Microfluidic Multitissue Platform for Advanced Embryotoxicity Testing In Vitro

Boos, Julia Alicia; Misun, Patrick M.; Michlmayr, Astrid; Hierlemann, Andreas; Frey, Olivier

doi:10.1002/advs.201900294

Cited by 37 publications

(43 citation statements)

References 36 publications

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“…The microfluidic hanging‐drop chip was designed as an open microfluidic system 41–45 . Figure 2 a displays the layout and dimensions of the chip in a top view, while cross‐sectional views are shown in Figure 2b and Figure S1a (Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

“…The microfluidic hanging-drop chip was designed as an open microfluidic system. [41][42][43][44][45] Figure 2a displays the layout and dimensions of the chip in a top view, while cross-sectional views are shown in Figure 2b and Figure S1a (Supporting Information). Due to surface tension and capillary action, small liquid volumes can be guided underneath the surface-patterned poly(dimethylsiloxane) (PDMS) substrate.…”

Section: The Microfluidic Perifusion Systemmentioning

confidence: 99%

“…The reaggregated primary islet model featured representative and homogeneous size and native‐like distribution of endocrine cells within each aggregate, as well as physiologically relevant beta cell function. The microfluidic system design is based on the hanging‐drop technology 39–45. Single islets were loaded into and inherently placed at the bottom of a hanging‐drop.…”

Section: Introductionmentioning

confidence: 99%

“…The microfluidic system design is based on the hanging-drop technology. [39][40][41][42][43][44][45] Single islets were loaded into and inherently placed at the bottom of a hanging-drop. Microfluidic hanging-drops provide precise perifusion control due to the minimal dead volume, fast liquid exchange, and operational simplicity, while islet viability is maintained through sufficient oxygen supply in the open system.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Platform for Studying Human Insulin Release Dynamics of Single Pancreatic Islet Microtissues at High Resolution

et al. 2020

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Insulin is released from pancreatic islets in a biphasic and pulsatile manner in response to elevated glucose levels. This highly dynamic insulin release can be studied in vitro with islet perifusion assays. Herein, a novel platform to perform glucose‐stimulated insulin secretion (GSIS) assays with single islets is presented for studying the dynamics of insulin release at high temporal resolution. A standardized human islet model is developed and a microfluidic hanging‐drop‐based perifusion system is engineered, which facilitates rapid glucose switching, minimal sample dilution, low analyte dispersion, and short sampling intervals. Human islet microtissues feature robust and long‐term glucose responsiveness and demonstrate reproducible dynamic GSIS with a prominent first phase and a sustained, pulsatile second phase. Perifusion of single islet microtissues produces a higher peak secretion rate, higher secretion during the first and second phases of insulin release, as well as more defined pulsations during the second phase in comparison to perifusion of pooled islets. The developed platform enables to study compound effects on both phases of insulin secretion as shown with two classes of insulin secretagogs. It provides a new tool for studying physiologically relevant dynamic insulin secretion at comparably low sample‐to‐sample variation and high temporal resolution.

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Section: Resultsmentioning

confidence: 99%

Section: The Microfluidic Perifusion Systemmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vitro Platform for Studying Human Insulin Release Dynamics of Single Pancreatic Islet Microtissues at High Resolution

et al. 2020

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“…Aeby et al used hanging hydrogel drops to form primary human liver microtissues for more than nine days [67]. In addition, Boos et al combined primary human liver microtissues with embryoid bodies in the same hanging drop platform and found that the metabolites of primary human liver microtissues were directly transported to the EBs [68].…”

