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    Organ-on-a-chip technologies that can transform ophthalmic drug discovery and disease modeling. Haderspeck Jasmin C,Chuchuy Johanna,Kustermann Stefan,Liebau Stefan,Loskill Peter Expert opinion on drug discovery INTRODUCTION:Disorders of the eye that lead to visual impairment are affecting millions of people worldwide. Nevertheless, for many of these disorders, there are still no effective treatment options available due to the lack of in vitro model systems that emulate the physiological in vivo structure and function of human eyes. Microphysiological organ-on-a-chip (OoC) technology represents a novel and powerful approach to overcome the limitations of conventional model systems and lead to a paradigm shift in ophthalmic research. Areas covered: This review provides an overview of the various tissues of interest in ophthalmology and summarizes existing model systems, including their applications and limitations. Additionally, novel OoC systems with applications in ophthalmology are described and the advantages of these systems compared to conventional models are highlighted. Expert opinion: The physiological relevance of the first ophthalmic OoC systems that mimic human ocular compartments, such as the cornea and retina, has been successfully demonstrated in recent years. There is a great potential for the application of these platforms for future pharmacological target identification, safety, and efficacy testing, as well as personalized medicine. Further improvements and the development of new systems are of upmost importance, especially to model complex disorders affecting several tissues. 10.1080/17460441.2019.1551873
    Organ/body-on-a-chip based on microfluidic technology for drug discovery. Kimura Hiroshi,Sakai Yasuyuki,Fujii Teruo Drug metabolism and pharmacokinetics Although animal experiments are indispensable for preclinical screening in the drug discovery process, various issues such as ethical considerations and species differences remain. To solve these issues, cell-based assays using human-derived cells have been actively pursued. However, it remains difficult to accurately predict drug efficacy, toxicity, and organs interactions, because cultivated cells often do not retain their original organ functions and morphologies in conventional in vitro cell culture systems. In the μTAS research field, which is a part of biochemical engineering, the technologies of organ-on-a-chip, based on microfluidic devices built using microfabrication, have been widely studied recently as a novel in vitro organ model. Since it is possible to physically and chemically mimic the in vitro environment by using microfluidic device technology, maintenance of cellular function and morphology, and replication of organ interactions can be realized using organ-on-a-chip devices. So far, functions of various organs and tissues, such as the lung, liver, kidney, and gut have been reproduced as in vitro models. Furthermore, a body-on-a-chip, integrating multi organ functions on a microfluidic device, has also been proposed for prediction of organ interactions. We herein provide a background of microfluidic systems, organ-on-a-chip, Body-on-a-chip technologies, and their challenges in the future. 10.1016/j.dmpk.2017.11.003
    3D cell culture models and organ-on-a-chip: Meet separation science and mass spectrometry. Lin Ann,Sved Skottvoll Frøydis,Rayner Simon,Pedersen-Bjergaard Stig,Sullivan Gareth,Krauss Stefan,Ray Wilson Steven,Harrison Sean Electrophoresis In vitro derived simplified 3D representations of human organs or organ functionalities are predicted to play a major role in disease modeling, drug development, and personalized medicine, as they complement traditional cell line approaches and animal models. The cells for 3D organ representations may be derived from primary tissues, embryonic stem cells or induced pluripotent stem cells and come in a variety of formats from aggregates of individual or mixed cell types, self-organizing in vitro developed "organoids" and tissue mimicking chips. Microfluidic devices that allow long-term maintenance and combination with other tissues, cells or organoids are commonly referred to as "microphysiological" or "organ-on-a-chip" systems. Organ-on-a-chip technology allows a broad range of "on-chip" and "off-chip" analytical techniques, whereby "on-chip" techniques offer the possibility of real time tracking and analysis. In the rapidly expanding tool kit for real time analytical assays, mass spectrometry, combined with "on-chip" electrophoresis, and other separation approaches offer attractive emerging tools. In this review, we provide an overview of current 3D cell culture models, a compendium of current analytical strategies, and we make a case for new approaches for integrating separation science and mass spectrometry in this rapidly expanding research field. 10.1002/elps.201900170
