Emerging heart-on-a-chip platforms are promising approaches to establish cardiac cell/tissue models in vitro for research on cardiac physiology, disease modeling and drug cardiotoxicity as well as for therapeutic discovery. Challenges still exist in obtaining the complete capability of in situ sensing to fully evaluate the complex functional properties of cardiac cell/tissue models. Changes to contractile strength (contractility) and beating regularity (rhythm) are particularly important to generate accurate, predictive models. Developing new platforms and technologies to assess the contractile functions of in vitro cardiac models is essential to provide information on cell/tissue physiologies, drug-induced inotropic responses, and the mechanisms of cardiac diseases. In this review, we discuss recent advances in biosensing platforms for the measurement of contractile functions of in vitro cardiac models, including single cardiomyocytes, 2D monolayers of cardiomyocytes, and 3D cardiac tissues. The characteristics and performance of current platforms are reviewed in terms of sensing principles, measured parameters, performance, cell sources, cell/tissue model configurations, advantages, and limitations. In addition, we highlight applications of these platforms and relevant discoveries in fundamental investigations, drug testing, and disease modeling. Furthermore, challenges and future outlooks of heart-on-a-chip platforms for in vitro measurement of cardiac functional properties are discussed.

Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca²⁺ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK^R211A) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality worldwide. Despite effective antimicrobial therapy, CAP can induce pulmonary endothelial hyperpermeability resulting in life-threatening lung failure due to an exaggerated host-pathogen interaction. Treatment of acute lung injury is mainly supportive because key elements of inflammation-induced barrier disruption remain undetermined. Angiopoietin-1 (Ang-1)-mediated Tie2 activation reduces, and the Ang-1 antagonist Ang-2 increases, inflammation and endothelial permeability in sepsis. Vasculotide (VT) is a polyethylene glycol-clustered Tie2-binding peptide that mimics the actions of Ang-1. The aim of our study was to experimentally test whether VT is capable of diminishing pneumonia-induced lung injury. VT binding and phosphorylation of Tie2 were analyzed using tryptophan fluorescence spectroscopy and phospho-Tie-2 enzyme-linked immunosorbent assay. Human and murine lung endothelial cells were investigated by immunofluorescence staining and electric cell-substrate impedance sensing. Pulmonary hyperpermeability was quantified in VT-pretreated, isolated, perfused, and ventilated mouse lungs stimulated with the pneumococcal exotoxin pneumolysin (PLY). Furthermore, Streptococcus pneumoniae-infected mice were therapeutically treated with VT. VT showed dose-dependent binding and phosphorylation of Tie2. Pretreatment with VT protected lung endothelial cell monolayers from PLY-induced disruption. In isolated mouse lungs, VT decreased PLY-induced pulmonary permeability. Likewise, therapeutic treatment with VT of S. pneumoniae-infected mice significantly reduced pneumonia-induced hyperpermeability. However, effects by VT on the pulmonary or systemic inflammatory response were not observed. VT promoted pulmonary endothelial stability and reduced lung permeability in different models of pneumococcal pneumonia. Thus, VT may provide a novel therapeutic perspective for reduction of permeability in pneumococcal pneumonia-induced lung injury.

Significance: The HtrA2 protease plays a critical role in ensuring proper cellular function and in regulating a variety of different processes, including programmed cell death. Although the three-dimensional structure of a trimeric form of the enzyme has been determined, the mechanism by which this important molecule is regulated remains to be elucidated. Our data reveal that this is accomplished through a second conformation of the enzyme in which it forms a hexamer with much lower affinity for substrate and by the fact that the enzyme remains in a low-activity state until substrate binding leads to domain reorientations, exposing the catalytic center. Together, these two regulatory features help to minimize proteolysis of nonsubstrate proteins that are required for cellular health.