A robotic system can microinject individual heart cells between beats and could help identify potential treatments for cardiac arrhythmias, study findings suggest.
The robotic cell manipulator assesses the function of gap junctions, which are channels between heart cells that allow them to communicate electrically and beat in a coordinated manner.
The system was used to screen for drugs that could treat arrhythmogenic cardiomyopathy (ACM), a leading cause of sudden cardiac death among young adults.
The search identified a compound that, when tested, was able to reduce heartbeat irregularities in a mouse model of ACM.
“Although gap junction dysfunction has long been recognized as a contributing factor in many human diseases, the notion of modulating gap junction function is a relatively new and emerging treatment paradigm,” Wenkun Dou, PhD, from the University of Toronto in Canada, and collaborators noted in the journal Science Robotics.
“Our robotic microinjection assay provides a suitable platform for future screening of drugs across different cardiomyocytes and disease models to identify innovative gap junction–focused therapies.”
ACM is most commonly associated with gene mutations that encode proteins in desmosomes, which are intercellular junctions that help cells adhere to one another.
Specifically, the heart arrhythmia has been linked with mutations in the desmosomal protein plakophilin-2 (PKP2), which leads to faulty gap junctions.
But while gap junctions are vital to cardiac function, assessing their action has largely relied on laborious manual experimental techniques.
In an attempt to improve on the situation, researchers developed a robotic cell manipulation system with visual feedback from digital holographic microscopy.
Through this, they were able to create three-dimensional and label-free images of human induced pluripotent stem cell–derived cardiomyocytes.
The system was able to measure cell height and microinject dye at a consistent depth across cardiomyocytes in their resting phase.
Microinjection in beating cardiomyocytes was possible at a speed of approximately 20 cells per minute, with a dye deposition success rate of 95.2% and high reproducibility and post-injection cell viability.
The researchers used the robotic system to study the permeability of healthy and diseased cells and identified five compounds that could improve gap junction permeability in cardiomyocytes where PKP2 was affected.
One of these, PCO 400 (pinacidil), could reduce beating irregularities in a mouse model of ACM.
The researchers pointed out that gap junctions play a pivotal role in mediating cell-to-cell communication and are involved in a broad spectrum of human conditions including those affecting the skin and joints, as well as inflammatory, neurodegenerative, and heart diseases.
They concluded: “The obtained results demonstrated that our robotic system allows for rapid and reliable assessment of gap junction permeability in vitro, facilitating therapeutic development for diseases characterized by aberrant gap junction activity, such as ACM.”