    Human in vitro vascularized micro-organ and micro-tumor models are reproducible organ-on-a-chip platforms for studies of anticancer drugs. Liu Yizhong,Sakolish Courtney,Chen Zunwei,Phan Duc T T,Bender R Hugh F,Hughes Christopher C W,Rusyn Ivan Toxicology Angiogenesis is a complex process that is required for development and tissue regeneration and it may be affected by many pathological conditions. Chemicals and drugs can impact formation and maintenance of the vascular networks; these effects may be both desirable (e.g., anti-cancer drugs) or unwanted (e.g., side effects of drugs). A number of in vivo and in vitro models exist for studies of angiogenesis and endothelial cell function, including organ-on-a-chip microphysiological systems. An arrayed organ-on-a-chip platform on a 96-well plate footprint that incorporates perfused microvessels, with and without tumors, was recently developed and it was shown that survival of the surrounding tissue was dependent on delivery of nutrients through the vessels. Here we describe a technology transfer of this complex microphysiological model between laboratories and demonstrate that reproducibility and robustness of these tissue chip-enabled experiments depend primarily on the source of the endothelial cells. The model was highly reproducible between laboratories and was used to demonstrate the advantages of the perfusable vascular networks for drug safety evaluation. As a proof-of-concept, we tested Fluorouracil (1-1,000 μM), Vincristine (1-1,000 nM), and Sorafenib (0.1-100 μM), in the perfusable and non-perfusable micro-organs, and in a colon cancer-containing micro-tumor model. Tissue chip experiments were compared to the traditional monolayer cultures of endothelial or tumor cells. These studies showed that human in vitro vascularized micro-organ and micro-tumor models are reproducible organ-on-a-chip platforms for studies of anticancer drugs. The data from the 3D models confirmed advantages of the physiological environment as compared to 2D cell cultures. We demonstrated how these models can be translated into practice by verifying that the endothelial cell source and passage are critical elements for establishing a perfusable model. 10.1016/j.tox.2020.152601
    Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review. Cong Ye,Han Xiahe,Wang Youping,Chen Zongzheng,Lu Yao,Liu Tingjiao,Wu Zhengzhi,Jin Yu,Luo Yong,Zhang Xiuli Micromachines Organ-on-a-chip academic research is in its blossom. Drug toxicity evaluation is a promising area in which organ-on-a-chip technology can apply. A unique advantage of organ-on-a-chip is the ability to integrate drug metabolism and drug toxic processes in a single device, which facilitates evaluation of toxicity of drug metabolites. Human organ-on-a-chip has been fabricated and used to assess drug toxicity with data correlation with the clinical trial. In this review, we introduced the microfluidic chip models of liver, kidney, heart, nerve, and other organs and multiple organs, highlighting the application of these models in drug toxicity detection. Some biomarkers of toxic injury that have been used in organ chip platforms or have potential for use on organ chip platforms are summarized. Finally, we discussed the goals and future directions for drug toxicity evaluation based on organ-on-a-chip technology. 10.3390/mi11040381
    A multi-organ-chip co-culture of liver and testis equivalents: a first step toward a systemic male reprotoxicity model. Baert Y,Ruetschle I,Cools W,Oehme A,Lorenz A,Marx U,Goossens E,Maschmeyer I Human reproduction (Oxford, England) STUDY QUESTION:Is it possible to co-culture and functionally link human liver and testis equivalents in the combined medium circuit of a multi-organ chip? SUMMARY ANSWER:Multi-organ-chip co-cultures of human liver and testis equivalents were maintained at a steady-state for at least 1 week and the co-cultures reproduced specific natural and drug-induced liver-testis systemic interactions. WHAT IS KNOWN ALREADY:Current benchtop reprotoxicity models typically do not include hepatic metabolism and interactions of the liver-testis axis. However, these are important to study the biotransformation of substances. STUDY DESIGN, SIZE, DURATION:Testicular organoids derived from primary adult testicular cells and liver spheroids consisting of cultured HepaRG cells and hepatic stellate cells were loaded into separate culture compartments of each multi-organ-chip circuit for co-culture in liver spheroid-specific medium, testicular organoid-specific medium or a combined medium over a week. Additional multi-organ-chips (single) and well plates (static) were loaded only with testicular organoids or liver spheroids for comparison. Subsequently, the selected type of medium was supplemented with cyclophosphamide, an alkylating anti-neoplastic prodrug that has demonstrated germ cell toxicity after its bioactivation in the liver, and added to chip-based co-cultures to replicate a human liver-testis systemic interaction in vitro. Single chip-based testicular organoids were used as a control. Experiments were performed with three biological replicates unless otherwise stated. PARTICIPANTS/MATERIALS, SETTING, METHODS:The metabolic activity was determined as glucose consumption and lactate production. The cell viability was measured as lactate dehydrogenase activity in the medium. Additionally, immunohistochemical and real-time quantitative PCR end-point analyses were performed for apoptosis, proliferation and cell-specific phenotypical and functional markers. The functionality of Sertoli and Leydig cells in testicular spheroids was specifically evaluated by measuring daily inhibin B and testosterone release, respectively. MAIN RESULTS AND THE ROLE OF CHANCE:Co-culture in multi-organ chips with liver spheroid-specific medium better supported the metabolic activity of the cultured tissues compared to other media tested. The liver spheroids did not show significantly different behaviour during co-culture compared to that in single culture on