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Transepithelial electrical resistance assay

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The Transepithelial Electrical Resistance (TEER) Assay is a cell-based quantitative method for measuring the integrity of tight cell junctions of endothelial or epithelial monolayers based on TEER values (in ohms). The TEER Assay uses an electrical current to run through the cell monolayer to measure the resistance of a monolayer's tight junctions. The higher the ohm value measured the tighter the junction is between the barrier cells in a monolayer. TEER Assay has been used as a diagnostic tool for measuring the effectiveness of permeabilization agents particularly in drug delivery. TEER assays can be used to model drug or toxicant kinetics through a monolayer in-vitro, and so the assay is typically used for different biological barriers such as the blood-brain barrier (BBB), gastrointestinal (GI) tract, and pulmonary models.[1]

In typical TEER assays, monolayers are first formed on Transwell inserts that are then placed in wells on a well-plate. The insert is placed in cell medium beneath and above the insert, creating a basal (bottom) side and an apical (top) side of monolayer in the well. A device called an epithelial voltohmeter (EVOM) is then used to measure and display TEER measurements using two probes connected to it. One of probes is placed in the basal side, while the other probe is placed on the apical side. The measurements are performed in real-time; additionally, the measurements are very sensitive and can be significantly altered by factors such as temperature, medium formulation, and passage number of cells.[1]


TEER Measurement Method[edit]

Ohm's Law[edit]

The TEER Assay applies an alternating current (AC) through the monolayer to determine the resistance and thus the integrity of a biological barrier. To determine the resistance measurement of a monolayer, a recorded reading of a blank Transwell insert without cells is subtracted from a measured reading of an insert with the grown monolayer. TEER measurements are typically inversely proportional to the effective area of the monolayer in the insert, meaning that TEER measurements become higher as the effective area decreases and vice versa. This inversely proportional relationship between TEER value of a tissue (R) and effective area of the membrane (M) can be shown through the following equation:[1]

Applications/Examples in Biological Modeling[edit]

TEER Assays have been used in various research studies to determine the integrity of cell junctions in-vitro for the following:

Blood-Brain Barrier (BBB)[edit]

TEER Assays are developed for the BBB since in-vivo models from different species, such as rat and mice, don't translate very well to humans. Therefore, researchers have been looking into a reliable in-vitro model to measure the barrier integrity of the BBB. Two challenges associated with creating a proper human BBB model is the lack of human BBB cells and poor barrier formation when attempting to grow human endothelial cells. Currently, there has been development of a human BBB model for TEER Assay using a combination of pluripotent stem cells and chemical treatment.[2][3]

Gastrointestinal (GI) Tract[edit]

TEER Assays are attempted to be applied to GI tract since a proper model could give insight into how nutrients and drugs are delivered through the GI tract's epithelial layer junctions. Some research studies have developed Caco-2 endothelial cells from the colon or rectum to imitate GI epithelial cells and its integrity has shown to be properly measured by the TEER assay.[4][5]

Pulmonary Models[edit]

Lung epithelial cells are characterized by tight junctions that are covered by a lung surfactant. TEER Assays are attempted to be applied to pulmonary airway models since the integrity of lung epithelial cells can be easily damaged from shear and/or mechanical stresses. Pulmonary models have been replicated using each using cells that have been individually isolated from rat, dog, bovine, horse, and human. These endothelial cells have been grown using an air-liquid interface where cell medium is placed beneath the growing cells, but the top layer is only exposed to air instead of cell medium.[6][7]

Organ-on-Chips[edit]

Lung On a Chip Model

Since there are many external environmental factors that could affect TEER measurements, TEER Assays have been commonly implemented into organ-on-chip models that use small electrodes and a small effective area of an organ to create consistent results that would be unaffected by factors such as temperature, medium formulation, and human error that could occur from manually handling the probes. TEER Assays have been implemented to chips that have been used to model the function of a human placenta.[1][8]

Notes and References[edit]

  1. 1.0 1.1 1.2 1.3 Srinivasan, Balaji; Kolli, Aditya R.; Esch, Mandy B.; Abaci, Hasan E.; Shuler, Michael L.; Hickman, James J. (April 2015). "TEER measurement techniques for in vitro barrier model systems". Journal of Laboratory Automation. 20 (2): 107–126. doi:10.1177/2211068214561025. PMC 4652793. PMID 25586998.
  2. Lippmann, Ethan S.; Azarin, Samira M.; Kay, Jennifer E.; Nessler, Randy A.; Wilson, Hannah K.; Al-Ahmad, Abraham; Palecek, Sean P.; Shusta, Eric V. (August 2012). "Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells". Nature Biotechnology. 30 (8): 783–791. doi:10.1038/nbt.2247. ISSN 1546-1696. PMC 3467331. PMID 22729031.
  3. Lippmann, Ethan S.; Azarin, Samira M.; Kay, Jennifer E.; Nessler, Randy A.; Wilson, Hannah K.; Al-Ahmad, Abraham; Palecek, Sean P.; Shusta, Eric V. (August 2012). "Human Blood-Brain Barrier Endothelial Cells Derived from Pluripotent Stem Cells". Nature Biotechnology. 30 (8): 783–791. doi:10.1038/nbt.2247. ISSN 1087-0156. PMC 3467331. PMID 22729031.
  4. Ferruzza, Simonetta; Rossi, Carlotta; Scarino, Maria Laura; Sambuy, Yula (December 2012). "A protocol for in situ enzyme assays to assess the differentiation of human intestinal Caco-2 cells". Toxicology in Vitro. 26 (8): 1247–1251. doi:10.1016/j.tiv.2011.11.007. ISSN 1879-3177. PMID 22123491.
  5. Matsumoto, H.; Erickson, R. H.; Gum, J. R.; Yoshioka, M.; Gum, E.; Kim, Y. S. (May 1990). "Biosynthesis of alkaline phosphatase during differentiation of the human colon cancer cell line Caco-2". Gastroenterology. 98 (5 Pt 1): 1199–1207. doi:10.1016/0016-5085(90)90334-w. ISSN 0016-5085. PMID 2323513.
  6. Pezzulo, Alejandro A.; Starner, Timothy D.; Scheetz, Todd E.; Traver, Geri L.; Tilley, Ann E.; Harvey, Ben-Gary; Crystal, Ronald G.; McCray, Paul B.; Zabner, Joseph (January 2011). "The air-liquid interface and use of primary cell cultures are important to recapitulate the transcriptional profile of in vivo airway epithelia". American Journal of Physiology. Lung Cellular and Molecular Physiology. 300 (1): L25–31. doi:10.1152/ajplung.00256.2010. ISSN 1522-1504. PMC 3023285. PMID 20971803.
  7. Lin, Hongxia; Li, Hong; Cho, Hyun-Jong; Bian, Shengjie; Roh, Hwan-Jung; Lee, Min-Ki; Kim, Jung Sun; Chung, Suk-Jae; Shim, Chang-Koo; Kim, Dae-Duk (February 2007). "Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studies". Journal of Pharmaceutical Sciences. 96 (2): 341–350. doi:10.1002/jps.20803. ISSN 0022-3549. PMID 17080426.
  8. Pemathilaka, Rajeendra L. (2016). "Analysis of trans-epithelial electrical resistance (TEER) in organ-on-chips to study the functions of human placenta". Iowa State University Digital Repository. Retrieved November 17, 2019. Unknown parameter |url-status= ignored (help)




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