The core of the work is a technical answer to a long-standing problem in preclinical drug testing. Cardiomyocytes, the contractile cells of the heart, respond to pharmacological agents in vivo within minutes, and those responses are strongly influenced by the dynamic delivery of the drug through the bloodstream. Conventional two-dimensional cultures and static three-dimensional constructs cannot replicate these fluid flow kinetics, which limits how well they predict what will happen in a patient. The Mera system, developed by Hooke Bio, is designed to address this by supporting long-term culture and functional analysis of three-dimensional cardiac spheroids built from human induced pluripotent stem cell-derived cardiomyocytes together with cardiac fibroblasts, the supporting cells that help give heart tissue its structure and signaling environment.

Architecturally, Mera is ambitious. The platform is designed to accommodate up to 640 spheroids per run across a modular layout, integrating automated imaging, automated fluid handling, and user-friendly software, all operating under tightly controlled physiological conditions of 37 degrees Celsius and 5 percent carbon dioxide. Flow rates are tunable between zero and 12.5 milliliters per minute, a range intended to mimic the perfusion conditions cells would experience inside the body. In the study now published, however, the researchers deliberately worked at a smaller experimental scale, using up to 18 spheroids per condition, and they are explicit that full-scale throughput and parallelisation remain to be validated in future work. That honesty about scale matters, because throughput claims in the organ-on-a-chip field have often outpaced what has actually been demonstrated.

The biological building blocks of the assay are spheroids, tiny spherical aggregates of cells that self-organize into tissue-like structures. Combining cardiomyocytes with cardiac fibroblasts in three dimensions is known to improve the maturation and tissue-like features of such constructs, and the spheroid format offers a practical compromise between physiological relevance and the numbers needed for statistically meaningful drug testing. Inside Mera, these spheroids are perfused with medium while an automated imaging system tracks their beating. Because the contraction of cardiomyocytes produces visible motion, beat rate can be quantified from video, giving a functional readout that changes in real time as drugs flow past the cells.

To validate the platform, the team turned to a pharmacopoeia of cardiac pharmacology. Verapamil, a calcium channel blocker, slows the heart by reducing calcium entry into cardiomyocytes; isoproterenol, a beta-adrenergic agonist, accelerates beating by mimicking the sympathetic nervous system’s fight-or-flight signals; calcium chloride increases the calcium available to the contractile machinery; and propranolol, a beta-blocker, dampens adrenergic stimulation. Under dynamic flow in Mera, all four drugs produced real-time, reversible modulation of the spheroids’ beat rate. Crucially, the researchers observed recovery following drug-induced suppression, meaning that when the drug was washed out by the flowing medium, the cells resumed their baseline rhythm. That reversibility is a key indicator that the observed effects reflect genuine pharmacology rather than irreversible damage to the tissue.

The quantitative output of these experiments also passed a demanding test. Dose-response studies on the platform yielded IC50 values, the concentrations at which a drug produces half of its maximal effect, that were consistent with values reported in the scientific literature. Matching known potency benchmarks is one of the strongest arguments that a new in vitro system is behaving in a physiologically meaningful way rather than generating artifacts. The team also assessed how much the platform’s measurements varied from run to run and from spheroid to spheroid, finding that system variability was comparable to a temperature-controlled reference platform. That comparison supports the use of standard statistical analysis on Mera’s data, an unglamorous but essential requirement for any technology that hopes to influence regulatory decisions.

One of the most consequential framing devices in the paper is the concept of a new approach methodology, or NAM, a term increasingly used by regulators to describe non-animal testing strategies that can inform safety assessment. Cardiac toxicity has historically been a leading cause of drug withdrawal and of costly late-stage clinical failures, and current testing relies heavily on animal models that often translate poorly to humans, alongside in vitro systems that lack the dynamics of the bloodstream. By enabling dynamic drug exposure, automated analysis, and human-cell-based tissue, Mera is positioned as a candidate NAM for cardiac drug response testing. The researchers are careful, however, to note what the platform does not yet do: incorporation of contractility measurements, which capture the force of each beat, and electrophysiological readouts, which capture the electrical signals that coordinate the rhythm, will be an important next step toward supporting its use in predictive cardiac safety assessment.

