Advances in Multidimensional Cardiac Biosensing Technologies: From Electrophysiology to Mechanical Motion and Contractile Force

Abstract

Cardiovascular disease (CVD) is the number one killer in the world. According to the World Health Organization (WHO) estimation, about 17.9 million people died from CVD each year, accounting for 31% of all deaths worldwide. [1] Among these deaths, about 7.4 million died from coronary heart disease, while 6.7 million from a stroke. According to China cardiovascular disease report in 2018, [2] around 290 million people suffer from CVD, including 13 million strokes, 11 million coronary heart disease, 5 million pulmonary heart disease, 4.5 million heart failure, 2.5 million rheumatic heart disease, 2 million congenital heart disease, and 270 million hypertension. Cardiovascular disease was also the leading cause of all death in rural and urban areas, with 45.01% in rural areas and 42.61% in urban areas. According to heart disease and stroke statistics from the American Heart Association (AHA) in 2018, [3] around 92.1 million American adults have a certain form of cardiovascular disease or suffer from stroke sequelae. CVD killed 836546 Americans in 2015. Coronary heart disease was the leading cause (43.8%) of death in CVD, followed by stroke (16.8%), heart failure (9.0%), hypertension (9.4%), arterial disease (3.1%) and other cardiovascular diseases (17.9%). According to the European cardiovascular disease statistics in 2017, [4] around 3.9 million people died from CVD each year, which accounts for 45% of all deaths in Europe. Ischemic heart disease (IHD) and stroke are the main forms of CVD in Europe. Among all deaths in Europe each year, IHD is the leading single cause of mortality, responsible for 19% and 20% among men and women, while stroke is the second most common single cause of death, accounting for 9% in men and 13% in women. Therefore, the prevention and treatment of CVD have aroused extensive public concern worldwide. Moreover, cardiac toxicity induced by drugs has been the main cause of the withdrawal from the market and drugs attrition during the last decades. [5,6] On the one hand, drug-induced cardiotoxicity will also threaten people's health, even life. For example, acute arrhythmia can lead to sudden death, while Cardiovascular disease is currently a leading killer to human, while druginduced cardiotoxicity remains the main cause of the withdrawal and attrition of drugs. Taking clinical correlation and throughput into account, cardiomyocyte is perfect as in vitro cardiac model for heart disease modeling, drug discovery, and cardiotoxicity assessment by accurately measuring the physiological multiparameters of cardiomyocytes. Remarkably, cardiomyocytes present both electrophysiological and biomechanical characteristics due to the unique excitation-contraction coupling, which plays a significant role in studying the cardiomyocytes. This review mainly focuses on the recent advances of biosensing technologies for the 2D and 3D cardiac models with three special properties: electrophysiology, mechanical motion, and contractile force. These high-performance multidimensional cardiac models are popular and ef...

Fabrication and Biomedical Applications of Heart-on-a-chip

“…For the microsensors based on optical method, it is complex to measure the contraction force. The strain microsensors can read out the contraction force directly, but the stability, linearity, and accuracy of the microsensors are not satisfying[ 7 ]. With the advances of wearable and flexible electronics, more microsensors have been invented.…”

Microengineered platforms for characterizing the contractile function of in vitro cardiac models

“…Multiparameter analysis of cardiac functional properties in vitro has recently been reported 68 , 104 , 108 , 207 . For example, a label-free electromechanical detection strategy based on microelectrodes and IDEs can synchronously monitor the electrophysiology and contraction of 2D cardiomyocyte monolayers 56 , 208 . Van Meer et al developed a high-speed optical system capable of measuring contraction, action potential, and calcium influx simultaneously using fluorescent voltage- and calcium-sensitive dyes and live membrane-labeling dyes 104 .…”

“…Several biosensing techniques have been implemented in heart-on-a-chip platforms for the measurement of contractile functions of in vitro cardiac models 49 , 51 – 54 . Existing review papers have focused on the biological development of in vitro cardiac models 55 , 56 , with contractility measurement only briefly discussed. We comprehensively review the development of biosensing platforms for the measurement of contractile functions of in vitro cardiac models.…”

Hybrid Integrated Cardiomyocyte Biosensors for Bitter Detection and Cardiotoxicity Assessment

“…So, it is necessary and important to assess the potential cardiotoxicity of bitter compounds, which may help to understand the mechanism of bitterness. With the rapid development of micro/nanomanufacturing and biosensing technology, cardiomyocyte-based biosensors have emerged as an effective tool to study the physiological function of the heart in vitro and have been widely used in the fields of drug discovery, toxicology, and cardiovascular diseases. , …”

“…With the rapid development of micro/nanomanufacturing and biosensing technology, cardiomyocyte-based biosensors have emerged as an effective tool to study the physiological function of the heart in vitro and have been widely used in the fields of drug discovery, toxicology, and cardiovascular diseases. 24,25 In this study, we proposed a novel hybrid integrated cardiomyocyte biosensor (HICB) for bitter detection and cardiotoxicity assessment, where the extracellular field potential (EFP) and mechanical beating (MB) signal of cardiomyocytes can be synchronously recorded by the hybrid integrated biosensor (Figure 1). Four types of bitter agonists (denatonium benzoate/Dena, diphenidol, quinine, and arbutin) that can activate different bitter receptors in cardiomyocytes were administrated to the HICB, and HICB can quickly respond to bitter stimulation.…”