CAMBRIDGE, MA—A new approach in drug development is to use organ-on-a-chip human tissue models because they provide more human-like results than animal studies. Drug companies and government agencies are currently using these tiny chip models to determine the impact of various drugs and chemical compounds on the liver, lung, intestine, mouth and even the brain.
Now, a new study by scientists at Draper adds to the toolbox researchers can use in understanding the biological processes underway in organ-chips. They discovered a new indicator of toxicity in kidney-chips, an advance in the science that has the potential to reduce the financial burden of drug failures in pharmaceutical development.
Erin Shaughnessey, a Draper Scholar, the paper’s first author and a Ph.D. candidate studying biomedical engineering at Tufts University, sees promise in testing drugs on kidney-chips. “Acute kidney injury is one of the most commonly reported drug-induced complications. With so many cases, we need new strategies to pre-clinically assess kidney toxicity. Kidney-on-a-chip is showing promise.”
In a study published in Scientific Reports, Draper scientists tested and evaluated a batch of kidney-chips in an instrumented, high-throughput microenvironment in a lab-friendly footprint. They paid special attention to tissue responses, toxicity levels, fluid shear stress (FSS) and other dynamics.
Specifically, the study assessed the ability of transepithelial electrical resistance (TEER) to serve as a sensitive readout to cisplatin-induced toxicity. While doing so, the scientists measured tissue response under both mono- and co-culture conditions as well as two levels of FSS. The results of this study demonstrate that TEER has potential as a rapid, early and label-free indicator of toxicity in microfluidic kidney proximal tubule microvascular co-culture models, the paper concluded.
Until now, TEER has been a challenging readout to measure in low-barrier tissues, like the kidney proximal tubule, researchers said, in part because TEER sensors in general haven't been sensitive enough or weren't integrated to the tissues' microenvironment.
The microenvironment platform, developed at Draper and called PREDICT96, generated TEER readouts for 96 individual kidney-chips in less than 8 minutes, a significant improvement over conventional toxicity assays or barrier metrics like tight junction expression, according to Else Vedula, senior author of the paper and a principal member of the technical staff at Draper. Vedula’s main research topics include in vitro tissue modeling and biomimetic microsystem development.
“Scientists investigating drug-induced kidney toxicity can benefit from our discoveries in several ways, most notably in understanding the utility of non-invasive sensing for assessing toxicity in kidney-chips used in drug development,” Vedula said. “The PREDICT96 kidney model gives scientists the tools to interrogate kidney function, control flow and culture medium and detect dose-dependent changes and nephrotoxicity. This is a new level of control in drug development.”
PREDICT96 gives scientists a way to interrogate tissue models and detect changes in tissue structure and function better than a single cell type in a static culture testbed. Scientists have the ability to screen the impact of microenvironmental cues with traditional and new readouts and validate those readouts with pre-screened tissue for toxicity assessment. Draper’s biotechnology portfolio includes tissue models of the intestine, lung, liver, vasculature, kidney, blood brain barrier, tumor and gingival tissue. PREDICT96 is also being used to evaluate immune-oncology approaches.
The paper is based on research by Shaughnessey, Vedula, Hesham Azizgolshani, principal member of the technical staff at Draper; Samuel Kann, a Draper Scholar and Ph.D. candidate studying mechanical engineering at Boston University; Lauren Black III, Ph.D. and associate professor of biomedical engineering at Tufts University; and Joseph Charest, a former member of the Draper team.
Since 1973, the Draper Scholar Program, formerly the Draper Fellow Program, has supported more than 1,000 graduate students pursuing advanced degrees in engineering and the sciences. Draper Scholars are from both civilian and military backgrounds and Draper Scholar alumni excel worldwide in the technical, corporate, government, academic and entrepreneurship sectors.