Featured Kidney Publications:

Recapitulate In Vivo Polarity

Caetano-Pinto, Pedro, et al. “Epidermal growth factor receptor mediates the basolateral uptake of phosphorothioate-modified antisense oligonucleotides in the kidney” Organs-on-a-Chip, Volume 4 (2022): 2666-1020.

ParVivo™ Chips enable a highly polarized renal epithelium, allowing researchers to study uptake of ASOs from the basolateral side of the kidney proximal tubule where 2D cultures can not.

Key words: Antisense oligonucleotide, Proximal tubule on a chip, Megalin, Epidermal growth factor receptor

Predict Clinical Outcomes

Nieskens, Tom TG, et al. "Nephrotoxic antisense oligonucleotide SPC5001 induces kidney injury biomarkers in a proximal tubule-on-a-chip." Archives of Toxicology 95.6 (2021): 2123-2136.

AstraZeneca researchers demonstrate ability to predict outcome in clinical trials using the Nortis ParVivo™ Platform, where prior preclinical in vitro and in vivo testing methods failed.

Key words: Human renal proximal tubule epithelial cells, Drug-induced toxicity, Kidney injury biomarkers, Kidney proximal tubule-on-a-chip, Antisense oligonucleotides

Mimic Tubular Physiology

Sakolish, Courtney, et al. "Predicting tubular reabsorption with a human kidney proximal tubule tissue-on-a-chip and physiologically-based modeling." Toxicology in Vitro 63 (2020): 104752.

This study combines the Nortis Human Kidney Chip with a physiological kinetic model to evaluate renal clearance and reabsorption of xenobiotics in the human proximal tubule, demonstrating a qualitative and quantitative mimicking of in vivo tubular kinetics.

Key words: Xenobiotic clearance/reabsorption, pharmacokinetics, renal clearance, renal/tubular reabsorption

Nieskens, Tom TG, et al. "A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization–Dependent Cisplatin Toxicity." Drug Metabolism and Disposition 48.12 (2020): 1303-1311.

AstraZeneca and University of Washington researchers use the Nortis Platform to demonstrate cisplatin-induced nephrotoxicity observed upon basolateral, but not apical delivery in proximal 3D-engineered tubules, resembling in vivo drug transporter activity.

Key words: Drug-induced kidney injury, nephrotoxicity, cell polarity

Chapron, Alenka, et al. "An improved vascularized, dual-channel microphysiological system facilitates modeling of proximal tubular solute secretion." ACS pharmacology & translational science 3.3 (2020): 496-508.

University of Washington researchers use Nortis Chips to develop a vascularized proximal tubule microenvironment.

Key words: Vascularized kidney model, vectoral transport, vascularized kidney

Maass, Christian, et al. "Translational assessment of drug‐induced proximal tubule injury using a kidney microphysiological system." CPT: pharmacometrics & systems pharmacology 8.5 (2019): 316-325.

This study addressed how drug-induced proximal tubule damage can be recapitulated and measured in vitro, how in vitro findings can be translated to clinical outcomes, and how the optimal dosing regimen can be identified preclinically.

Key words: Drug-induced kidney injury, preclinical nephrotoxicity model

**Yeung, Catherine K., and Jonathan Himmelfarb. "Kidneys on chips: emerging technology for preclinical drug development." Clinical Journal of the American Society of Nephrology 14.1 (2019): 144-146.**

An article summarizing the physiological relevance of the Nortis enabled kidney-on-chip model, highlighting its utility in preclinical drug development.

Key words: Preclinical nephrotoxicity model

**Sakolish, Courtney, et al. "Technology transfer of the microphysiological systems: a case study of the human proximal tubule tissue chip." Scientific reports 8.1 (2018): 1-14.**

This paper demonstrates a cross-laboratory testing case study, validating results generated by Nortis of biologically relevant effects of nephrotoxic compounds in the Nortis Human Kidney Chip model performed in an independent laboratory (Texas A&M).

Key words: technology transfer, nephrotoxicity, performance standards, nephrotoxicity biomarkers, protein/gene expression, vitamin-D metabolism, ammoniagenesis, long-term viability

**Weber, Elijah J., et al. "Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity." JCI insight 3.24 (2018).**

In this collaborative study, researchers from the University of Washington, Harvard Medical School, Helsinki University Medical School, and Northern Antibiotics Ltd., use the Nortis Human Kidney Chip to investigate the mechanism of polymyxin nephrotoxicity and to compare the safety of polymyxin-b to its structural analogs.

Key words: Polymyxin nephrotoxicity, Drug-induced kidney injury, acute kidney injury

**Miller, Chris P., et al. "A 3D human renal cell carcinoma-on-a-chip for the study of tumor angiogenesis." Neoplasia 20.6 (2018): 610-620.**

This study reveals the first ever report of the induction of endothelial sprouting in primary patient-derived tumor cells in a 3D microphysiological system from six independent donors.

