title: Flexible and waterproof micro-sensors to uncover zebrafish circadian rhythms: The next generation of cardiac monitoring for drug screening.
abstract: Flexible electronics are the next generation of sensors for mobile health and implantation. Zebrafish (Danio rerio) is an emergent strategy for pre-clinical drug development and toxicity testing. To address the confounding effects from sedation of fish and removal from the aquatic habitat for micro-electrocardiogram (µECG) measurements, we developed waterproof and wearable sensors to uncover the circadian variation in heart rate (HR) and heart rate variability (HRV) (Massin et al., 2000). The parylene-C based ECG sensor consisted of an ultra-soft silicone integrated jacket designed to wrap around the fish during swimming. The Young's modulus of this silicone jacket matched with the fish surface, and an extended parylene cable connected the underwater chest electrodes with the out-of water electronics. In addition, embedded micro-glass spheres in the silicone effectively reduced the effective density of the jacket to ~1 g cm(-3). These innovations enabled physiological ECG telemetry in the fish's natural habitat without the need for sedation. Furthermore, a set of non-linear signal processing techniques filtered out the breathing and electromagnetic artifacts from the recorded signals. We observed a reduction in mean HR and an increase in HRV over 24h at 10 dpa, accompanied by QT prolongation as well as diurnal variations, followed by normalization in mean HR and QT intervals at 26 days post ventricular amputation (dpa). We revealed Amiodarone-mediated QTc prolongation, HR reduction and HRV increase otherwise masked by sedation. The novel features of the flexible silicon jacket for µECG telemetry unraveled the biological clock and normalization of QT intervals at 26 dpa, providing the first evidence of new physiological phenomena during cardiac injury and repair as well as cardiac drug-mediated aberrant rhythms. Thus, the light weight and waterproof design holds promise to advance the next generation of mobile health and drug discovery.
authors.affiliation: Department of Medical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Bioengineering, UCLA School of Engineering & Applied Sciences, Los Angeles, CA 90095.
authors.forename: Tyler
authors.initials: T
authors.lastname: Beebe
authors.affiliation: Department of Bioengineering, UCLA School of Engineering & Applied Sciences, Los Angeles, CA 90095.
authors.forename: Nelon
authors.initials: N
authors.lastname: Jen
authors.affiliation: Division of Cardiology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095.
authors.forename: Chia-An
authors.initials: CA
authors.lastname: Lee
authors.affiliation: Department of Medical Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Yuchong
authors.initials: Y
authors.lastname: Tai
authors.affiliation: Department of Bioengineering, UCLA School of Engineering & Applied Sciences, Los Angeles, CA 90095.|Division of Cardiology, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095.
authors.forename: Tzung K
authors.initials: TK
authors.lastname: Hsiai
mesh_terms: D000638:Amiodarone / Q000627:therapeutic use*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac; D015374:Biosensing Techniques / Q000295:instrumentation*; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D002940:Circadian Rhythm; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation*; D004562:Electrocardiography / Q000295:instrumentation*; D004566:Electrodes; D004867:Equipment Design; D006329:Heart Conduction System / Q000002:abnormalities; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000293:injuries* / Q000503:physiopathology; D013686:Telemetry / Q000295:instrumentation; D015027:Zebrafish
chemical_list: D000889:Anti-Arrhythmia Agents; D000638:Amiodarone
keywords: Circadian Rhythm; Drug screening; Flexible and waterproof multi-electrode arrays; Toxicity testing; Zebrafish