multi-organ-chips. The testicular organoids also developed accordingly and produced higher inhibin B but lower testosterone levels than the static culture in plates with testicular organoid-specific medium. By comparison, testosterone secretion by testicular organoids cultured individually on multi-organ-chips reached a similar level as the static culture at Day 7. This suggests that the liver spheroids have metabolised the steroids in the co-cultures, a naturally occurring phenomenon. The addition of cyclophosphamide led to upregulation of specific cytochromes in liver spheroids and loss of germ cells in testicular organoids in the multi-organ-chip co-cultures but not in single-testis culture. LARGE-SCALE DATA:N/A. LIMITATIONS, REASONS FOR CAUTION:The number of biological replicates included in this study was relatively small due to the limited availability of individual donor testes and the labour-intensive nature of multi-organ-chip co-cultures. Moreover, testicular organoids and liver spheroids are miniaturised organ equivalents that capture key features, but are still simplified versions of the native tissues. Also, it should be noted that only the prodrug cyclophosphamide was administered. The final concentration of the active metabolite was not measured. WIDER IMPLICATIONS OF THE FINDINGS:This co-culture model responds to the request of setting up a specific tool that enables the testing of candidate reprotoxic substances with the possibility of human biotransformation. It further allows the inclusion of other human tissue equivalents for chemical risk assessment on the systemic level. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by research grants from the Scientific Research Foundation Flanders (FWO), Universitair Ziekenhuis Brussel (scientific fund Willy Gepts) and the Vrije Universiteit Brussel. Y.B. is a postdoctoral fellow of the FWO. U.M. is founder, shareholder and CEO of TissUse GmbH, Berlin, Germany, a company commercializing the Multi-Organ-Chip platform systems used in the study. The other authors have no conflict of interest to declare. 10.1093/humrep/deaa057
    Global Trends of Organoid and Organ-On-a-Chip in the Past Decade: A Bibliometric and Comparative Study. Wang Zhen,He Xingdao,Qiao Haowen,Chen Pu Tissue engineering. Part A Organoid and organ-on-a-chip have evolved as two critical but distinct approaches to develop human physiologically and pathologically relevant models. Although rapid progress has been witnessed in the past decade, there is no systematic comparison of their status and trends based on the scientometric analysis. In this study, we performed a comparative study of organoid and organ-on-a-chip using bibliometric methods. A total of 2790 documents published between 2009 and 2018 were retrieved and analyzed. Our results showed that both organoid and organ-on-a-chip had experienced rapid growth in their academic and social impacts and influenced a wide spectrum of disciplines, but with a major distinct focus on Cell Biology and Nanoscience Nanotechnology, respectively. The hotspots of organoid research were expanding from differentiation of Lgr5 stem cells to mechanistic studies of diseases, while the hotspots of the organ-on-a-chip research were transiting from the establishment of microfluidic devices for cell culture to stem cell differentiation and tissue engineering. Interestingly, there was a growing trend of combining organoid with organ-on-a-chip in the last few years. This comparative study presented a unique perspective to understand the evolutive history and future trends of organoid and organ-on-a-chip for emerging human relevant organotypic models. Impact statement Organoid and organ-on-a-chip, which served as emerging human physiologically and pathologically relevant models, hold a great promise to revolutionize the conventional paradigm in basic and clinical research. The fields of organoid and organ-on-a-chip have advanced rapidly over the past decade while lacking comparative studies based on bibliometric methods. This article provided the first scientometric study of these two fields from the unique perspectives of their research hotspots, influencing scientific areas, and global trends. Our bibliometric work will provide a quantitative and timely summary of these two fields for the researchers in the tissue engineering field. 10.1089/ten.TEA.2019.0251
    Mimicking the Kidney: A Key Role in Organ-on-Chip Development. Paoli Roberto,Samitier Josep Micromachines Pharmaceutical drug screening and research into diseases call for significant improvement in the effectiveness of current in vitro models. Better models would reduce the likelihood of costly failures at later drug development stages, while limiting or possibly even avoiding the use of animal models. In this regard, promising advances have recently been made by the so-called "organ-on-chip" (OOC) technology. By combining cell culture with microfluidics, biomedical researchers have started to develop microengineered models of the functional units of human organs. With the capacity to mimic physiological microenvironments and vascular perfusion, OOC devices allow the reproduction of tissue- and organ-level functions. When considering drug testing, nephrotoxicity is a major cause of attrition during pre-clinical, clinical, and post-approval stages. Renal toxicity accounts for 19% of total dropouts during phase III drug evaluation-more than half the drugs abandoned because of safety concerns. Mimicking the functional unit of the kidney, namely the nephron, is therefore a crucial objective. Here we provide an extensive review of the studies focused on the development of a nephron-on-chip device. 10.3390/mi7070126
