CAMBRIDGE, MA—There are many reasons that promising drugs fail during pharmaceutical development, and one of them is kidney damage. Many experimental drugs, it turns out, cause damage to the extent that they inhibit a kidney’s cell metabolism and critical oxygen consumption rate (OCR)—vexing side effects that can render a potential drug toxic in humans.
These and other failures can make drug development “expensive, inefficient and often unproductive,” says Draper researcher Samuel Kann. Accurately predicting a drug’s effect in humans during clinical trials isn’t easy. Only one in eight new drugs makes it to market. A major hurdle in preclinical trials is a reliance on animal models or on cell culture models that fail to replicate key functions of the human body.
Kann and a research team at Draper studied the problem in a series of experiments that used Draper’s human cell-based kidney-on-a-chip. They exposed kidney-chips to three benchmark drug compounds—Antimycin, Oligomycin and FCCP—and watched for previously hard-to-measure changes in the kidney proximal tubule epithelial cells, which are the most populous cell type in the kidney, and its mitochondria, a key target in drug development.
The team used an oxygen sensing system integrated into Draper’s PREDICT96 microenvironment containing 96 kidney-on-chip tissues, enabling them to measure a cell’s oxygen consumption rate, an important readout of mitochondrial function.
PREDICT96 is an organ-on-a-chip device seamlessly configured into an industry-standard multi-well cell culture plate, composed of 96 individual co-culture devices and a perfusion system driven by 192 microfluidic pumps integrated into the plate lid. PREDICT96’s ability to mimic the perfusion flow conditions in the human kidney enabled researchers to measure drug-induced metabolic shifts resulting from drug treatments.
Kann and his co-authors published their findings in the journal Microsystems & Nanoengineering. “For the first time, we measured changes in oxygen in a membrane bilayer format and used a finite element analysis model to estimate cell oxygen consumption rates, allowing comparison with OCRs from other cell culture systems,” the researchers said. The research demonstrated a capability that will be valuable for analyzing flow-responsive and physiologically complex tissues during drug development and disease research, according to the paper.
Else Vedula, one of the senior authors of the paper and a principal member of the technical staff at Draper, said that PREDICT96’s versatility brings immense potential to enhance human health research. “With it, we are bringing the benefits of organ-on-a-chip technology out of the research laboratory and into the standard pharmaceutical manufacturing environment.”
PREDICT96 gives scientists a way to interrogate miniature human tissues (models) and detect changes in tissue structure and function better than a single cell type in a static culture testbed or many animal models. Scientists have the ability to screen the impact of microenvironmental cues with traditional and new readouts and use those readouts with pre-screened tissue for predicting toxicity assessment in humans. 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 Kann, a Draper Scholar and Ph.D. candidate studying mechanical engineering at Boston University; Erin Shaughnessey; Jonathan Coppeta; Hesham Azizgolshani; Brett Isenberg; and Vedula, of Draper; Xin Zhang, a professor of mechanical, electrical, computer and biomedical engineering and materials science at Boston 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.