Abstract
Purpose :
A critical barrier to regenerating the optic nerve is directing long distance growth of damaged retinal ganglion cell (RGC) axons. We have generated significant evidence that suggests that the application of electric fields (EFs) may be a viable approach for promoting optic nerve regeneration. Here, we present an approach involving computational modeling paired with ex vivo and in vivo experiments to develop minimally invasive approaches to improve the voltage gradient along the electrically stimulated optic nerve.
Methods :
We employed our AM/NEURON computational modeling tool to test different electrical stimulation strategies for improving the voltage gradient along the optic nerve. Ex vivo experiments with Long Evan rats were then performed for verification of computational predictions. Finally, we tested our best model in vivo using the optic nerve crush model. Electrodes were implanted and optic nerves were crushed. One week after crush, optic nerves were exposed to an asymmetric charge-balanced biphasic waveform for 5 hours daily x 10 days. Regenerative response past the crush site in stimulated animals was assessed by quantifying the number of axons at various distances past the injury site and compared to controls.
Results :
Computational modeling showed the largest and most linear voltage gradient with the proposed stimulation setup. Ex vivo experiments showed that this setup generated an EF nearly 1.5X higher in amplitude compared to the intra-orbital/cranial electrodes (Voltage gradients: 176.5±10.7 vs 102.7±15.9 mV/mm (cathode); 80.7±7.6 vs 35.6±5.2 mV/mm (anode); p<0.0002 and p<0.003 respectively, n=3). Preliminary in vivo experiments showed that the minimally invasive set up was able to direct 3-fold more regeneration over controls, similar to rates directed by intra-orbital/cranial electrodes (n=1).
Conclusions :
Here, we show that minimally invasive electrodes are more effective at generating an EF along the optic nerve compared to intra-orbital/cranial electrodes. Moreover, these electrodes are able to direct RGC axon regeneration after degeneration from crush injury has set in. This has important implications as there may be a delay between when patients develop optic neuropathies and their ability to receive care.
This is a 2021 ARVO Annual Meeting abstract.