Organic Semiconducting Nanoparticles for Neural Interfacing: Integrating Mechanical, Chemical and Optoelectronic Stimuli for Wireless Neuromodulation

<br/>Electronic devices capable of stimulating neurons have revolutionized the treatment of several neurological conditions by providing a direct interface with the nervous system. These devices hold great potential for treating disorders such as Parkinson's disease, epilepsy, spinal cord injuries, and even blindness.^[1] However, the use of traditional electronic materials such as metals and silicon in such devices have significant limitations due to poor biocompatibility,^[2] mechanical mismatch with tissue, low spatial selectivity, and the requirement for external power supplies. Soft and flexible organic semiconducting materials represent a new frontier in electronic materials that are capable of overcoming these challenges.^[3] The solution processability of organic semiconductors also enable several additional attractive features, including low-cost manufacturing of devices on flexible substrates using industrial scale printing techniques, addition of neurotransmitter molecules to the electroactive solutions to chemically assist neuromodulation, adjustable surface topography to induce mechanical cues for neuron attachment and growth, and optically triggered charge generation for wireless electrical neuromodulation.<br/><br/>In this study, we present our recent endeavours to tackle these challenges of mechanical, chemical and electronic stimulation of neuronal cells simultaneously in a single bioelectrode. We achieve this by forming soft carbon-based organic conductors into aqueous nanoparticle dispersions using established solution-based mini-emulsion chemistry methods.^[4] We subsequently integrate the organic nanoparticle dispersions with neurotrophic factors prior to the device fabrication process. These pharmaceutical components subsequently enhance cell adhesion and neural network outgrowth upon release from solid films cast from the electroactive nanoparticle dispersions.<br/><br/>Bioelectronic nanoparticle-based devices were fabricated from n-type material <i>Poly(9,9-dioctylfluorene-alt-bithiophene </i>(F8T2), which were shown to exhibit high biocompatibility with primary neuron cultures from mice via anatomical (live-dead assay) and functional (neuronal cell stain) protocols. Kelvin Probe Force Microscopy measurements demonstrated the creation of photo-capacitive charge under direct light stimulus, potentially capable of depolarising the neuronal cell membrane and generating action potentials (<i>wireless</i> <i>electronic neuromodulation</i>). By adjusting the surface roughness of devices by tailoring the nanoparticle size during synthesis, we verified by AFM analysis an optimal nano-topography that promotes neuronal cell growth (<i>mechanical neuromodulation</i>). Finally, by extensive neuronal morphology analysis we demonstrated the direct effect of sustained and locally delivered neurotrophic factors (<i>chemical neuromodulation</i>) on cell survival and neuronal outgrowth through neurite elongation.<br/><br/>References:<br/>[1] Lewis, P.M., Ayton, L.N., Guymer, R.H., Lowery, A.J., Blamey, P.J., Allen, P.J., Luu, C.D. and Rosenfeld, J.V. (2016), Advances in implantable bionic devices for blindness: a review. ANZ Journal of Surgery, 86: 654-659. https://doi.org/10.1111/ans.13616<br/>[2] T. Someya, Z. Bao, G. G. Malliaras, Nature, <b>2016</b>, <i>540</i>, 379.<br/>[3] Fahlman, M., Fabiano, S., Gueskine, V. <i>et al.</i> Interfaces in organic electronics. <i>Nat Rev Mater</i> <b>4</b>, 627– 650 (2019). https://doi.org/10.1038/s41578-019-0127-y<br/>[4] <i>Phys.Chem.Chem.Phys., </i>2019, 21, 5705