The technical significance of adding flow deserves emphasis, because it changes more than just the delivery of drugs. Perfusion continuously refreshes nutrients and oxygen, removes metabolic waste, and subjects cells to shear stress, all of which influence how stem cell-derived cardiomyocytes mature and behave. It also eliminates a subtle but well-documented problem in microfluidic devices: certain small molecules are absorbed by the silicone polymer commonly used to fabricate chips, distorting the effective drug concentration that cells actually experience. Dynamic, controlled perfusion with automated fluid handling gives experimenters a much firmer grip on the dose that reaches the tissue, which in turn makes dose-response curves and derived potency values more trustworthy.

The study also reflects a broader shift in how organ-on-a-chip technologies are being engineered. Early microphysiological systems were often bespoke devices built by academic labs, powerful as proofs of concept but difficult to operate, hard to reproduce, and impractical for the throughput that pharmaceutical screening demands. Mera’s design philosophy runs in the opposite direction: modular architecture, automated imaging and fluidics, and software intended to be usable by operators who are not microfluidics specialists. The authors acknowledge the financial support of Ireland’s Disruptive Technologies Innovation Fund and the European Innovation Council, and they are transparent that all authors are or were employees of Hooke Bio, the company that developed the system, with some holding shares or stock options. That commercial stake does not invalidate the data, but it is the kind of disclosure that readers weighing the technology’s maturity should keep in view.

What emerges from the study is a platform that has demonstrated, at modest scale, that human cardiac spheroids can be cultured long-term under physiologically relevant flow and interrogated with clinically important drugs in real time. The reversible beat-rate responses, the literature-consistent IC50 values, and the reproducibility relative to a reference platform together make a credible case that Mera captures something genuinely physiological about how the human heart responds to pharmacological challenge. The road ahead is clearly mapped by the authors themselves: scaling to the full 640-spheroid capacity, adding force and electrical measurements, and validating the system against a wider panel of compounds, including known cardiotoxins. If those steps succeed, the vision is a future in which a drug’s effects on the human heartbeat can be measured in a perfused, human-cell model before it ever reaches a patient, replacing some animal studies with experiments that are faster, more human, and conducted entirely under glass.

Subject of Research: A microphysiological system for assessing human cardiomyocyte beat-rate responses to drugs under dynamic flow

Article Title: Functional assessment of cardiac beat dynamics under dynamic flow: insights from the Mera microphysiological system

Article References: Almeida, N., Sum-Coffey, V., Costello, P., Madden, C., Devitt, S., Mukkunda, S. R., Keshava, B. B., Sunil, S., Riley, L. G., Deely, S., de Benedictis, C. A., Lyons, M., & Cliffe, F. E. (2026). Functional assessment of cardiac beat dynamics under dynamic flow: insights from the Mera microphysiological system. Biomedical Microdevices, 28(4), Article 70. https://doi.org/10.1007/s10544-026-00839-5

Image Credits: AI Generated

DOI: 10.1007/s10544-026-00839-5

Keywords: microphysiological system, heart-on-a-chip, cardiomyocytes, cardiac toxicity, drug testing, organ-on-a-chip, microfluidics, induced pluripotent stem cells, beat rate, new approach methodology, cardiac spheroids, pharmacology

The case for better models is straightforward. Mouse and rat hearts, the traditional workhorses of cardiovascular research, differ from human hearts in fundamental ways. They beat far faster, burn energy at a higher basal rate, and rely predominantly on a different myosin heavy chain isoform than the adult human ventricle, which is enriched in the beta form. These species differences help explain why promising preclinical results so often collapse in human trials, producing either unexpected cardiotoxicity or disappointing therapeutic benefit. Two-dimensional cultures, meanwhile, are cheap and fast but strip away the three-dimensional architecture, multicellular crosstalk and maturation cues that define living heart tissue. Cardiac MPS emerged to fill this void, and the review traces their remarkable evolution from the first beating embryoid bodies generated from stem cells in 1993, through engineered heart tissue in 2004, to the landmark 2021 creation of scaffold-free, self-organizing cardiac organoids called cardioids that recapitulate key features of early human heart development.

