Restoration of vision in patients blinded glaucoma requires therapies that promote retinal ganglion cell (RGC) survival and direct RGC axon regeneration. The aim of this collaboration is to demonstrate that electric field (EF) application is an effective strategy to address this clinical need. EFs have been shown to increase RGC survival after optic nerve injury and to direct RGC axon growth in vitro. Despite this, translation into the clinical arena lost momentum due to dependence on direct current (DC), which is unsafe. Alternating current, the natural alternative, is ineffective at directing axon growth. Instead, our group is exploiting advances in neuro-electrical engineering by applying hybrid, asymmetric charge-balanced (ACB) waveforms to direct optic nerve regeneration. ACB waveforms are charge-balanced but have asymmetry that allow them to direct cellular processes similar to DC current. Here, we present compelling preliminary data that show that 1) ACB waveforms direct RGC axon growth in vitro, 2) EF stimulation of crushed optic nerves with ACB waveforms applied two weeks after optic nerve injury directed 3-fold more RGC survival and 3-fold more axon regeneration over controls, 3) minimally invasive electrodes generate larger EFs along the optic nerve, and 4) an external non-foster circuit can increase the EF gradient generated by our system. Leveraging the expertise of Dr. Lazzi, an electrical engineer, and Dr. Gokoffski, a neuro-ophthalmologist/neurobiologist, our collaboration employs computational engineering approaches paired with cell biology and animal experiments to test the hypotheses that 1) minimally invasive application of EFs to crushed optic nerves will robustly promote RGC survival and direct RGC axon growth over untreated controls and 2) addition of an external non-foster circuit will synergistically direct RGC axon regeneration over traditional ACB waveforms. This project has tremendous potential for commercialization and for inducing a paradigm shift in the field of optic nerve regeneration, bringing electrical modulation to the forefront.
