Advancing preclinical drug testing with Organ-on-a-Chip innovations
Drug development is a time-consuming process that often takes up to 15 years and involves both preclinical and clinical stages. Nearly 10 % of drugs fail in clinical trials due to unsuitable preclinical models that provide inaccurate estimation of drug efficacy, toxicity, and pharmacokinetics-pharmacodynamics. The innovative Organ-on-a-Chip technology is gaining ground over conventional 2D cell cultures as a preclinical model for testing drug efficacy and toxicity. This system comprises a setup of microfluidic channels and chambers seeded with living cells to mimic the structure and function of human organs. Importantly, it allows researchers to study complex physiological processes in a controlled laboratory environment.
Measuring the electrical properties of tissues in Organ-on-a-Chip devices
To ensure that Organ-on-a-Chip devices continuously maintain their integrity and function, the PORTable STaNDOuTs project proposed to integrate a sensor conventionally used to assess epithelial and endothelial tissue barriers. Existing in various places in the body such as the skin, the eyes, and the intestine, they are responsible for maintaining organ homeostasis and regulating interaction with other tissues/organs. The research of PORTable STaNDOuTs was undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA) programme and allowed the collaboration Divyasree Prabhakaran, expert in novel materials and biosensors, and her incorporation to the team. The work involved the measurement of the electrical resistance across the cell monolayers in the Organ-on-a-Chip through the method of transepithelial electrical resistance (TEER). TEER quantifies the passage of ions and molecules across cellular barriers in a rapid and non-invasive manner, providing valuable information about cellular and tissue function. “Our goal was to evaluate the barrier properties in Organ-on-a-Chip devices based on multi-well cell-culture standards as an accurate way of monitoring physiological conditions and drug responses,” explains project coordinator Antoni Homs-Corbera. The team developed a novel multi-well cell culture plate with sensors that was combined with other patented technologies of the Cherry Biotech SAS company to generate a sensor prototype capable of providing measurements in 3D human cell cultures under controlled conditions for several days. The monitored parameters offered an accurate estimation of tissue permeability in real time and predicted drug transport across these barriers in the early stages of drug discovery.
Applications and beyond
“One of the most significant achievements of PORTable STaNDOuTs was the compatibility of the TEER sensor with standard experimental pipelines which is expected to widen the use of microfluidics and Organ-on-a-Chip in drug toxicity testing,” emphasises Homs-Corbera. The overarching goal is to establish a robust microfluidic platform that offers the possibility of concurrently monitoring diverse biochemical and physiological parameters such as TEER, dissolved oxygen, pH, glucose, and lactate. The development of an all-in-one device containing compartments that mimic the intestine, liver, and kidney functions would offer a reliable way of assessing drug absorption, distribution, metabolism, and excretion. Moreover, it would assess both drug impact on tissue integrity and drug-induced organ toxicity due to metabolites from oral drugs. This chip would pave the way towards animal-free testing during drug development. Integration of other technologies, such as AI, in a highly user-friendly platform that requires minimum expert training would further enhance the device capabilities. The project team aims to continue integrating their novel electrophysiological capacity in drug testing platforms and refine the preliminary results. They also plan to validate the platform using known drugs already tested in humans and with known pharmacokinetics-pharmacodynamics.
Keywords
PORTable STaNDOuTs, drug development, toxicity, Organ-on-a-Chip, microfluidic, transepithelial electrical resistance, TEER, tissue barrier