The review organizes cardiac MPS into two construction paradigms. The first is developmentally guided self-organization, in which human pluripotent stem cells are coaxed through timed bursts and pauses of WNT signaling, together with factors such as BMP4, activin A and FGF2, to form chamber-like organoids containing cardiomyocytes, fibroblasts, endothelial cells, neural crest cells and more. Elaborate versions add vascular-promoting cues like VEGF, foregut patterning, or even blood-generating signals to produce organoids with vascular compartments and hematopoietic progenitors. The second paradigm is engineering-driven assembly, which imposes external control through biomaterial scaffolds, 3D bioprinting and microfluidic heart-on-a-chip platforms. Self-organizing organoids offer unmatched developmental fidelity, making them ideal for studying embryonic cardiogenesis and congenital defects, while engineered tissues deliver superior reproducibility, spatial control and compatibility with quantitative drug screening. The review stresses that neither approach is universally superior; the choice depends entirely on the scientific question.

Biomaterials sit at the heart of the engineering approach, and the review provides an unusually detailed tour of the options. Naturally derived materials such as collagen, fibrin, hyaluronic acid, gelatin and decellularized extracellular matrix offer rich biological signals but suffer from batch variability and weak mechanics. Synthetic polymers like PEG, PCL and PLGA provide precise control and manufacturability but must be functionalized with cell-adhesive motifs. Hybrid systems blend the two philosophies. Electroconductive hydrogels laced with carbon nanotubes or conductive polymers can boost electrical coupling and connexin 43 expression, improving contraction synchrony, though dosing must be tuned carefully to avoid cytotoxicity. Scaffold stiffness matters enormously: native myocardium sits near 10 to 30 kilopascals, while scarred, fibrotic tissue stiffens to 35 to 70 kilopascals or more, and abnormal stiffness can actively drive disease-like cell states through epigenetic remodeling rather than merely accompanying them. Topographic cues from electrospun and micropatterned scaffolds guide cardiomyocyte alignment and restore the anisotropic architecture of real heart muscle.

Bioprinting adds another layer of control, depositing cell-laden bioinks layer by layer to fabricate vascular-like cardiac constructs with defined geometry. The review distinguishes carefully between biomaterial scaffolds, which can be processed under cell-free conditions, and true bioinks, which must keep living cells viable during extrusion or photopolymerization. Extrusion printing demands shear-thinning materials that recover quickly after deposition, while light-based printing requires finely tuned cross-linking kinetics. The technology’s strengths include spatial patterning of endothelialized structures, reproducible geometry, multicellular integration and controllable anisotropy. But a persistent trade-off between printing resolution and cell survival remains unresolved, and constructing a full hierarchical vascular network, from large vessels down to capillaries, still eludes the field. Microfluidics complements these efforts by providing perfusion, controlled shear stress, real-time biosensing and, in multi-organ chip formats, the ability to couple heart tissue with liver or kidney modules to capture systemic drug responses.

Perhaps the review’s most important contribution is its rigorous framework for assessing maturation, the property that ultimately determines whether a heart model is physiologically meaningful. Structural benchmarks include sarcomere length approaching the adult range of roughly 2.2 micrometers, organized Z-discs and A-bands, polarized connexin 43 at cell junctions, chamber-like cavity formation, and organized populations of fibroblasts, endothelial cells, macrophages and sympathetic neurons. Molecularly, the developmental shift from the TNNI1 to the TNNI3 troponin isoform is tracked quantitatively, though even the most mature organoids reported so far reach only about 18 percent TNNI3, corresponding roughly to a twenty-week human fetal heart, a sobering reminder that in vitro maturation still falls short of adulthood.

