Nephroscreen: A robust and versatile renal tubule-on-a-chip platform for nephrotoxicity assessment

Vriend, Jelle; Vormann, Marianne K.; Lanz, Henriëtte L.; Joore, Jos; Trietsch, Sebastiaan J.; Rüssel, Frans G. M.; Jacobsen, Björn; Roth, Adrian; Lu, Shuyan; Polli, Joseph W.; Naidoo, Anita A.; Masereeuw, Rosalinde; Wilmer, Martijn J.; Suter‐Dick, Laura

doi:10.1016/j.cotox.2021.03.001

Cited by 8 publications

(9 citation statements)

References 27 publications

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“…The previous acute hypoxia models set by 1% oxygenation on 2D monolayer culture revealed a decrease in proliferation rate in a range of 30–95% [ 9 , 12 – 14 ] at 24 h and 65–99% [ 14 , 82 ] at 48 h by MTT/MTS assays. 3D microfluidic systems similarly detected a decrease in proliferation rate of PT cells in a range of 10–99% in drug-induced AKI models by WST-8 [ 69 , 72 – 74 ]. Our data related to proliferation decrease on 2D monolayer controls were totally in line with previous literature and our 3D microfluidic platform have been successful to sense the decrease in epithelial cells and screen acute hypoxic injury.…”

Section: Discussionmentioning

confidence: 99%

“…Those prototypes require pumps and external tubing for each chip, thus lacking ease of use in routine assays of PT epithelium. In recent studies, gravity-driven platforms without an artificial membrane screened 3D PT structure by zonula occludens 1 (ZO-1) and acetylated α-tubulin immunostaining [ 69 – 71 ], cellular proliferation assays [ 69 , 71 – 74 ] and epithelial barrier integrity assays [ 69 , 73 , 74 ] for drug-induced AKI. These microphysiological systems may real-time evaluate cellular therapeutics for acute hypoxic PT injury in AKI [ 61 , 75 – 77 ].…”

Section: Introductionmentioning

confidence: 99%

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Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window

Çam,

Çiftci,

Gürbüz

et al. 2024

Stem Cell Res Ther

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Background Acute hypoxic proximal tubule (PT) injury and subsequent maladaptive repair present high mortality and increased risk of acute kidney injury (AKI) - chronic kidney disease (CKD) transition. Human bone marrow mesenchymal stem cell-derived exosomes (hBMMSC-Exos) as potential cell therapeutics can be translated into clinics if drawbacks on safety and efficacy are clarified. Here, we determined the real-time effective dose and treatment window of allogeneic hBMMSC-Exos, evaluated their performance on the structural and functional integrity of 3D microfluidic acute hypoxic PT injury platform. Methods hBMMSC-Exos were isolated and characterized. Real-time impedance-based cell proliferation analysis (RTCA) determined the effective dose and treatment window for acute hypoxic PT injury. A 2-lane 3D gravity-driven microfluidic platform was set to mimic PT in vitro. ZO-1, acetylated α-tubulin immunolabelling, and permeability index assessed structural; cell proliferation by WST-1 measured functional integrity of PT. Results hBMMSC-Exos induced PT proliferation with ED50 of 172,582 µg/ml at the 26th hour. Hypoxia significantly decreased ZO-1, increased permeability index, and decreased cell proliferation rate on 24–48 h in the microfluidic platform. hBMMSC-Exos reinforced polarity by a 1.72-fold increase in ZO-1, restored permeability by 20/45-fold against 20/155 kDa dextran and increased epithelial proliferation 3-fold compared to control. Conclusions The real-time potency assay and 3D gravity-driven microfluidic acute hypoxic PT injury platform precisely demonstrated the therapeutic performance window of allogeneic hBMMSC-Exos on ischemic AKI based on structural and functional cellular data. The novel standardized, non-invasive two-step system validates the cell-based personalized theragnostic tool in a real-time physiological microenvironment prior to safe and efficient clinical usage in nephrology.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window

Çam,

Çiftci,

Gürbüz

et al. 2024

Stem Cell Res Ther

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“…The company reports "working with nearly all major pharmaceutical companies and many top-tier academic institutes". In 2021, MIMETAS Inc. and some of their collaborators, including Roche Innovation Centre, Pfizer, GlaxoSmithKline, the University of Applied Sciences, north-western Switzerland, and the Swiss Centre for Applied Human Toxicology, published their research for a renal tubule-on-a-chip for detecting drug-induced toxicology [70]. Hesperos Inc. claims the title "the original human-on-a-chip company" with CEO Michel Shuler coining the model "animal-on-a-chip" which would later become "OOC" in the early 1990s.…”

