MR Imaging of Peripheral Nerves Using Targeted Application of Contrast Agents: An Experimental Proof-of-Concept Study

Abstract

Introduction: Current imaging modalities for peripheral nerves display the nerve's structure but not its function. Based on a nerve's capacity for axonal transport, it may be visualized by targeted application of a contrast agent and assessing the distribution through radiological imaging, thus revealing a nerve's continuity. This concept has not been explored, however, may potentially guide the treatment of peripheral nerve injuries. In this experimental proof-of-concept study, we tested imaging through MRI after administering gadolinium-based contrast agents which were then retrogradely transported.Methods: We synthesized MRI contrast agents consisting of paramagnetic agents and various axonal transport facilitators (HSA-DTPA-Gd, chitosan-DTPA-Gd or PLA/HSA-DTPA-Gd). First, we measured their relaxivity values in vitro to assess their radiological suitability. Subsequently, the sciatic nerve of 24 rats was cut and labeled with one of the contrast agents to achieve retrograde distribution along the nerve. One week after surgery, the spinal cords and sciatic nerves were harvested to visualize the distribution of the respective contrast agent using 7T MRI. In vivo MRI measurements were performed using 9.4 T MRI on the 1st, 3rd, and the 7th day after surgery. Following radiological imaging, the concentration of gadolinium in the harvested samples was analyzed using inductively coupled mass spectrometry (ICP-MS).Results: All contrast agents demonstrated high relaxivity values, varying between 12.1 and 116.0 mM−1s−1. HSA-DTPA-Gd and PLA/HSA-DTPA-Gd application resulted in signal enhancement in the vertebral canal and in the sciatic nerve in ex vivo MRI. In vivo measurements revealed significant signal enhancement in the sciatic nerve on the 3rd and 7th day after HSA-DTPA-Gd and chitosan-DTPA-Gd (p < 0.05) application. Chemical evaluation showed high gadolinium concentration in the sciatic nerve for HSA-DTPA-Gd (5.218 ± 0.860 ng/mg) and chitosan-DTPA-Gd (4.291 ± 1.290 ng/mg).Discussion: In this study a novel imaging approach for the evaluation of a peripheral nerve's integrity was implemented. The findings provide radiological and chemical evidence of successful contrast agent uptake along the sciatic nerve and its distribution within the spinal canal in rats. This novel concept may assist in the diagnostic process of peripheral nerve injuries in the future.

Development of polarization-sensitive optical coherence tomography imaging platform and metrics to quantify electrostimulation-induced peripheral nerve injury in vivo in a small animal model

“…Interestingly, progress is being made for peripheral nerve MRI contrast agents. 63 Ultimately, endpoint histology is the only reliable method to detect overstimulation or nerve damage, which is a completely invasive and destructive method to the site and nerve tissue.…”

“…Furthermore, many techniques cannot distinguish nerve tracts from surrounding tissue and instead rely on known structural cues. Interestingly, progress is being made for peripheral nerve MRI contrast agents 63 . Ultimately, endpoint histology is the only reliable method to detect overstimulation or nerve damage, which is a completely invasive and destructive method to the site and nerve tissue.…”

A scoping review of current and emerging techniques for evaluation of peripheral nerve health, degeneration and regeneration: part 2, non-invasive imaging

“…Additional agents have been developed and some FDA approved including polyaminocarboxylate chelates, which induce hyperintense signal on T1weighted MR images [35]. Some exciting advances include nanoparticles (nanoneurotracers) functionalized with an antibody for targeted deployment in combination with high field strength MRI [79][80][81]; these could be developed for selective imaging of multiple cell types [81]. Label-free imaging will always be preferable, but the selectivity and strength of signal achievable with safe and target-specific labels and contrast agents likely represents the field that will most advance resolution and quantification of nerve health, in particular in the lab, but with a tradeoff clinically due to the delay associated with FDA approval.…”