Organs-on-chips (OoCs), also known as microphysiological systems or "tissue chips" (the terms are synonymous), have garnered substantial interest in recent years owing to their potential to be informative at multiple stages of the drug discovery and development process. These innovative devices could provide insights into normal human organ function and disease pathophysiology, as well as more accurately predict the safety and efficacy of investigational drugs in humans. Therefore, they are likely to become useful additions to traditional preclinical cell culture methods and in vivo animal studies in the near term, and in some cases, replacements for them in the longer term. In the last decade, the OoC field has seen dramatic advances in the sophistication of biology and engineering, in the demonstration of physiological relevance, and in the range of applications. These advances have also revealed new challenges and opportunities, and expertise from multiple biomedical and engineering fields will be needed to fully realize the promise of OoCs for fundamental and translational applications. This Review provides a snapshot of this fast-evolving technology, discusses current applications and caveats for their implementation, and offers suggestions for directions in the next decade.

Functional ␥-secretase inhibitors (FGSIs) can block the cleavage of several transmembrane proteins including amyloid precursor protein (APP), and the cell fate regulator Notch-1. FGSIs, by inhibiting APP processing, block the generation of amyloid ␤ (A␤) peptides and may slow the development of Alzheimer's disease. FGSIs used to inhibit APP processing may disrupt Notch processing, thus interfering with cell fate determination. Described herein is a FGSI-mediated gastrointestinal toxicity characterized by cell population changes in the ileum of rats, which are indicative of Notch signaling disruption. Microarray analysis of ileum from FGSItreated rats revealed differential expression responses in a number of genes indicative of Notch signaling perturbation, including the serine protease adipsin. We were able to show that FGSI-treated rats had elevated levels of adipsin protein in gastrointestinal contents and feces, and by immunohistochemistry demonstrated that adipsin containing ileum crypt cells were increased in FGSI-treated rats. The mouse Adipsin proximal promoter contains a putative binding site for the Notchinduced transcriptional regulator Hes-1, which we demonstrate is able to bind Hes-1. Additional studies in 3T3-L1 preadipocytes demonstrate that this FGSI inhibits Hes-1 expression while up-regulating adipsin expression. Overexpression of Hes-1 was able to down-regulate adipsin expression and block pre-adipocyte differentiation. We propose that adipsin is a Hes-1-regulated gene that is de-repressed during FGSI-mediated disruption of Notch/Hes-1 signaling. Additionally, the aberrant expression of adipsin, and its presence in feces may serve as a noninvasive biomarker of gastrointestinal toxicity associated with perturbed Notch signaling.The small intestine can be a site of injury associated with drug treatment (1-3). Tissue organization within the small intestine relies upon a small number of stem cells in the intestinal crypts to continuously produce several types of differentiated cells that together comprise the villous epithelium (enterocytes, goblet cells, paneth cells, and enteroendocrine cells) (4). This rapid maturation, transport, and cell loss make the small intestine particularly susceptible to toxicants that affect cell differentiation and proliferation (5, 6). The process by which dividing intestinal epithelial stem cells in the crypt produce differentiated progeny requires the transcriptional regulation of genes necessary for cell fate determination. The control of this cell fate determination pathway is dependent on a number of positive and negative transcription factors that operate in undifferentiated precursor cells of the crypt (6 -8). For example, the bHLH transcriptional repressor protein Hairy and Enhancer of split homologue-1 (Hes-1) 1 has been shown to be important in determining whether differentiating intestinal epithelial stem cells adopt an exocrine/secretory (goblet cell, enteroendocrine cell, paneth cell) fate or an absorptive (enterocyte) fate (9). Expression of Hes-1 is kn...

Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated in the etiology of this condition; however, effective therapies to block glucagon signaling and thereby regulate glucose metabolism do not exist. To determine the extent to which blocking glucagon action would reverse hyperglycemia, we targeted the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2′-methoxyethyl-modified phosphorothioate-antisense oligonucleotide (ASO) inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. Importantly, in addition to decreasing expression of cAMP-regulated genes in liver and preventing glucagon-mediated hepatic glucose production, GCGR inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP-1) and insulin levels in pancreatic islets. Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic β cell function.

Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated in the etiology of this condition; however, effective therapies to block glucagon signaling and thereby regulate glucose metabolism do not exist. To determine the extent to which blocking glucagon action would reverse hyperglycemia, we targeted the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2′-methoxyethyl-modified phosphorothioate-antisense oligonucleotide (ASO) inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. Importantly, in addition to decreasing expression of cAMP-regulated genes in liver and preventing glucagon-mediated hepatic glucose production, GCGR inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP-1) and insulin levels in pancreatic islets. Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic β cell function.

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The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Japan (JSTP), Europe (ESTP), Great Britain (BSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The primary purpose of this publication is to provide a standardized nomenclature for characterizing lesions observed in the cardiovascular (CV) system of rats and mice commonly used in drug or chemical safety assessment. The standardized nomenclature presented in this document is also available electronically for society members on the internet (http://goreni.org). Accurate and precise morphologic descriptions of changes in the CV system are important for understanding the mechanisms and pathogenesis of those changes, differentiation of natural and induced injuries and their ultimate functional consequence. Challenges in nomenclature are associated with lesions or pathologic processes that may present as a temporal or pathogenic spectrum or when natural and induced injuries share indistinguishable features. Specific nomenclature recommendations are offered to provide a consistent approach.

Tissue chips are poised to deliver a paradigm shift in drug discovery. By emulating human physiology, these chips have the potential to increase the predictive power of preclinical modeling, which in turn will move the pharmaceutical industry closer to its aspiration of clinically relevant and ultimately animal-free drug discovery. Despite the tremendous science and innovation invested in these tissue chips, significant challenges remain to be addressed to enable their routine adoption into the industrial laboratory. This article describes the main steps that need to be taken and highlights key considerations in order to transform tissue chip technology from the hands of the innovators into those of the industrial scientists. Written by scientists from 13 pharmaceutical companies and partners at the National Institutes of Health, this article uniquely captures a consensus view on the progression strategy to facilitate and accelerate the adoption of this valuable technology. It concludes that success will be delivered by a partnership approach as well as a deep understanding of the context within which these chips will actually be used. Impact statement The rapid pace of scientific innovation in the tissue chip (TC) field requires a cohesive partnership between innovators and end users. Near term uptake of these human-relevant platforms will fill gaps in current capabilities for assessing important properties of disposition, efficacy and safety liabilities. Similarly, these platforms could support mechanistic studies which aim to resolve challenges later in development (e.g. assessing the human relevance of a liability identified in animal studies). Building confidence that novel capabilities of TCs can address real world challenges while they themselves are being developed will accelerate their application in the discovery and development of innovative medicines. This article outlines a strategic roadmap to unite innovators and end users thus making implementation smooth and rapid. With the collective contributions from multiple international pharmaceutical companies and partners at National Institutes of Health, this article should serve as an invaluable resource to the multi-disciplinary field of TC development.

Opportunities in the drug discovery/development process for potential MPS incorporation.