Section: Synergistic Partnerships Between Industry and Regulatory Bodies Are Driving Broad Adoption Of Oocs And Mpssmentioning

confidence: 99%

Modelling Human Physiology on-Chip: Historical Perspectives and Future Directions

2021

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For centuries, animal experiments have contributed much to our understanding of mechanisms of human disease, but their value in predicting the effectiveness of drug treatments in the clinic has remained controversial. Animal models, including genetically modified ones and experimentally induced pathologies, often do not accurately reflect disease in humans, and therefore do not predict with sufficient certainty what will happen in humans. Organ-on-chip (OOC) technology and bioengineered tissues have emerged as promising alternatives to traditional animal testing for a wide range of applications in biological defence, drug discovery and development, and precision medicine, offering a potential alternative. Recent technological breakthroughs in stem cell and organoid biology, OOC technology, and 3D bioprinting have all contributed to a tremendous progress in our ability to design, assemble and manufacture living organ biomimetic systems that more accurately reflect the structural and functional characteristics of human tissue in vitro, and enable improved predictions of human responses to drugs and environmental stimuli. Here, we provide a historical perspective on the evolution of the field of bioengineering, focusing on the most salient milestones that enabled control of internal and external cell microenvironment. We introduce the concepts of OOCs and Microphysiological systems (MPSs), review various chip designs and microfabrication methods used to construct OOCs, focusing on blood-brain barrier as an example, and discuss existing challenges and limitations. Finally, we provide an overview on emerging strategies for 3D bioprinting of MPSs and comment on the potential role of these devices in precision medicine.

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“…[25] High-throughput microfluidic systems have the added benefit of efficiency by providing more parallel replicates to examine a variety of endpoints. [26][27][28] Several studies have evaluated highthroughput microfluidic systems for nephrotoxicity screening applications, [28][29][30] but few studies have utilized this technology to establish in vitro models of kidney IRI. Vormann et al recently described a co-culture model of kidney IRI in a high-throughput platform consisting of 40 distinct microfluidic devices, but this system relied on a rocker to drive fluid flow, resulting in bidirectional fluid shear stress (FSS) not experienced by PT tissues in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…High‐throughput microfluidic systems have the added benefit of efficiency by providing more parallel replicates to examine a variety of endpoints. [ 26–28 ] Several studies have evaluated high‐throughput microfluidic systems for nephrotoxicity screening applications, [ 28–30 ] but few studies have utilized this technology to establish in vitro models of kidney IRI. Vormann et al.…”

Section: Introductionmentioning

confidence: 99%

Human Kidney Proximal Tubule‐Microvascular Model Facilitates High‐Throughput Analyses of Structural and Functional Effects of Ischemia‐Reperfusion Injury

Shaughnessey,

Kann,

Charest

et al. 2023

Advanced Biology

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Kidney ischemia reperfusion injury (IRI) poses a major global healthcare burden, but effective treatments remain elusive. IRI involves a complex interplay of tissue‐level structural and functional changes caused by interruptions in blood and filtrate flow and reduced oxygenation. Existing in vitro models poorly replicate the in vivo injury environment and lack means of monitoring tissue function during the injury process. Here, a high‐throughput human primary kidney proximal tubule (PT)‐microvascular model is described, which facilitates in‐depth structural and rapid functional characterization of IRI‐induced changes in the tissue barrier. The PREDICT96 (P96) microfluidic platform's user‐controlled fluid flow can mimic the conditions of IR to induce pronounced changes in cell structure that resemble clinical and in vivo phenotypes. High‐throughput trans‐epi/endo‐thelial electrical resistance (TEER) sensing is applied to non‐invasively track functional changes in the PT‐microvascular barrier during the two‐stage injury process and over repeated episodes of injury. Notably, ischemia causes an initial increase in tissue TEER followed by a sudden increase in permeability upon reperfusion, and this biphasic response occurs only with the loss of both fluid flow and oxygenation. This study demonstrates the potential of the P96 kidney IRI model to enhance understanding of IRI and fuel therapeutic development.

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Nephroscreen: A robust and versatile renal tubule-on-a-chip platform for nephrotoxicity assessment

Cited by 8 publications

References 27 publications

Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window

Allogeneic bone marrow mesenchymal stem cell-derived exosomes alleviate human hypoxic AKI-on-a-Chip within a tight treatment window

Modelling Human Physiology on-Chip: Historical Perspectives and Future Directions

Human Kidney Proximal Tubule‐Microvascular Model Facilitates High‐Throughput Analyses of Structural and Functional Effects of Ischemia‐Reperfusion Injury

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