Woongki Hong

Photothermal neuromodulation, a rapidly advancing technique in neuroscience, has been introduced as an incredibly versatile platform for the in‐depth study of neural electrophysiological signals and the development of treatments for various neurological disorders. Particularly, nanomaterial‐based photothermal neuromodulation technologies have advantages compared to optogenetic stimulation methods, such as non‐genetic modification, minimally invasive, and reduced immune response. Photothermal neuromodulation research has introduced various nanomaterials and stimulation methods to regulate thermosensitive ion channels or modify cell membrane capacitance, enabling excitation and inhibition of neural activity. Recent advances in nanomaterials have significantly improved the precision and efficiency of photothermal neuromodulation, expanding its potential applications in neuroscience research. In the photothermal neuromodulation studies, different temperature measurement methods have been used but do not satisfy all the requirements necessary to analyze this phenomenon. An ideal temperature sensor for a photothermal neuromodulation study must have high transparency, high thermal sensitivity, and high spatial and temporal resolution. This review aims to cover the current status of thermally induced neuromodulation studies and the transparent temperature sensing methodologies that can be used for photothermal neuromodulation.

Various temperature sensitive biological mechanisms have been utilized for new biomedical engineering tools such as neuromodulation, cancer cell hyperthermia or photothermal therapy. Optically transparent and high spatio‐temporal resolution temperature sensors are needed to precisely analyze the biological effects that occur in response to the temperature changes. In this work, semi‐transparent p‐NiO/n‐ZnO heterojunction diode‐based temperature sensors with 100 µm‐diameter ultrathin transparent Au/Ag metal anodes is introduced. The fabricated diode temperature sensors accurately measure temperature changes from 25 to 80 °C, which is of significant interest in many biomedical engineering applications. The sensors also exhibit adequate transparency over the entire visible light spectrum for biomedical imaging including fluorescent microscopy. Low‐power operation of the temperature sensor (<0.2 nW) is achieved to avoid a self‐heating effect. The micro‐scale spatial resolution of the transparent temperature sensors is especially useful for cellular resolution bio‐imaging, optical neural recording, and optical bio‐modulation where transparency and high‐resolution temperature sensing are necessary.

Electro‐optical neural interface technologies provide great potential and versatility in neuroscience research. High temporal resolution of electrical neural recording and high spatial resolution of optical neural interfacing such as calcium imaging or optogenetics complimentarily benefit the way information is accessed from neuronal networks. To develop a hybrid neural interface platform, it is necessary to build transparent, soft, flexible microelectrode arrays (MEAs) capable of measuring electrical signals without light‐induced artifacts. In this work, flexible and transparent ultrathin (<10 nm) gold MEAs are developed using a biocompatible polyelectrolyte multilayer (PEM) metallic film nucleation‐inducing seed layer. With the polymer seed layer, the thermally evaporated ultrathin gold film shows good conductivity while providing high optical transmittance and excellent mechanical flexibility. In addition, strong electrostatic interaction via the PEM alters the electrode‐electrolyte interfaces, thereby reducing the electrode impedance and baseline noise level. With a simple modification of the fabrication process of the MEA using biocompatible materials, both excellent transmittance, and electrochemical interface characteristics are achieved, which is promising for efficient electro‐optical neural interfaces.

Optical neuromodulation is a versatile neural stimulation technology that enables highly localized excitatory or inhibitory stimulation of neuronal activities. Photothermal neural stimulation using thermoplasmonic metallic nanoparticles for light to heat conversion has been suggested as an optical neural stimulation technology without genetic modification. Optical fibers implementing the thermoplasmonic effect were recently developed for localized neural stimulation, and the successful demonstration of localized neural stimulation in vitro was reported. However, before photothermal neural stimulation is further applied in the brains of live animals and ultimately in human trials, a safety analysis must carefully be performed for the thermal effect of stimulation in vivo. With the complexity of the physical structure and different thermal properties of the brain and surrounding body, the resulting thermal effect could vary despite the same power of light delivered to the optical fiber. In addition, dynamic thermal properties of the brain such as the daily blood perfusion rate change or metabolic heat generation must also be carefully considered for the precise implementation of photothermal neural stimulation. In this work, an in-depth computational analysis was conducted of the photothermal effects using a thermoplasmonic optical fiber for in vivo neural stimulation. The effects of the experimental design and stimulation protocols on the thermal effect in the brain were analyzed. We believe that the results provide a good experimental guideline for safely conducting photothermal neural stimulation using the thermoplasmonic optical fiber technology.

Thermo-plasmonic effect based neural stimulation has been suggested as an alternative optical neural stimulation technology without genetic modification. Integration of near infrared light with plasmonic gold nanoparticles has been demonstrated as a neuromodulation tool on in vitro neuronal network models. In order to further test the validity of the thermo-plasmonic neural stimulation across multiple biological models (in vitro, ex vivo, and in vivo) avoiding genetic modification in optical neuromodulation, new versatile engineering approaches to apply the thermo-plasmonic effect would be required. In this work, we developed a gold nanorod attached optical fiber technology for the localized neural stimulation based on thermo-plasmonic effect. A simple fabrication process was developed for efficient nanoparticle coating on commercial optical fibers. The thermo-plasmonic optical fiber proved that it can locally modulate the neural activity in vitro. Lastly, we simulated the spatiotemporal temperature change by the thermo-plasmonic optical fiber and analyzed its applicability to in vivo animal models.