Researchers at Carnegie Mellon University (CMU) and Nanyang Technological University (NTU) in Singapore have developed an organ-on-an-electronic-chip biosensor technology that can measure the electrophysiology of heart cell structures in three dimensions. The biosensor array essentially self-rolls around elongated spheroids of stem cell-derived cardiac cells—similar to how a “slap bracelet” wraps around a wrist—giving researchers the ability to study how heart cells communicate in multicellular systems.

The team hopes that the organ-on-e-chip platform can be used to evaluate new drugs, or as a drug or toxin screening tool, as well as provide new insights into the electrophysiological basis of heart disorders such as arrhythmias. “For decades, electrophysiology was done using cells and cultures on two-dimensional surfaces, such as culture dishes,” explained Tzahi Cohen-Karni, PhD, associate professor of Biomedical Engineering (BME) and Materials Science & Engineering (MSE) at CMU. “We are trying to circumvent the challenge of reading the heart’s electrical patterns in 3D by developing a way to shrink-wrap sensors around heart cells and extracting electrophysiological information from this tissue.”

Cohen-Karni and colleagues report on the new technology in Science Advances, in a paper titled, “Organ-on-e-chip: Three-dimensional self-rolled biosensor array for electrical interrogations of human electrogenic spheroids.”

Cell-to-cell communication is fundamental to the coordination and function of biological systems, the authors wrote. “In their native three-dimensional (3D) environment, cells are intimately connected to each other and the surrounding matrix to form a complex and highly dynamic system.” To date, however, laboratory studies have been largely confined to cells grown in two dimensions in culture dishes. Yet, as the investigators pointed out, cells cultured in 2D grow, behave, and communicate very differently to those in their natural 3D environment.

The researchers developed a 3D self-rolled biosensor array (3D-SR-BA) that can make electrophysiological measurements in 3D stem cell-derived cardiomyocyte spheroids. The organ-on-e-chip device is fabricated as a flat rectangular biosensor array, which can be likened to a slap bracelet. A slap bracelet has the basic shape of a ruler when laid out flat under tension, but when the tension is released the bracelet self-coils around the wrist. The team’s 3D-SR-BA device is constructed on the same basic principle. An array of biosensors made from either metallic electrodes or graphene sensors is attached to the chip surface, then a bottom layer of germanium—known as the sacrificial layer—is scraped off. Once this is removed, the biosensor array is released and it rolls up to form a barrel-shaped structure. “The arrays obtained a 3D conformation upon etching off the sacrificial layer as they spontaneously self-rolled,” the investigators noted.

For their reported experiments the investigators developed a biosensor array that would wrap around spheroids of stem cell-derived cardiomyocytes, which have the structure of elongated organoids about the width of 2–3 human hairs. Tests with the system showed that the biosensor array was able to make precise recordings of electrical signals generated by the cells in this 3D structure. “Measuring the electrical activity of the entire 3D construct from all sides provides a unique opportunity to gain an understanding of signal propagation in the total construct,” the authors wrote.

3D Self Rolling Biosensor
A spheroid encapsulated by 3D self-rolling biosensor arrays (top) and a spheroid that is not encapsulated (bottom). Imaged at (i) 0 hours (immediately after encapsulation), (ii) 1 hour, (iii) 2 hours, and (iv) 3 hours. Green, red, and blue denote live cells, dead cells, and cell nuclei, respectively. [Carnegie Mellon University]

“Essentially, we have created 3D self-rolling biosensor arrays for exploring the electrophysiology of induced pluripotent stem cell derived cardiomyocytes,” stated study first author Anna Kalmykov, a BME PhD student. “This platform could be used to do research into cardiac tissue regeneration and maturation that potentially can be used to treat damaged tissue after a heart attack, for example, or developing new drugs to treat disease.”

Importantly, the type and arrangement of the electrodes and the size and curvature of the 3D sensing device can be configured to match the cell type, 3D structure, and measurements required. “To achieve a desired curvature, mechanics and mechanical properties of the materials used to construct these devices play a central role,” the investigators explained. “The 3D-SR-BA platform is flexible and can accommodate a variety of sensor types to be used in either electrophysiological investigations of tissue state or detection of biomolecules released by the tissues.”

“Mechanics analysis of the roll-up process enables us to precisely control the shape of the sensors to ensure conforming contact between the sensors and the cardiac tissue,” noted NTU professor Jimmy Hsia, PhD. “The technique also automatically adjusts the level of the delicate ‘touch’ between the sensors and the tissue such that high-quality electric signals are measured without changing in the physiological conditions of the tissue due to external pressure.”

The researchers suggest that further development and scaling up of the platform could allow the use of 3D-SR-BAs for long-term electrophysiological studies of 3D systems, such as during tissue development and maturation. “In addition, it will allow testing of the drug effects on spheroids with diseased and healthy phenotypes,” they noted.

“The whole idea is to take methods that are traditionally done in planar geometry and do them in three dimensions,” concluded Cohen-Karni. “Our organs are 3D in nature. For many years, electrophysiology was done using just cells cultured on a 2D tissue culture dish. But now, these amazing electrophysiology techniques can be applied to 3D structures.”

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