessment-and-economic-analysis-of-a-human-1axbl3c5.pdf

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

A 3D microfluidic liver model for high throughput compound toxicity screening in the OrganoPlate

The poor predictability of human liver toxicity is still causing high attrition rates of drug candidates in the pharmaceutical industry at the non-clinical, clinical, and post-marketing authorization stages. This is in part caused by animal models that fail to predict various human adverse drug reactions (ADRs), resulting in undetected hepatotoxicity at the non-clinical phase of drug development. In an effort to increase the prediction of human hepatotoxicity, different approaches to enhance the physiological relevance of hepatic in vitro systems are being pursued. Three-dimensional (3D) or microfluidic technologies allow to better recapitulate hepatocyte organization and cell-matrix contacts, to include additional cell types, to incorporate fluid flow and to create gradients of oxygen and nutrients, which have led to improved differentiated cell phenotype and functionality. This comprehensive review addresses the drug-induced hepatotoxicity mechanisms and the currently available 3D liver in vitro models, their characteristics, as well as their advantages and limitations for human hepatotoxicity assessment. In addition, since toxic responses are greatly dependent on the culture model, a comparative analysis of the toxicity studies performed using two-dimensional (2D) and 3D in vitro strategies with recognized hepatotoxic compounds, such as paracetamol, diclofenac, and troglitazone is performed, further highlighting the need for harmonization of the respective characterization methods. Finally, taking a step forward, we propose a roadmap for the assessment of drugs hepatotoxicity based on fully characterized fit-for-purpose in vitro models, taking advantage of the best of each model, which will ultimately contribute to more informed decision-making in the drug development and risk assessment fields.

/pdf/a-critical-perspective-on-3d-liver-models-for-drug-141p3qfw4n.pdf

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies.

Cell therapies offer a tailorable, personalized treatment for use in tissue engineering to address defects arising from trauma, inefficient wound repair, or congenital malformation. However, most cell therapies have achieved limited success to date. Typically injected in solution as monodispersed cells, transplanted cells exhibit rapid cell death or insufficient retention at the site, thereby limiting their intended effects to only a few days. Spheroids, which are dense, three-dimensional (3D) aggregates of cells, enhance the beneficial effects of cell therapies by increasing and prolonging cell-cell and cell-matrix signaling. The use of spheroids is currently under investigation for many cell types. Among cells under evaluation, spheroids formed of mesenchymal stromal cells (MSCs) are particularly promising. MSC spheroids not only exhibit increased cell survival and retained differentiation, but they also secrete a potent secretome that promotes angiogenesis, reduces inflammation, and attracts endogenous host cells to promote tissue regeneration and repair. However, the clinical translation of spheroids has lagged behind promising preclinical outcomes due to hurdles in their formation, instruction, and use that have yet to be overcome. This review will describe the current state of preclinical spheroid research and highlight two key examples of spheroid use in clinically relevant disease modeling. It will highlight techniques used to instruct the phenotype and function of spheroids, describe current limitations to their use, and offer suggestions for the effective translation of cell spheroids for therapeutic treatments. 

/pdf/strategies-to-capitalize-on-cell-spheroid-therapeutic-4ul23j3q.pdf

Strategies to capitalize on cell spheroid therapeutic potential for tissue repair and disease modeling

Organ-on-chip (OoC) technology is full of engineering and biological challenges, but it has the potential to revolutionize the Next-Generation Risk Assessment of novel ingredients for consumer products and chemicals. A successful incorporation of OoC technology into the Next-Generation Risk Assessment toolbox depends on the robustness of the microfluidic devices and the organ tissue models used. Recent advances in standardized device manufacturing, organ tissue cultivation and growth protocols offer the ability to bridge the gaps towards the implementation of organ-on-chip technology. Next-Generation Risk Assessment is an exposure-led and hypothesis-driven tiered approach to risk assessment using detailed human exposure information and the application of appropriate new (non-animal) toxicological testing approaches. Organ-on-chip presents a promising in vitro approach by combining human cell culturing with dynamic microfluidics to improve physiological emulation. Here, we critically review commercial organ-on-chip devices, as well as recent tissue culture model studies of the skin, intestinal barrier and liver as the main metabolic organ to be used on-chip for Next-Generation Risk Assessment. Finally, microfluidically linked tissue combinations such as skin-liver and intestine-liver in organ-on-chip devices are reviewed as they form a relevant aspect for advancing toxicokinetic and toxicodynamic studies. We point to recent achievements and challenges to overcome, to advance non-animal, human-relevant safety studies. 

/pdf/implementing-organ-on-chip-in-a-next-generation-risk-dbmcju47.pdf

Implementing organ-on-chip in a next-generation risk assessment of chemicals: a review

Three-Dimensional Spheroids With Primary Human Liver Cells and Differential Roles of Kupffer Cells in Drug-Induced Liver Injury

In vitro primary human hepatocyte 3D spheroid model for hepatotoxicity studies

A kit for temperature maintenance and shipment integrity of a cell culture is provided, including a well plate, a cell culture, culture media, an insulated receptacle, and a temperature maintenance element. The kit may include a heat release element. The well plate includes a plurality of wells. The cell culture is arranged within each of the plurality of wells of the well plate. Culture media is arranged within each of the plurality of wells of the well plate, where the culture media encapsulates the cell culture. The well plate is arranged within the insulated receptacle. The temperature maintenance element is arranged within the insulated receptacle. The heat release element is also arranged within the insulated receptacle.

Kits and methods for temperature maintenance and shipment integrity of cell cultures during transportation

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Three-Dimensional Spheroids With Primary Human Liver Cells and Differential Roles of Kupffer Cells in Drug-Induced Liver Injury

In vitro primary human hepatocyte 3D spheroid model for hepatotoxicity studies

Kits and methods for temperature maintenance and shipment integrity of cell cultures during transportation