Sparing nerves from injury remains a huge problem for surgeons. Researchers in Oregon have developed a possible solution: nerve-specific fluorescent dyes that allow operators to view nerves deeper within tissues than previously possible.
“Having a way to see nerves during surgery could significantly decrease injuries,” said Summer Gibbs, Ph.D., an associate professor of biomedical engineering in the OHSU School of Medicine.
Image: The lumbar nerve in a pig stands out clearly after injection with one of the new fluorescent agents.
Surgeries cause about 600,000 nerve injuries annually in the U.S. Even with magnification, some nerves are nearly impossible for a surgeon to see clearly. That is the case for the delicate nerves often damaged in surgery for prostate cancer, causing impotence and loss of bladder control.
Fluorescent compounds can highlight nerves for surgeons to detect. But existing compounds only work on nerves exposed near the surface of tissues. Gibbs and her team created new contrast agents capable of brightly illuminating nerves at depths up to three millimeters within tissue. And they work with existing guided surgery instruments.
“The surgeons we’ve talked to are pretty excited about it,” Gibbs said. “They want to know when they can start using it.” She points out that further animal studies are needed to confirm the agents’ safety before human clinical testing can begin. Gibbs is the senior author of a paper describing the technology in Science Translational Medicine. Co-authors include Lei Wang, Ph.D., a postdoctoral fellow, and Connor Barth, Ph.D., a senior research scientist, both in the Gibbs laboratory.
Videos published with the journal report show how the contrast agents light up lumbar and iliac nerves within the body wall and pelvis of pigs undergoing robotic surgery. The nerves are invisible in conventional white-light endoscopy. Nerves highlighted by the contrast agents clearly stand out from muscle, fat, blood vessels and connective tissue. Lack of nerve specificity has been a limiting problem for the field.
The research team first built an extensive library of candidate molecules by making various, purposeful modifications to a basic fluorescent agent, an oxazine fluorophore. Structure-activity relationships unearthed through library compound screening yielded insight into nerve-binding fluorophore molecular design principles. From the synthesized candidate molecules, the researchers identified contrast agents that are highly nerve-specific and that emit light in the optimum range of near infrared. Near-infrared light is the most capable of penetrating tissue, Gibbs said, and existing surgical imaging systems are equipped for near infrared viewing.
Gibbs, Wang, and Barth have co-founded a startup company, Inherent Targeting, LLC, to raise money for clinical testing and commercialization of the technology. It’s been a long journey for Gibbs, who started the project 12 years ago when she was still a postdoctoral researcher
Near-infrared nerve-binding fluorophores for buried nerve tissue imaging by Lei G. Wang, Connor W. Barth, Catherine H. Kitts, Mubark D. Mebrat, Antonio R. Montaño, Broderick J. House, Meaghan E. McCoy, Alexander L. Antaris, S. N. Galvis, Ian McDowall, Jonathan M. Sorger and Summer L. Gibbs. Science Translational Medicine (May 6, 2020)
This work was funded by the National Institute of Biomedical Imaging and Bioengineering (R01EB021362) and was also supported by the National Center for Advancing Translational Sciences in the National Institutes of Health (UL1TR002369), and the OHSU Foundation through the University Venture Development Fund.
Competing interests: Wang, Barth, and Gibbs are inventors on a U.S. patent application held by OHSU that covers the composition and methods of use of the nerve-specific oxazine compounds. Antaris, Galvis, McDowall, and Sorger are employees of Intuitive Surgical Inc.