Using these techniques in in vitro experiments, the team discovered that the blood vessel lining cells that regulate blood flow between vessels and surrounding tissues (called endothelial cells) play a previously underestimated but crucial role in the rapid and functional maturation of stem-cell derived cardiomyocytes. When cultured together in a 3D cardiac tissue matrix, cardiomyocytes underwent extraordinary electrical maturation in the presence of endothelial cells.

Over the course of seven weeks of monitoring the developing organoids, the team observed that proximity to endothelial cells had a direct impact. Cardiomyocytes cultured next to endothelial cells matured faster compared to cardiomyocytes located farther away from endothelial cells, and they also displayed electrical characteristics typically found in healthy heart tissue.

The new insight is a leap forward for engineering stem-cell derived cardiac tissues. Experimental preclinical research in animals with human-like hearts has proven its difficult to engineer and transplant stem-cell derived cardiomyocytes that can beat in tandem with surrounding heart tissue for extended periods of time. Immature cardiomyocytes transplanted into an animals heart tend to beat to their own drum, and this electrical misfire can cause dangerous irregular heartbeats. Thats why the discovery that co-culturing stem-cell-derived cardiomyocytes with endothelial cells can create more functionally mature cardiomyocytes is so significant.

In their new paper, the team also describes using a novel machine-learning-based analysis to interpret the electrical activity captured by the tissue-embedded nanoelectronic devices, enabling continuous monitoring of the electrical waves generated by maturing cardiomyocytes of interest and enabling a better understanding of how the tissue microenvironment influences electrical stability.

Liu says the nanoelectronic devices and machine-learning-based analysis represent new platform technologies for monitoring and managing stem-cell derived tissue implants enabling scientists to culture cyborgs made from both living tissues and electronics that can be controlled with a high degree of specificity. In cardiac tissues, he envisions that someday these cyborgs could even be used in a sophisticated, real-time feedback system to detect abnormal electrical activity in cardiomyocytes and provide highly targeted voltage, acting like a nanoscale pacemaker, to help correct implanted cells and ensure they continue to beat in rhythm with the rest of the heart.

If we have both nanoelectronic sensors and stimulators, we can monitor electrical activity and use feedback to pace implanted tissues into the same frequency as surrounding tissues, Liu says. This approach could be adapted to so many other types of stem-cell-derived tissues, such as neuronal tissues and pancreatic organoids.

He also says this nanoelectronics platform approach could be used in drug screening, providing single-cell-level, continuous analysis of how tissues respond to different compounds and therapies.

Harvards Office of Technology Developmenthas protected the intellectual property arising from this study and is exploring commercialization opportunities.

Additional authors include Zuwan Lin, Jessica C. Garbern, Ren Liu, Qiang Li, Estela M. Juncosa, Hannah L.T. Elwell, Morgan Sokol, Junya Aoyama, Undine-Sophie Deumer, Emma Hsiao, and Hao Sheng.

This work was supported by the National Institutes of Health (K08 HL150335, HL151684, HL137710, and 1DP1DK130673), National Science Foundation (NSF ECCS-2038603), the William Milton Fund, a Harvard Stem Cell Collaborative Seed Grant, a Blavatnik Biomedical Accelerator Pilot Grant, an American Heart Association Career Development Award, a Boston Childrens Hospital Office of Faculty Development Career Development Award, and an Aramont Fellowship for Emerging Science Research.

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Cyborg technology analyzes the functional maturation of stem-cell ... - Harvard School of Engineering and Applied Sciences