NCATS Supports Award-Winning Technology for Drug Development

Most potential drugs fail in clinical trials despite showing promising results in preclinical studies. Thirty percent of these drugs fail because they prove to be too toxic. Not only do these failures delay getting new treatments to patients, they also put patients at risk. 

To address this challenge in drug development, NCATS supported research on a device designed to make the preclinical drug testing process more efficient and reliable. Essentially a series of pumps and valves controlled by a computer, the MultiWell MicroFormulator enables researchers to mix and deliver very small amounts of drugs or other solutions to laboratory cell models quickly and automatically. The 96-well plate is a standard tool for screening drugs for their effects on cells, with each well serving as a tiny test tube. With the MultiWell MicroFormulator, researchers can independently control the addition and removal of solution for each well, allowing them to run 96 different experiments simultaneously in one plate.

The transformative potential of the new device was acknowledged with an R&D 100 Award from R&D Magazine in late 2017. Commonly referred to as the “Oscars of Innovation,” the R&D Awards recognize the most pioneering technologies of the year. John P. Wikswo, Ph.D., professor at Vanderbilt University and director of the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE), developed the MultiWell MicroFormulator with NCATS’ support through its Tissue Chip for Drug Screening (Tissue Chip) and Small Business Innovation Research (SBIR) programs.

“The MultiWell MicroFormulator provides researchers a level of control over cell studies not previously possible,” Wikswo said. “It’s a revolutionary concept.”

Better Models for Predicting Drug Response

John Wikswo, Ph.D. (right), director of Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE), and Ronald Reiserer (left), laboratory manager of VIIBRE, receiving an R&D 100 Award from R&D Magazine for the MultiWell MicroFormulator.

One reason translating preclinical knowledge about a potential drug to the clinic can be difficult is that cell and animal models have inherent limitations. Human cell cultures, grown in the laboratory in a plate or dish, are more simplistic than the multiple cell types and 3-D structure that make up organs and tissues in the body. Animal models have biological differences from humans that can affect how a drug is metabolized and how well it works. And some diseases cannot be modeled in laboratory animals at all.

Through the development of tissue chips or “organs-on-chips,” which consist of live human tissues on a small chip, NCATS seeks to reproduce the biology and physiology of organs and tissues and model diseases in unprecedented ways. NCATS — in collaboration with nine other NIH Institutes and Centers and the U.S. Food and Drug Administration — leads the Tissue Chip program, which is designed to improve the translational science process for predicting whether drugs will be safe and effective in humans. Wikswo’s team at Vanderbilt was among 12 grantees funded in 2012 to develop tissue chips that modeled a specific organ or tissue. Using supplemental funding to model additional organs, Wikswo realized that he could engineer pumps and valves to deliver hormones or nutrients to a tissue chip system that would essentially stand in for a missing organ. This sparked the idea for the MicroFormulator, a simplified version of the award-winning device.

An early version of the MultiWell MicroFormulator delivered to AstraZeneca. (Vanderbilt University) 

After seeing Wikswo present on the MicroFormulator, the pharmaceutical company AstraZeneca approached him about adapting the device to address another challenge in drug development. When a person takes a drug, the concentration of the drug rises in the blood, reaches a maximum level, and then gradually tapers off. This process, known as a pharmacokinetic profile, is very different from adding a drug to cells in a dish or plate all at once. The company realized the device could both add a drug to and remove it from cells in a timed fashion, mimicking a real-world pharmacokinetic profile. But they wanted the device adapted to the standard 96-well plate so that it could quickly test different pharmacokinetic profiles for a given drug to identify which profile led to the best effect in cells. With that knowledge in hand, the research team could go back and modify the drug to achieve that profile.

In 2016, NCATS awarded SBIR funding for the project through CFD Research Corporation in Huntsville, Alabama, which was working with Wikswo on similar devices. The award supported hardware development as well as a computer programmer who created the software to control the pumps and valves.

The MultiWell MicroFormulator project soon achieved the ultimate goal for SBIR awards: commercialization. The U.K. biotechnology company CN Bio Innovations licensed the device in 2017.

“The software development was absolutely critical to the survival of the project,” Wikswo said. “There was marvelous confluence between the NCATS SBIR program, the needs of AstraZeneca, and the work we were doing on pumps and valves with Tissue Chip program support.”

Improving Drug Screening with 3-D Printed Tissues

NCATS also saw another potential application for the technology: to adapt it for use in 3-D bioprinted tissues. The NCATS bioprinting team creates human tissue from cells, printing them on standard cell plates to use for drug screening in place of traditional cell culture, which is just a single layer of cells. Growing tissues in plates rather than on chips has challenges. Tissue thickness requires laboratory staff to repeatedly change the culture solutions to supply the tissue with fresh nutrients and remove waste. The process is time-consuming, and removing the cells from the incubator exposes the tissues to stressful changes in temperature. In between solution changes, the tissues sit in their own waste, which does not happen in the body. All of these stresses affect how well the cells mature into a native-like tissue.

Early version of the SmartLid, which will be delivered to the NCATS 3-D Bioprinting Laboratory later in 2018. (Vanderbilt University) 

With additional NCATS SBIR support awarded in 2017, Wikswo and his partners at CFD Research Corporation are now close to completing work on a first version of a device called a “SmartLid.” The SmartLid will change the culture media automatically and continuously while the tissue plates remain in the incubator, which keeps the tissues at their preferred temperature and oxygen level. The idea is to help tissues mature more efficiently and successfully, leading to an increase in reproducible research.

“Having a standardized and scalable process for maintaining tissues and monitoring their maturation will be a major advance in the field,” said Marc Ferrer, Ph.D., 3-D bioprinting team lead in the NCATS Division of Preclinical Innovation.

Wikswo noted the importance of having support at different stages of the technology development process, from inception to getting the MultiWell MicroFormulator across the finish line to commercialization.

“There are many challenges in the tissue field,” said Lucie Low, Ph.D., program manager for the Tissue Chip program at NCATS. “This is a nice example of how, working collaboratively with academia and industry, we can spur progress in the field to ultimately deliver more treatments to patients more quickly.”

Posted March 2018