A heart-on-a-chip to better understand the human heart's response to drugs

The development of new drugs is a long, costly process with a high failure rate: nearly 90% of drug candidates do not make it past clinical development. One of the main causes is cardiotoxicity—the adverse effects that some drugs can have on the heart and that, in many cases, are not detected until advanced stages of clinical trials. Now, a team from IDIBELL’s Regenerative Medicine Program (RegenBell), led by Dr. Ángel Raya, in collaboration with the Institute of Microelectronics of Barcelona (IMB-CNM-CSIC), has developed a "heart-on-a-chip," a small microfluidic device capable of replicating key aspects of the human heart’s function.

The research team presented their findings in a recent study published in the journal Advanced Healthcare Materials. The model integrates three types of cardiac cells, cardiomyocytes, cardiac fibroblasts, and endothelial cells, derived from a single stem cell line, allowing for a more accurate recreation of the structure and actual behavior of living tissue. As a result, the chip—designed using bioengineering and manufactured entirely at the IMB-CNM-CSIC—could significantly improve the way drug safety is evaluated before the medication reaches patients.

A more accurate alternative to current models

Most experimental models currently used to study drug toxicity rely on cardiomyocytes—heart cells specialized in contraction—and expose the compounds directly to the tissue. However, this approach oversimplifies the heart’s complex organization, overlooking other cell types important to tissue architecture, and fails to replicate how drugs actually reach the organ in the human body.

To overcome this limitation, researchers have turned to organ-on-a-chip devices—microfluidic systems in which living cells are organized into compartments that recreate the physiological microenvironment. Essentially, they replicate the functioning of human tissues on a miniature scale. Their potential has sparked great interest in recent years as an alternative to animal models used in biomedical research.

"They have the potential to reduce animal testing in preclinical trials, but also to improve the reliability of models, since they allow us to work with human cells," notes Dr. José Yeste, a researcher at the IMB-CNM and one of the study’s authors. "Animal cells do not always respond in the same way as human cells to certain compounds," he adds. However, for now, these technologies remain in the research phase, and their industrial application has not yet been fully established.

A miniature heart for drug testing

In this case, the team has developed a heart-on-a-chip composed of three layers of cells: cardiomyocytes, cardiac fibroblasts (which provide consistency and structure to the tissue), and endothelial cells (which line blood vessels). All three cell populations come from the same stem cell line, "which greatly reduces genetic variability and helps ensure that interactions between cells more closely resemble those that actually occur in the body," explains Dr. Ángel Raya, coordinator of RegenBell and co-director of the study. Furthermore, the endothelial cells are what set this approach apart. “By incorporating the endothelial layer, drugs are not administered directly to the cardiac tissue but first pass through the vascular layer, mimicking how medications reach the heart via the coronary circulation,” he adds.

Regarding the technology, IMB-CNM researcher and study co-director Dr. Rosa Villa explains that “the chip consists of a system of microfluidic channels that allows for the organized co-culture of different cell types, as well as the control of the flow of nutrients and compounds.” This architecture facilitates the observation of cellular behavior under dynamic conditions that more closely resemble those of the physiological environment.

The endothelial layer: a form of protection for the heart

To validate the model, the team studied its response to various drugs, such as doxorubicin, a widely used chemotherapy drug known for its cardiotoxic effects. The results showed a significant difference between conventional models and the new three-layer system with endothelial cells: in models without an endothelial layer, cardiomyocytes suffer significant structural and functional deterioration; whereas, in models with endothelial cells, the cardiac tissue retains much of its contractile capacity and cellular organization.

These findings suggest that endothelial cells play a protective role against certain toxic effects and that simplified experimental models may be overestimating the cardiac toxicity of some compounds because they lack an endothelium. According to the researchers, this limitation could contribute to the premature discarding of potentially useful therapeutic candidates during the preclinical phases of drug development.

Another step forward in the creation of advanced human tissues

This work is part of IDIBELL’s strategic commitment to regenerative medicine and builds on the advances made by RegenBell in the development of increasingly complex and realistic human models. Thanks to the collaboration with the IMB-CNM, which has a strategic focus on promoting the development of microtechnologies in the biomedical field, this project takes that trajectory a step further with the creation of a miniaturized, vascularized heart-on-a-chip capable of more accurately reproducing how the human heart responds to medications. The ultimate goal is to develop experimental systems that increasingly closely mimic human physiology, thereby enabling a better understanding of diseases, accelerating the development of new therapies, and progressively reducing the need for animal models in research, with preclinical models that are increasingly accurate and transferable to clinical practice.

The development of the platform was made possible through close collaboration between the technology of the IMB-CNM Biomedical Applications Group and the biology expertise of IDIBELL. While the IMB-CNM was responsible for the design and fabrication of the microfluidic device, the IDIBELL team carried out the generation, integration, and culture of human cardiac cells. Both groups are part of the CIBER-BBN (Biomedical Research Network Center for Biomaterials, Nanomedicine, and Bioengineering), a network that promotes interdisciplinary studies that, in fact, were the origin of this line of research.

_{Reference article: A Tri-Culture Heart-on-a-Chip Platform With iPSC-Derived Cardiac Cells for Predictive Cardiotoxicity Testing. Advanced Healthcare Materials, 2026. https://doi.org/10.1002/adhm.202505524}

• Figures 1 and 2: Assembled heart-on-a-chip platform. The porous membrane is sandwiched between the upper and lower chambers. Cardiomyocytes and cardiac fibroblasts are cultured in the upper chamber, endothelial cells in the lower chamber, and medium is perfused from the endothelial side toward the cardiac tissue.
• Figure 3: Heart-on-a-chip platform maintained inside the incubator under controlled temperature, humidity, and CO₂ conditions. TEER is continuously monitored, and live-cell imaging is used throughout the experiment to record cell viability and cardiomyocyte contractility.
• Figure 4: A three-layer structure of cardiac cells that make up the “heart-on-a-chip”: cardiomyocytes, in green; cardiac fibroblasts, in turquoise; and endothelial cells, in red.