Real-Time Monitoring of Changes in Cardiac Contractility Using Silicon Cantilever Arrays Integrated with Strain Sensors

Abstract

This paper proposes the use of sensor-integrated silicon cantilever arrays to measure drug-induced cardiac toxicity in real time. The proposed cantilever sensors, unlike the conventional electrophysiological methods, aim to evaluate cardiac toxicity by measuring the contraction force of the cardiomyocytes corresponding to the target drugs. The surface of the silicon cantilever consists of microgrooves to maximize the alignment and the contraction force of the cardiomyocytes. This type of surface pattern also helps in the maturation of the cardiomyocytes by increasing the sarcomere length. The preliminary characterization of the cantilever sensors was performed on the cantilever surface, with the cardiomyocytes seeded with a density of 1000 cells/mm 2 , and the cardiac contractility was measured as a function of the culture days. The change in the contraction force of the cardiomyocytes due to the drug concentration was successfully measured through the integrated strain sensor in the culture media. The reliability of the sensor-integrated cantilevers and the feasibility of their mass production ensure that they meet the practical requirements in the medical applications.

Crack Sensing of Cardiomyocyte Contractility with High Sensitivity and Stability

“…These techniques are either not suitable for continuous monitoring or require complicated and time-consuming focusing/alignment. Piezoresistive sensors have also been reported for measuring CMs’ contractility by continuously monitoring the electrical resistance change inside a controlled incubator environment, implemented by dispersing a conductive filler such as carbon black nanoparticles and carbon nanotubes (CNTs) in a polymer matrix. − Compared to the piezoresistive sensors, crack sensors were shown to be more sensitive by 3 orders of magnitude (e.g., gauge factor: 2000), − inspired by the structure of spider crack-shaped slit organ. For measuring CMs’ contractility, a metal-crack sensor was encapsulated into a rubber cantilever .…”

Heart-on-a-chip systems: disease modeling and drug screening applications

“…These sensors are typically placed downstream from the cell culture chamber to capture secreted biomarkers, such as proteins and small molecules. 162,166,175 Mechanical properties, such as contractile force, can be probed using two-pillar constructs, [176][177][178] flexible cantilevers, 164,179,180 and piezoelectric materials. 181 The two-pillar structure typically serves more as a guide for tissue formation, rather than a sensor per se, and it often requires a microscope to visualize contraction dynamics.…”

“…However, some recent examples have integrated electrical strain sensors with the flexible cantilever to monitor contraction mechanics. 180,182,183 Similarly, permanent magnets can be incorporated into one of the two pillars to generate an electromagnetic signal to characterize mechanical contractions. 184 Piezoelectric materials inherently convert mechanical energy into an electrical output, making these materials well-suited for recording contraction profiles from cardiomyocytes.…”

“…Many of the proarrhythmic drugs block one or more of the ion channels found in the heart (K + , Na + , Ca 2+ ), making HoC systems well-suited to study their effects. Examples include verapamil (a Ca 2+ channel blocker), 168,180,182,183,360,365,366,369,[391][392][393][394] quinidine (Na + -channel blocker), 182,359,392,395 E-4031 (hERG K + -channel blocker), 180,359,360,363,[396][397][398] sotalol (K + -channel blocker), 391 nifedipine (a Ca 2+ -channel blocker), 305,361,396,397 ranolazine (Na +channel blocker), 396 flecainide (Na + -channel blocker), 362,397,398 tetrodotoxin (Na + -channel blocker), 398 ouabain (Na + /K + -ATPase blocker), 359 ATX-II (Na + -channel blocker), 359 and dofetilide (K +channel blocker). 359,395 The Lee group has developed various iterations of cantilever-based sensors to monitor real-time changes in contractile function after exposing cardiac tissue to different concentrations of drugs known to be cardiotoxic, including quinidine, E-4031, and verapamil.…”

“…359,395 The Lee group has developed various iterations of cantilever-based sensors to monitor real-time changes in contractile function after exposing cardiac tissue to different concentrations of drugs known to be cardiotoxic, including quinidine, E-4031, and verapamil. 180,182,183,391,392 The cell culture surface is patterned with a series of microgrooves to promote tissue anisotropy and maturation (as discussed in section 4.1.1) and contractile function is characterized by measuring cantilever displacement (Fig. 5c).…”