Heart on a Chip: New Insights and Impact on Cardiac Research

Advancements in biomedical engineering are transforming how researchers study human health, and one of the most promising innovations is the “heart on a chip.” This technology replicates key functions of heart tissue in a controlled microenvironment, allowing scientists to investigate cardiac physiology, disease mechanisms, and drug responses with greater accuracy than traditional models.

By providing a predictive platform for testing treatments, this approach can accelerate drug development while reducing reliance on animal studies. Researchers continue refining these systems to enhance their accuracy and reliability.

Device Architecture

The structural design of a heart-on-a-chip system is engineered to replicate the biomechanical and electrophysiological properties of human cardiac tissue. The device consists of a microfluidic platform that houses living heart cells within a controlled environment. This platform includes interconnected chambers designed to mimic the spatial organization and function of myocardial tissue. It must support the alignment of cardiomyocytes, facilitate nutrient and oxygen exchange, and allow real-time monitoring of cellular responses. Microchannels simulate vascular perfusion, recreating blood flow dynamics essential for physiological function.

Flexible substrates enable cardiac cells to contract and relax, replicating the beating of a human heart. These substrates often feature microgrooves or extracellular matrix coatings to guide cardiomyocyte alignment, ensuring the formation of anisotropic tissue structures. This organization is critical, as coordinated electrical signals and mechanical forces drive the heart’s contractile function. Strain sensors within the device quantify contractile force, providing insights into mechanical properties.

Integrated electrodes capture action potentials and conduction velocities, assessing the electrical behavior of cardiac cells. Strategically positioned recording sites detect arrhythmic events and conduction abnormalities caused by disease or drug exposure. Optimized electrode placement ensures high signal fidelity while minimizing interference.

Materials Used In Construction

The materials used in heart-on-a-chip systems must support living cardiac cells while enabling precise mechanical and electrical measurements. The most common base material is polydimethylsiloxane (PDMS), a silicone elastomer that provides flexibility for cardiomyocyte contraction. Its optical transparency facilitates real-time imaging, while its gas permeability ensures oxygen exchange for cell viability. PDMS also supports microfabrication techniques like soft lithography, enabling the creation of intricate microchannel networks that mimic vascular perfusion.

Additional materials enhance specific properties of the device. Thermoplastics such as polymethyl methacrylate (PMMA) or cyclic olefin copolymers (COCs) offer improved chemical resistance, making them suitable for long-term drug exposure studies. Hydrogels like gelatin methacrylate (GelMA) or polyethylene glycol (PEG)-based materials provide a biomimetic extracellular matrix, supporting cellular attachment and differentiation. These hydrogels can be functionalized with biochemical cues to promote tissue organization and the formation of structured, anisotropic networks.

Conductive materials are essential for accurately recording and stimulating electrical activity. Gold and platinum electrodes are commonly embedded due to their conductivity and biocompatibility. Emerging materials like graphene and carbon nanotubes offer superior electrical properties, enhancing signal resolution. These nanomaterials can be incorporated into flexible substrates, enabling stretchable electronics that conform to tissue contractions and reduce mechanical mismatch.

Microfabrication Techniques

Heart-on-a-chip platforms rely on precise microfabrication techniques to create microscale environments that replicate cardiac tissue properties. Soft lithography is a fundamental approach, enabling the fabrication of microfluidic channels and flexible substrates with high spatial resolution. This method involves photolithography to pattern a silicon wafer, followed by casting PDMS to create a negative replica of the mold. The resulting structure forms the microfluidic network, allowing controlled fluid flow and cellular positioning.

Advancements in three-dimensional (3D) printing have expanded design possibilities. Unlike conventional lithographic techniques, which are largely limited to planar structures, 3D printing enables the creation of complex, multilayered architectures resembling native cardiac tissue. This is particularly useful for integrating vascular-like networks, as 3D-printed scaffolds support endothelial cell seeding and self-assembly into perfusable capillary structures. Digital light processing (DLP) and stereolithography (SLA) fabricate photopolymerized hydrogels with tunable mechanical properties, producing biomimetic extracellular matrices.