    Human organotypic bioconstructs from organ-on-chip devices for human-predictive biological insights on drug candidates. Cavero Icilio,Guillon Jean-Michel,Holzgrefe Henry H Expert opinion on drug safety INTRODUCTION:Historically, drug development and marketing failures have been experienced by pharma organizations largely from insufficient human-predictability of biological data. AREAS COVERED:Organs-on-chips (OOCs) are emerging, cutting edge microphysiology systems for production of microengineered three-dimensional, miniature organotypic constructs obtained by cultivating small amounts of human primary, or induced pluripotent stem, cells in native-like microhabitats. These preparations circumvent experimental limitations inherent to animal assays and two-dimensional monolayers, the mainstay core biological assays of traditional drug research. This report reviews the fundamental tenets, key components (chip plate, biomaterials, cell differentiation approaches, and monitoring sensors) and issues concerning OOC systems (engineered top-down and bottom-up strategies for tissue/organ assembly, public aids to OOC development, regulatory validation, advantages, limitations, prospective and perspective of OOCs, ethics). Examples of OOC platforms (cancer-, lung-, blood-brain barrier-, heart-, intestine-, kidney-, liver-, pharmacokinetics-, placenta and vessel-on-chip) and their importance for drug research and development are presented. EXPERT OPINION:OOC device-generated bioconstructs hold great promise as experimental human tissue and organ platforms for generating human-pertinent knowledge on drug candidates for clinical assessment and reducing reliance on animal models. MPS technologies currently enable ready-to-assemble tissue patches and, hopefully, in coming decades, full-size, patient-personalized organs for regenerative medical interventions. 10.1080/14740338.2019.1634689
    A virus-induced kidney disease model based on organ-on-a-chip: Pathogenesis exploration of virus-related renal dysfunctions. Wang Ji,Wang Cheng,Xu Na,Liu Zheng-Fei,Pang Dai-Wen,Zhang Zhi-Ling Biomaterials Renal dysfunctions usually happen in viral infections and many viruses specially infect distal renal tubules, however the pathogenesis remains unknown. Here, in order to explore the pathogenesis of virus-related renal dysfunctions, a Pseudorabies Virus (PrV) induced kidney disease model was built on a distal tubule-on-a-chip (DTC), for the first time. The barrier structure and Na reabsorption of distal renal tubules were successfully reconstituted in DTCs. After PrV infection, results showed electrolyte regulation dysfunction in Na reabsorption for the disordered Na transporters, the broken reabsorption barrier, and the transformed microvilli. And it would lead to virus induced serum electrolyte abnormalities. This work brought us a new cognition about the advantages of organ-on-a-chip (OOC) in virus research, for it had given us a better insight into the pathogenesis of virus induced dysfunctions, based on its unique ability in function reproduction. 10.1016/j.biomaterials.2019.119367
    Evolution of Biochip Technology: A Review from Lab-on-a-Chip to Organ-on-a-Chip. Azizipour Neda,Avazpour Rahi,Rosenzweig Derek H,Sawan Mohamad,Ajji Abdellah Micromachines Following the advancements in microfluidics and lab-on-a-chip (LOC) technologies, a novel biomedical application for microfluidic based devices has emerged in recent years and microengineered cell culture platforms have been created. These micro-devices, known as organ-on-a-chip (OOC) platforms mimic the in vivo like microenvironment of living organs and offer more physiologically relevant in vitro models of human organs. Consequently, the concept of OOC has gained great attention from researchers in the field worldwide to offer powerful tools for biomedical researches including disease modeling, drug development, etc. This review highlights the background of biochip development. Herein, we focus on applications of LOC devices as a versatile tool for POC applications. We also review current progress in OOC platforms towards body-on-a-chip, and we provide concluding remarks and future perspectives for OOC platforms for POC applications. 10.3390/mi11060599
    Potential of Drug Efficacy Evaluation in Lung and Kidney Cancer Models Using Organ-on-a-Chip Technology. Hwang Seong-Hye,Lee Sangchul,Park Jee Yoon,Jeon Jessie Sungyun,Cho Young-Jae,Kim Sejoong Micromachines Organ-on-a-chip (OoC) is an exponential technology with the potential to revolutionize disease, toxicology research, and drug discovery. Recent advances in OoC could be utilized for drug screening in disease models to evaluate the efficacy of new therapies and support new tools for the understanding of disease mechanisms. Rigorous validation of this technology is required to determine whether OoC models may represent human-relevant physiology and predict clinical outcomes in target disease models. Achievements in the OoC field could reveal exciting new avenues for drug development and discovery. This review attempts to highlight the benefits of OoC as per our understanding of the cellular and molecular pathways in lung and kidney cancer models, and discusses the challenges in evaluating drug efficacy. 10.3390/mi12020215