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Near-infrared nerve-binding fluorophores for buried nerve tissue imaging

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Science Translational Medicine  06 May 2020:
Vol. 12, Issue 542, eaay0712
DOI: 10.1126/scitranslmed.aay0712

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Avoiding hitting a nerve

Fluorescence-guided surgery uses contrast agents to identify nerves intraoperatively; however, existing agents have poor tissue specificity and high background or permit only surface-level imaging. Wang et al. developed near-infrared nerve-binding fluorophores that could be administered locally or systemically for deep nerve visualization. Testing the oxazine-based contrast agents in murine and porcine models identified buried nerves during laparoscopic surgery. These contrast agents could help avoid injuring nerves during surgery.

Abstract

Nerve-binding fluorophores with near-infrared (NIR; 650 to 900 nm) emission could reduce iatrogenic nerve injury rates by providing surgeons precise, real-time visualization of the peripheral nervous system. Unfortunately, current systemically administered nerve contrast agents predominantly emit at visible wavelengths and show nonspecific uptake in surrounding tissues such as adipose, muscle, and facia, thus limiting detection to surgically exposed surface-level nerves. Here, a focused NIR fluorophore library was synthesized and screened through multi-tiered optical and pharmacological assays to identify nerve-binding fluorophore candidates for clinical translation. NIR nerve probes enabled micrometer-scale nerve visualization at the greatest reported tissue depths (~2 to 3 mm), a feat unachievable with previous visibly emissive contrast agents. Laparoscopic fluorescent surgical navigation delineated deep lumbar and iliac nerves in swine, most of which were invisible in conventional white-light endoscopy. Critically, NIR oxazines generated contrast against all key surgical tissue classes (muscle, adipose, vasculature, and fascia) with nerve signal-to-background ratios ranging from ~2 (2- to 3-mm depth) to 25 (exposed nerve). Clinical translation of NIR nerve-specific agents will substantially reduce comorbidities associated with surgical nerve damage.

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