Functional maturation is assessed through an equally demanding battery of readouts. Electrophysiological maturity shows up as a more hyperpolarized resting membrane potential, adult-like action potentials and conduction velocities around 25 centimeters per second, with properly responsive beta-adrenergic signaling. Calcium handling reveals whether cardiomyocytes have built the T-tubule and dyad architecture needed for efficient excitation-contraction coupling, a feature most current systems still lack. Contractile performance is quantified by force generation; one progressively stretched engineered heart tissue achieved a specific twitch force of 11.28 millinewtons per square millimeter, a 5.1-fold improvement over controls. Metabolic maturation is measured through oxygen consumption rates and the shift from fetal glycolysis toward fatty acid beta-oxidation, which can be encouraged by substrate switching with fatty acids and galactose, thyroid hormone, or chronic electrical stimulation. In one conditioned tissue, mitochondria occupied 30 percent of the analyzed area, matching adult human myocardium. No single metric suffices, the review insists; maturity is a convergent, multidimensional phenotype.

The applications already demonstrated are striking. Multi-chamber cardioids have disentangled the regulatory relationship between the transcription factors HAND1 and NKX2-5 during early chamber formation. Organoids with microRNA-187 overexpression have reproduced congenital heart defect phenotypes that could be rescued by NIPBL supplementation. Gene-edited organoids carrying C10orf71 frameshift variants replicated the contractile defects of dilated cardiomyopathy, and the cardiac myosin activator omecamtiv mecarbil later restored function in a matching mouse model. Zonally oxygenated engineered tissues have recreated the infarct border zone with region-specific metabolic, fibrotic and calcium abnormalities that uniform hypoxia models miss entirely. Vascularized organoids showed that the blood pressure drug captopril protects cryoinjured tissue, while doxorubicin cardiotoxicity and even nanoplastic-induced injury have been modeled in organoid-on-chip formats. On the regenerative frontier, engineered heart muscle allografts have achieved durable remuscularization in rhesus macaques, though post-transplant arrhythmias highlight that electrical integration, not just survival, must be solved.

The review closes with a clear-eyed assessment of the remaining barriers: incomplete vascularization beyond the diffusion limit, fetal-like maturation, line-to-line variability, Matrigel batch effects, missing systemic physiology and the absence of standardized benchmarking. Its prescription is pragmatic rather than maximalist. Automated bioreactors, biosensors, AI-assisted closed-loop cultivation and standardized reference datasets could make cardiac MPS reproducible enough for regulated drug testing, while regenerative applications await perfusable vasculature and safe graft-host coupling. The message to the field is that progress should be judged not by how elaborate these tissues look, but by whether they become reliable, interpretable and genuinely predictive instruments of human cardiac medicine.

Subject of Research: Cardiac microphysiological systems for modeling human cardiac development, disease and drug responses

Article Title: Cardiac microphysiological systems in cardiovascular research: Construction paradigms, maturation trajectories, and translational frontiers

Article References: Xie, R., Zhao, H., Lei, Y., & Wang, X. (2026). Cardiac microphysiological systems in cardiovascular research: Construction paradigms, maturation trajectories, and translational frontiers. Bioengineering & Translational Medicine, Article e70167. https://doi.org/10.1002/btm2.70167

Image Credits: AI Generated

DOI: 10.1002/btm2.70167

Keywords: cardiac organoids, microphysiological systems, engineered heart tissue, cardiomyocyte maturation, 3D bioprinting, heart-on-a-chip, cardiotoxicity, disease modeling, vascularization, regenerative medicine, biomaterials, drug screening