Precision machining techniques such as laser ablation and micro-milling further refine fabrication. Laser ablation offers sub-micron resolution, creating microchannels and electrode integration sites with minimal material deformation. Micro-milling provides a scalable approach for fabricating thermoplastic-based chips, which offer superior chemical resistance compared to PDMS-based counterparts. These techniques are particularly valuable for long-term studies where material stability is critical.

Cardiac Cell Integration

Incorporating cardiac cells into a heart-on-a-chip system requires careful selection, preparation, and maintenance to ensure they function as they would in native tissue. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are preferred due to their ability to model patient-specific cardiac physiology and disease conditions. These cells must be seeded onto the chip in a way that promotes structural alignment and synchronized contraction, mimicking myocardial fiber organization. The substrate is often coated with extracellular matrix proteins such as fibronectin or laminin to enhance adhesion and guide tissue architecture formation.

Maturation is necessary for cardiomyocytes to develop adult-like electrophysiological and contractile properties. Mechanical and electrical stimulation reinforce sarcomere alignment and strengthen intercellular coupling via gap junctions. Cyclic mechanical strain promotes cardiomyocyte elongation and improves contractile force, while paced electrical stimulation enhances action potential propagation and synchronizes beating patterns. These stimuli help bridge the gap between immature stem cell-derived cardiomyocytes and their adult counterparts, improving the predictive accuracy of the model for drug testing and disease research.

Controlling Microenvironmental Conditions

Maintaining a physiologically relevant microenvironment is essential for accurately replicating cardiac function. Parameters such as temperature, pH, oxygen levels, and nutrient supply must be carefully controlled. Microfluidic channels facilitate continuous perfusion of culture media, mimicking the nutrient exchange and waste removal seen in native cardiac tissue. The flow rate must be calibrated to prevent shear stress while promoting efficient diffusion. Specialized coatings within the microchannels help modulate surface interactions and prevent unwanted protein adsorption.

Mechanical and electrical cues must also be precisely regulated to support cardiomyocyte function. Pulsatile flow systems replicate biomechanical forces exerted on heart tissue during contraction and relaxation, promoting physiologically relevant stress responses. Electrical stimulation applied at controlled frequencies synchronizes cellular activity, reinforcing the heart’s natural pacemaking properties. By fine-tuning these conditions, researchers can more accurately model healthy and diseased cardiac states, improving assessments of drug efficacy and toxicity.

Measuring Electromechanical Outputs

Assessing cardiomyocyte function within a heart-on-a-chip system requires precise measurement techniques for both electrical and mechanical outputs. Electrophysiological monitoring helps understand how cardiac cells generate and propagate electrical signals, as disruptions can lead to arrhythmias and other disorders. Microfabricated electrodes embedded within the device record action potentials and conduction velocities, offering insights into cardiomyocyte excitability and synchronization. These electrodes can be configured for extracellular field potential recordings or intracellular patch-clamp measurements for detailed ion channel analysis. Optical mapping methods visualize electrical wave propagation across the tissue, enabling studies of conduction abnormalities caused by genetic mutations or drug interactions.

Mechanical measurements complement electrophysiological analyses by quantifying contractile force and rhythmicity. Strain sensors embedded in the flexible substrate detect deformation during cardiomyocyte contraction, allowing continuous monitoring of contractile strength and frequency. Traction force microscopy measures forces exerted by cells on their surrounding matrix, providing insights into how mechanical stress influences cardiac function. Atomic force microscopy offers high-resolution assessments of tissue stiffness and elasticity, refining our understanding of biomechanical properties at the cellular level. Integrating both electrical and mechanical readouts ensures a comprehensive evaluation of cardiac health, making heart-on-a-chip systems an indispensable tool for studying disease mechanisms and testing new therapies.