Key words: clear cell renal cell carcinoma, endothelial sprouting, angiogenesis

**Chang, Shih-Yu, et al. "Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity." JCI insight 2.22 (2017).**

In this study, researchers from University of Washington and Stony Brook University use Nortis Chips to link a human kidney model to a human liver model, demonstrating that metabolism of a drug in the liver chip leads to its bioactivation, which results in nephrotoxicity in the kidney.

Key words: Drug-induced nephrotoxicity, Kidney-liver interaction, aristolochic acid nephrotoxicity, hepatic metabolism

**Weber, Elijah J., et al. "Development of a microphysiological model of human kidney proximal tubule function." Kidney international 90.3 (2016): 627-637.**

In this study, University of Washington researchers demonstrate that human renal proximal tubules in Nortis Chips exhibit long-term viability, retain polarity and function of key proteins, respond to physiological stimuli, and display reabsorption and clearance processes resembling in vivo physiology.

Key words: cell polarity, proximal tubule, cell survival

**Adler, Melanie, et al. "A quantitative approach to screen for nephrotoxic compounds in vitro." Journal of the American Society of Nephrology 27.4 (2016): 1015-1028.**

Researchers from Harvard Institutes of Medicine, University of Washington, and NIH use the Nortis ParVivo™ Platform to develop a cell-based approach for safety screening of nephrotoxic compounds, leading to the identification of sensitive biomarker for nephrotoxicity (heme oxygenase-1).

Key words: Acute kidney injury, chronic kidney disease, nephrotoxicity, HO-1

Lemos, Dario R., et al. “Maintenance of vascular integrity by pericytes is essential for normal kidney function” American Journal of Physiology-Renal Physiology331.6 (2016).

Researchers demonstrate functional role of supporting cells in kidney function using ParVivo™ Chip with human kidney microvascular endothelial cells with and without pericytes added to the matrix.

Key words: Acute Kidney Injury, Capillaries, Endothelium, Vascular, Kidney, Mice, Transgenic, Microvessels, Pericytes, Permeability

Featured Liver Publications:

**Sakolish, Courtney, et al. "Analysis of reproducibility and robustness of a human microfluidic four-cell liver acinus microphysiology system (LAMPS)." Toxicology 448 (2021): 152651.**

In the following cross-laboratory study published by University of Pittsburg researchers, a human microfluidic four-cell liver acinus MPS developed in Nortis Chips, constructed using primary human hepatocytes or human induced pluripotent stem cell (iPSC)-derived hepatocytes and 3 human cell lines for the endothelial, Kupffer and stellate cells was tested for reproducibility and robustness as a model for drug pharmacokinetics and toxicology. The results of this study show that the 3D liver model developed is highly robust and repeatable, and maintains stable basal liver function and metabolism for 10+ days in culture, and exhibits more physiologically relevant phenotypes compared to static 2D cultures.

Key words: Hepatotoxicity, drug toxicity, pharmacokinetics

**Van Ness, Kirk P., et al. "Microphysiological Systems in ADME Sciences." Clinical and Translational Science (2021).**

This review surveys current MPS developed for liver, kidney, and intestinal systems as stand-alone or interconnected organ systems, including the Nortis Platform, and evaluates each system for specific performance criteria recommended by regulatory authorities and MPS leaders that would render each system suitable for evaluating drug absorption, distribution, metabolism, elimination sciences (ADME).

Key words: ADME, liver-on-chip, kidney-on-chip, kidney-liver

**Chang, Shih-Yu, et al. "Characterization of rat or human hepatocytes cultured in microphysiological systems (MPS) to identify hepatotoxicity." Toxicology in Vitro 40 (2017): 170-183.**

This paper describes the development and validation of rat and human ‘liver-on-chip’ models using the Nortis ParVivo Platform.

Key words: Preclinical toxicology, Hepatotoxicity, In vitro models, ‘Liver-on-a-chip’, Human hepatocytes

**Vernetti, Lawrence A., et al. "A human liver microphysiological platform for investigating physiology, drug safety, and disease models." Experimental biology and medicine 241.1 (2016): 101-114.**

This paper describes the development and characterization of a human, 3D, microfluidic, four-cell, sequentially layered and self-assembled Nortis Chip enabled liver model of disease for drug safety and efficacy, fluorescent protein biosensors for mechanistic readouts as well as a MPS database to manage, analyze, and model data.

Key words: In vitro liver model, hepatotoxicity, high content analysis, liver disease models

Featured Vasculature, Cancer and Organ-Organ Combination Publications: