Leaky Opto-Electrical Neural Implants: A Multidisciplinary Approach to Parkinson’s Disease Therapy

Abstract

Parkinson’s disease is characterized by the degeneration of dopaminergic neurons in substantia nigra leading to a decrease in the dopamine level in striatum. The current dopaminergic therapies effectively alleviate the symptoms, but they do not halt the disease progression and result in additional complications. Transplanting healthy stem cell-derived dopaminergic neurons could replenish the dopamine levels without additional motor complications. However, the cells migrate after transplantation in vivo and it is difficult to stimulate them selectively to modulate on demand dopamine release to prevent dyskinesia. In order to address these issues, this project aims to replenish the loss of neurotransmitters via an implant capable of optically stimulating a large population of stem cell-derived neurons to modulate neurotransmitter release. The development of two types of implantable leaks opto-electrical neural implants to carry stem cell derived dopaminergic neurons into the brain is presented. The devices are based on commercial optical fibers and silicon microfabrication. Both devices contain two basic elements: a leaky optical element for optical stimulation of neurons and a pyrolytic carbon element for electrochemical detection of subsequent release of dopamine. Introduction of micro optical windows in the core of an optical fiber/waveguide leads to light leaking out of the optical element. The intensity and spatial distribution of light were optimized to stimulate a large population of neurons surrounding the optical element. Pyrolytic carbon obtained through the pyrolysis of polymer precursor was used as a substrate for cell culture due to its biocompatibility and excellent electrochemical properties. Oxidation of dopamine at the pyrolytic carbon surface indicates the quantity of dopamine released on demand from the neurons upon light stimulation. Genetically engineered human neural stem cells expressing the blue light sensitive opsin Channelrhodopsin-2, were differentiated into dopaminergic neurons on the pyrolytic carbon surface. Light leaking from the micro-optical windows stimulated the neurons leading to dopamine exocytosis, which was detected in realtime using amperometry. The multi-functional leaky opto-electrical neural implants described here provide the first proof of concept of a device for differentiating optogenetic human neural stem cells into dopaminergic neurons for on-demand release of dopamine to restore the dopamine levels in Parkinson’s disease.