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)[1]. 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 24 hours 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.

A 3D-Printed Sensor for Monitoring Biosignals in Small Animals

“…This allowed easy calculation of the heart rate. The mean heart rate of the zebrafish was 133.8 ± 17.9 bpm ( n = 5), which is consistent with previous studies on zebrafish heart rate [24, 25]. Then, the recorded ECG signals were overlaid (Figure 4(c)) and the individual waveforms were averaged (Figure 4(d)).…”

“…The mean PR and QT intervals were 84.21 ± 11.98 ms and 221.31 ms ± 6.91 ms, respectively. The ECG parameters obtained using the 3D-printed sensor were within the deviation range of those previously reported [24, 25, 28]. …”

“…A peak detection algorithm was used to detect and sort the R peaks from the recorded raw ECG signals. All waveforms from a minute gap-free signals within 30% difference in amplitude and duration that contained the same ECG shapes were matched together [24, 25]. Then, the obtained waveforms were averaged.…”

Automated Segmentation of Light-Sheet Fluorescent Imaging to Characterize Experimental Doxorubicin-Induced Cardiac Injury and Repair

“…In humans, injured myocardium undergoes apoptosis leading to fibrosis 1 , 2 , whereas zebrafish (Danio rerio) possess a capacity to undergo regression in fibrosis and regeneration of myocardium in injured hearts 3 . Despite having a two-chambered heart, the zebrafish cardiac action potential and electrocardiogram (ECG) patterns are similar to those of humans 4 , thus representing a viable vertebrate model for cardiac injury and repair 3 , 5 , 6 . In adult zebrafish, regenerating myocardium electrically couples with uninjured myocardium 6 , 7 providing a conserved cardiomyopathy model 8 .…”

An Insulin Microneedle Pen (IMP) for Self‐Subcutaneous Insulin Injection

“…[16] To verify the water resistance capacity of the parylene coating, the water vapor transmission rate (WVTR), which is a measure of the passage of water vapor through a coating (film) under specified conditions, [17] was analyzed for parylene coating of 500 and 1000 nm thickness as illustrated in Figure 3a (SEM images). Therefore, we employed the parylene coating technology to seal the surface of the water-soluble PVP mold.…”