Improved Intraoperative Visualization of Nerves through a Myelin-Binding Fluorophore and Dual-Mode Laparoscopic Imaging

Abstract

The ability to visualize and spare nerves during surgery is critical for avoiding chronic morbidity, pain, and loss of function. Visualization of such critical anatomic structures is even more challenging during minimal access procedures because the small incisions limit visibility. In this study, we focus on improving imaging of nerves through the use of a new small molecule fluorophore, GE3126, used in conjunction with our dual-mode (color and fluorescence) laparoscopic imaging instrument. GE3126 has higher aqueous solubility, improved pharmacokinetics, and reduced non-specific adipose tissue fluorescence compared to previous myelin-binding fluorophores. Dosing and kinetics were initially optimized in mice. A non-clinical modified Irwin study in rats, performed to assess the potential of GE3126 to induce nervous system injuries, showed the absence of major adverse reactions. Real-time intraoperative imaging was performed in a porcine model. Compared to white light imaging, nerve visibility was enhanced under fluorescence guidance, especially for small diameter nerves obscured by fascia, blood vessels, or adipose tissue. In the porcine model, nerve visualization was observed rapidly, within 5 to 10 minutes post-intravenous injection and the nerve fluorescence signal was maintained for up to 80 minutes. The use of GE3126, coupled with practical implementation of an imaging instrument may be an important step forward in preventing nerve damage in the operating room.

Real-time, functional intra-operative localization of rat cavernous nerve network using near-infrared cyanine voltage-sensitive dye imaging

“…Intriguing commercial solutions have been recently introduced such as the FireFly ™ (Intuitive Surgical Inc., United States) and the FLARE ™ systems (Curadel ResVet Imaging, LLC., United States) 10,11 , and several exogenous fluorophores targeted to specific tissue types have also been proposed. [12][13][14] Enthusiasm for FL imaging in academia and industry originated from its wide field-ofview (FOV) directly superimposable on the surgeon's visual field, making it amenable to conventional surgeries including RP. Most of the current nerve-specific fluorophores demonstrate nerve networks with high affinity, but this mechanism will only yield stationary locations of nerves, rather than portray their electrophysiological activity based on erection functionality.…”

“…Most of the current nerve-specific fluorophores demonstrate nerve networks with high affinity, but this mechanism will only yield stationary locations of nerves, rather than portray their electrophysiological activity based on erection functionality. 13,15 Furthermore, most of these nervespecific fluorophores provide a superficial imaging depth because they have peak absorption and emission wavelengths at the visible wavelength range (400-650nm). Although several research presentations have recently suggested the applicability of infrared dyes to intra-operative nerve localization, they are still based on a nerve-specific affinity mechanism, rather than on the functional resolution of a patient's erectile function.…”

Cranial nerve contrast using nerve-specific fluorophores improved by paired-agent imaging with indocyanine green as a control agent

“…Nerve damage is a major cause of surgery-associated morbidity that can lead to long-term loss of function, sensation, and chronic pain. [1][2][3][4][5][6][7][8][9] It is especially crucial to preserve cranial nerves (CN) because of their vital functions, and in skull base surgeries, this is a major challenge. [10][11][12] With a limited field-of-view (FOV) and close proximity of critical structures in these surgeries, nerve visualization is difficult.…”

“…Investigators from GE global research synthesized DSBs, such as GE3082 and GE3111, which demonstrated an affinity for myelin basic protein, a major constituent of the myelin sheath surrounding nerves. [7][8][9] Park et al 1 recently examined a variety of nerve-labeling fluorophores, and found Oxazine 4 to be the best contrast agent that most closely met the criteria of an ideal nerve contrast agent. A commonality in these studies is that nerve highlighting was done systemically and predominantly evaluated large nerves, such as the sciatic nerve and brachial plexus.…”

The quest for precision in transanal total mesorectal excision

“…There is currently no approved fluorescent dye to selectively label nerves. An elegant demonstration has been performed using myelinbinding fluorophores [58]. • See the microscopic Precise estimation of tumor margins is fundamental to any oncological procedure.…”