Mussel-inspired 3D fiber scaffolds for heart-on-a-chip toxicity studies of engineered nanomaterials

Abstract

Due to the unique physicochemical properties exhibited by materials with nanoscale dimensions, there is currently a continuous increase in the number of engineered nanomaterials (ENMs) used in consumer goods. However, several reports associate ENM exposure to negative health outcomes such as cardiovascular diseases. Therefore, understanding the pathological consequences of ENM exposure represents an important challenge, requiring model systems that can provide mechanistic insights across different levels of ENM-based toxicity. To achieve this, we developed a mussel-inspired 3D microphysiological system (MPS) to measure cardiac contractility in the presence of ENMs. While multiple cardiac MPS have been reported as alternatives to in vivo testing, most systems only partially recapitulate the native extracellular matrix (ECM) structure. Here, we show how adhesive and aligned polydopamine (PDA)/polycaprolactone (PCL) nanofiber can be used to emulate the 3D native ECM environment of the myocardium. Such nanofiber scaffolds can support the formation of anisotropic and contractile muscular tissues. By integrating these fibers in a cardiac MPS, we assessed the effects of TiO and Ag nanoparticles on the contractile function of cardiac tissues. We found that these ENMs decrease the contractile function of cardiac tissues through structural damage to tissue architecture. Furthermore, the MPS with embedded sensors herein presents a way to non-invasively monitor the effects of ENM on cardiac tissue contractility at different time points. These results demonstrate the utility of our MPS as an analytical platform for understanding the functional impacts of ENMs while providing a biomimetic microenvironment to in vitro cardiac tissue samples. Graphical Abstract Heart-on-a-chip integrated with mussel-inspired fiber scaffolds for a high-throughput toxicological assessment of engineered nanomaterials.

Inhalation of printer-emitted particles impairs cardiac conduction, hemodynamics, and autonomic regulation and induces arrhythmia and electrical remodeling in rats

“…We excluded arrhythmias (> 18% reduction or > 25% increase in RR relative to the average of the prior 4 RRs) and, on select days, identified and quantified them as previously described [86] while blind to treatment and with verification by examination of concurrent LVP waveforms. ECG waveforms were analyzed in 5-min segments continuously over all BL days, select exposure days (1,5,9,13,17,20,21), a recovery day (day 22), and all stress test days. HRV analyses generated the timedomain variables SDNN and RMSSD, as well as the frequency-domain variables, HF (0.75-3.50 Hz), LF (0.20-0.75 Hz), and their ratio (LF/HF) as previously described [86,94].…”

“…Due to their size, ENMs can bypass biological barriers, become systemic, interfere with cellular processes, and induce adverse health effects [5][6][7][8][9][10][11][12][13][14][15]. Despite that numerous studies have linked exposure to ambient ultrafine particles to cardiovascular dysfunction, autonomic dysregulation, and heart disease [16][17][18][19], there are only limited investigations into the cardiovascular effects of ENMs [20].…”

A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling

“…Profound physiological differences among species-in action potentials, ion current profiles, and contractile rates-motivate the development of human cardiac tissues for drug testing and disease modeling. Although ideal platforms should yield distinct atrial and ventricular tissues, most approaches using human pluripotent stem cells (hPSC) have focused on generating ventricular myocardium (Ahn et al, 2018;Eschenhagen et al, 2012;Lemoine et al, 2017;Lind et al, 2017a;MacQueen et al, 2018;Nunes et al, 2013;Schaaf et al, 2011;Tulloch et al, 2011);(Lemoine et al, 2018;Lind et al, 2017b;Tiburcy et al, 2017) and assessing adverse ventricular events (Vicente et al, 2015). This has been in part due to the lag in developing reliable chamber-specific hPSC differentiation protocols (Cyganek et al, 2018;Lee et al, 2017).…”

Evolution of Biochip Technology: A Review from Lab-on-a-Chip to Organ-on-a-Chip

“…Various concentrations of isoprenaline have been tested on this device which highlights the application of this heart-on-a-chip model in drug discovery and toxicology tests. A mussel-inspired microfluidic chip was fabricated by Ahn et al [93] to test cardiac contractility. Gelatins as an extracellular matrix as well as silver nanoparticles and titanium oxide have been used to fabrication of this three-dimension chip.…”