Nerve-Specific Fluorophores for Image-Guided Surgery

Gibbs Lab Research: Nerve-specific Fluorophores

Significance of Nerve Damage Research

Nerve damage is a significant morbidity associated with surgical intervention. Surgery is among the most commonly recommended treatments for acute and chronic disease with up to 40 million procedures conducted in the United States alone annually. A common, but under recognized side effect of surgical nerve damage is chronic pain following healing of the surgical site. Nerve damage during surgical intervention can also result in loss of function as in the case of nerve-sparing radical prostatectomy, where the functional nerve structures are difficult to visualize. Although neuroanatomy is well known, nerve visualization during surgery continues to challenge even the most experienced clinicians. This difficulty stems from the nature of nerve tissues, which are small, translucent structures that are typically protected deep within the muscle.

Visualization of Nerve Damage in the Operating Room

To aid in nerve visualization in the operating room, a nerve-specific fluorescent contrast agent, specifically one with near-infrared (NIR) absorption and emission would be of immediate benefit to both patients and surgeons. There are a few promising classes of small molecule fluorophores that are known to cross the blood nerve barrier and accumulate in the nerve tissue providing nerve-specific fluorescence signal following systemic administration. However, none of the current fluorophore classes, which include distyrylbenzene (DSB) fluorophores, styryl pyridinium (FM) fluorophores, carbocyanine derivatives, and oxazine fluorophores, are optimized for clinical use.

Gibbs Lab: Optimization of each class of nerve-specific fluorophores

Research in the Gibbs Laboratory is focused on chemical optimization of each class of nerve-specific small molecule fluorophores through derivative synthesis and investigation of the utility of novel agents for both systemic and site-specific administration during surgery. The Gibbs Lab is also collaborating with Dr. Adam Alani, Assistant Professor in the College of Pharmacy at Oregon State University (OSU), on developing customized formulations for delivery of nerve-specific fluorophores both systemically and locally. The Gibbs and Alani Laboratories have shared laboratory space with Dr. Oleh Taratula, Assistant Professor in the College of Pharmacy at OSU in the Collaborative Life Sciences Building (CLSB) to facilitate this project.

Distyrylbenzene Fluorophores for Simultaneous Nerve and Vessel Imaging


Photographs of gross anatomy, and distyrylbenzene (DSB)-treated swine brachial plexus during surgery.

Figure 1: The Gibbs lab has utilized DSB fluorohpores for simultaneous nerve (arrow) and vessel (arrowhead imaging during swine surgery.

Modified from Gibbs-Strauss SL, Nasr K, Fish KM, Khullar O, Siclovan T, Barnhard NE, Tan Hehir CA, Frangioni JV. Nerve-Highlighting Fluorescent Contrast Agents for Image-Guided Surgery. Mol Imaging. 2011;10(2):91-101.


Cross Reactivity of Distyrylbenzene Fluorophores with ex vivo human nerve tissue


Microphotographs comparing 5 different DSB nerve fluorophores.

Figure 2: The Gibbs Lab has demonstrated cross reactivity of the DSB fluorohpores with ex vivo human sciatic nerve tissue.

Modified from Gibbs SL, Xie Y, Goodwill HL, Nasr KA, Ashitate YA, Madigan VJ, Siclovan TM, Zavodszky M, Tan Hehir CA, Frangioni JV. Structure-Activity Relationship of Nerve-Highlighting Fluorophores. PLoS One. 2013, 8(9): e73493

Acknowledgments

This research is funded by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the Oregon Clinical & Translational Research Institute (OCTRI).