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Significance: Selecting a nerve-specific lead fluorescent agent for translation in fluorescence-guided surgery is time-consuming and expensive. Preclinical fluorescent agent studies rely primarily on animal models, which are a critical component of preclinical testing, but these models may not predict fluorophore performance in human tissues.
Aim: The primary aim of this study was to evaluate and compare two preclinical models to test tissue-specific fluorophores based on discarded human tissues. The secondary aim was to use these models to determine the ability of a molecularly targeted fluorophore, LGW16-03, to label ex vivo human nerve tissues.
Approach: Patients undergoing standard-of-care transtibial or transfemoral amputation were consented and randomized to topical or systemic administration of LGW16-03 following amputation. After probe administration, nerves and background tissues were surgically resected and imaged to determine nerve fluorescence signal-to-background tissue ratio (SBR) and signal-to-noise ratio (SNR) metrics. Analysis of variance (ANOVA) determined statistical differences in metric means between administration cohorts and background tissue groups. Receiver operating characteristic (ROC) curve-derived statistics quantified the discriminatory performance of LGW16-03 fluorescence for labeling nerve tissues.
Results: Tissue samples from 18 patients were analyzed. Mean nerve-to-adipose SBR was greater than nerve-to-muscle SBR (p = 0.001), but mean nerve-to-adipose SNR was not statistically different from mean nerve-to-muscle SNR (p = 0.069). Neither SBR nor SNR means were statistically different between fluorophore administration cohorts (p ≥ 0.448). When administration cohorts were combined, nerve-to-adipose SBR was greater than nerve-to-muscle SBR (mean ± standard deviation; 4.2 ± 2.9 vs. 1.8 ± 1.9; p < 0.001), but SNRs for nerve-to-adipose and nerve-to-muscle were not significantly different (5.1 ± 4.0 vs. 3.1 ± 3.4; p = 0.055). ROC curve-derived statistics to quantify LGW16-03 nerve labeling performance varied widely between patients, with sensitivities and specificities ranging from 0.2-99.9% and 0.4-100.0%.
Conclusion: Systemic and topical administration of LGW16-03 yielded similar fluorescence labeling of nerve tissues. Both administration approaches provided nerve-specific contrast similar to that observed in preclinical animal models. Fluorescence contrast was generally higher for nerve-to-adipose versus nerve-to-muscle. Ex vivo human tissue models provide safe evaluation of fluorophores in the preclinical phase and can aid in the selection of lead agents prior to first-in-human trials.
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