Section: Liver Chips Based On Matrixless 3d Spheroid Culturementioning

confidence: 99%

Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

et al. 2019

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Hepatology and drug development for liver diseases require in vitro liver models. Typical models include 2D planar primary hepatocytes, hepatocyte spheroids, hepatocyte organoids, and liver-on-a-chip. Liver-on-a-chip has emerged as the mainstream model for drug development because it recapitulates the liver microenvironment and has good assay robustness such as reproducibility. Liver-on-a-chip with human primary cells can potentially correlate clinical testing. Liver-on-a-chip can not only predict drug hepatotoxicity and drug metabolism, but also connect other artificial organs on the chip for a human-on-a-chip, which can reflect the overall effect of a drug. Engineering an effective liver-on-a-chip device requires knowledge of multiple disciplines including chemistry, fluidic mechanics, cell biology, electrics, and optics. This review first introduces the physiological microenvironments in the liver, especially the cell composition and its specialized roles, and then summarizes the strategies to build a liver-on-a-chip via microfluidic technologies and its biomedical applications. In addition, the latest advancements of liver-on-a-chip technologies are discussed, which serve as a basis for further liver-on-a-chip research.

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Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

et al. 2020

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Pharmacokinetic DDIs arise upon modulation of the absorption, distribution, and metabolism or excretion (ADME) properties of one drug by co-administration of another drug and can lead to massive changes of drug plasma concentrations with potentially life-threatening consequences. [6] Most commonly, a perpetrator drug modulates the metabolism of a victim drug by chemical inhibition or transcriptional induction of drug-metabolizing enzymes. In both cases, such an interaction leads to an altered metabolic fate of the victim drug. [7] The clinical implications of such interactions can result in a lack of efficacy, especially in the context of so-called prodrugs. Prodrugs are drug variants with enhanced solubility or lifetime, which rely on in vivo bioconversion to exert their pharmacological activity. [8] Positive treatment outcomes in prodrug therapies strongly depend on the ability of the patient to endogenously bioactivate the prodrug compound to its pharmacologically active metabolite(s). [9] Drug metabolism predominantly occurs in the liver and is mainly catalyzed by enzymes of the cytochrome P450 (CYP) family. These enzymes oxidize, reduce, and hydrolyze a wide range of drugs or chemical entities. Therefore, it does not come as a surprise that inhibition or induction of CYP enzymes is largely involved in clinical DDIs and has led to severe ADRs and the withdrawal of multiple drugs from the market. [10] In many cases, DDIs manifest themselves in secondary organs, to which liver-generated metabolites are transported through systemic circulation. Such tissues include kidney, heart, brain, gut, and lungs, and drug target tissues, such as tumors. [11] Oncology patients are considered especially prone to toxic DDI events owing to i) the wide use of anticancer prodrugs, [12,13] ii) the inherent toxicity of anticancer agents and their very narrow therapeutic index, iii) the likelihood of cancer patients to receive many different medications for the management of other illnesses, [14] and iv) the increasing use of combination therapies with more than one anticancer medication. [15] Hence, clinicians are confronted with the growing risk of prescribing drug combinations that can inadvertently lead to severe clinical implications. [16] Additionally, genetic polymorphisms in the liver can lead to individual patterns of CYP-enzyme-mediated metabolism for different patients. [17] Management of DDIs is, therefore, crucial in oncology therapy, where the altered Drug-drug interactions (DDIs) occur when the pharmacological activity of one drug is altered by a second drug. As multimorbidity and polypharmacotherapy are becoming more common due to the increasing age of the population, the risk of DDIs is massively increasing. Therefore, in vitro testing methods are needed to capture such multiorgan events. Here, a scalable, gravity-driven microfluidic system featuring 3D microtissues (MTs) that represent different organs for the prediction of drug-drug interactions is used. Human liver microtissues (hLiMTs) are combined with tumor m...

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Microfluidic Multitissue Platform for Advanced Embryotoxicity Testing In Vitro

Cited by 37 publications

References 36 publications

In Vitro Platform for Studying Human Insulin Release Dynamics of Single Pancreatic Islet Microtissues at High Resolution

In Vitro Platform for Studying Human Insulin Release Dynamics of Single Pancreatic Islet Microtissues at High Resolution

Engineered Liver-On-A-Chip Platform to Mimic Liver Functions and Its Biomedical Applications: A Review

Predicting Metabolism‐Related Drug–Drug Interactions Using a Microphysiological Multitissue System

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