Electrophysiological mapping of chronic atrial fibrillation (AF) at high throughput and high resolution is critical for understanding its underlying mechanism and guiding definitive treatment such as cardiac ablation, but current electrophysiological tools are limited by either low spatial resolution or electromechanical uncoupling of the beating heart. To overcome this limitation, we herein introduce a scalable method for fabricating a tissue-like, high-density, fully elastic electrode (elastrode) array capable of achieving real-time, stable, cellular level-resolution electrophysiological mapping in vivo. Testing with acute rabbit and porcine models, the device is proven to have robust and intimate tissue coupling while maintaining its chemical, mechanical, and electrical properties during the cardiac cycle. The elastrode array records epicardial atrial signals with comparable efficacy to currently available endocardial-mapping techniques but with 2 times higher atrial-to-ventricular signal ratio and >100 times higher spatial resolution and can reliably identify electrical local heterogeneity within an area of simultaneously identified rotor-like electrical patterns in a porcine model of chronic AF.

Organs-on-Chips (OoCs) are poised to reshape dramatically the study of biology by replicating in vivo the function of individual and coupled human organs. Such microphysiological systems (MPS) have already recreated complex physiological responses necessary to simulate human organ function not evident in two-dimensional in vitro biological experiments. OoC researchers hope to streamline pharmaceutical development, accelerate toxicology studies, limit animal testing, and provide new insights beyond the capability of current biological models. However, to develop a physiologically accurate Human-on-a-Chip, i.e., an MPS homunculus that functions as an interconnected, whole-body, model organ system, one must couple individual OoCs with proper fluidic and metabolic scaling. This will enable the study of the effects of organ-organ interactions on the metabolism of drugs and toxins. Critical to these efforts will be the recapitulation of the complex physiological signals that regulate the endocrine, metabolic, and digestive systems. To date, with the exception of research focused on reproductive organs on chips, most OoC research ignores homuncular endocrine regulation, in particular the circadian rhythms that modulate the function of all organ systems. We outline the importance of cyclic endocrine regulation and the role that it may play in the development of MPS homunculi for the pharmacology, toxicology, and systems biology communities. Moreover, we discuss the critical end-organ hormone interactions that are most relevant for a typical coupled-OoC system, and the possible research applications of a missing endocrine system MicroFormulator (MES-µF) that could impose biological rhythms on in vitro models. By linking OoCs together through chemical messenger systems, advanced physiological phenomena relevant to pharmacokinetics and pharmacodynamics studies can be replicated. The concept of a MES-µF could be applied to other standard cell-culture systems such as well plates, thereby extending the concept of circadian hormonal regulation to much of in vitro biology. Impact statement Historically, cyclic endocrine modulation has been largely ignored within in vitro cell culture, in part because cultured cells typically have their media changed every day or two, precluding hourly adjustment of hormone concentrations to simulate circadian rhythms. As the Organ-on-Chip (OoC) community strives for greater physiological realism, the contribution of hormonal oscillations toward regulation of organ systems has been examined only in the context of reproductive organs, and circadian variation of the breadth of other hormones on most organs remains unaddressed. We illustrate the importance of cyclic endocrine modulation and the role that it plays within individual organ systems. The study of cyclic endocrine modulation within OoC systems will help advance OoC research to the point where it can reliably replicate in vitro key regulatory components of human physiology. This will help translate OoC work into pharmaceutical applications...

Newborn mammals, including piglets, exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). The electrophysiologic properties of this naturally regenerated myocardium have not been examined. We hypothesized that epicardial conduction is preserved after P1 MI in piglets. Yorkshire-Landrace piglets underwent left anterior descending coronary artery ligation at age P1 (n = 6) or P7 (n = 7), After 7 weeks, cardiac magnetic resonance imaging was performed with late gadolinium enhancement for analysis of fibrosis. Epicardial conduction mapping was performed using custom 3D-printed high-resolution mapping arrays. Age- and weight-matched healthy pigs served as controls (n = 6). At the study endpoint, left ventricular (LV) ejection fraction was similar for controls and P1 pigs (46.4 ± 3.0% vs. 40.3 ± 4.9%, p = 0.132), but significantly depressed for P7 pigs (30.2 ± 6.6%, p < 0.001 vs. control). The percentage of LV myocardial volume consisting of fibrotic scar was 1.0 ± 0.4% in controls, 9.9 ± 4.4% in P1 pigs (p = 0.002 vs. control), and 17.3 ± 4.6% in P7 pigs (p < 0.001 vs. control, p = 0.007 vs. P1). Isochrone activation maps and apex activation time were similar between controls and P1 pigs (9.4 ± 1.6 vs. 7.8 ± 0.9 ms, p = 0.649), but significantly prolonged in P7 pigs (21.3 ± 5.1 ms, p < 0.001 vs. control, p < 0.001 vs. P1). Conduction velocity was similar between controls and P1 pigs (1.0 ± 0.2 vs. 1.1 ± 0.4 mm/ms, p = 0.852), but slower in P7 pigs (0.7 ± 0.2 mm/ms, p = 0.129 vs. control, p = 0.052 vs. P1). Overall, our data suggest that epicardial conduction dynamics are conserved in the setting of natural heart regeneration in piglets after P1 MI.

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