Tissue-Embedded 3D Stretchable Nanoelectronics for Multimodal Charting of the Human Stem Cell-Derived Organoids

The development of human induced pluripotent stem cells (hiPSCs) technology has revolutionized the field of disease modeling and holds immense potential for personalized regenerative cell therapies. A comprehensive understanding of stem cell-derived tissues and organoids requires advanced multimodal techniques capable of capturing cell functions with high spatiotemporal resolution in three-dimensional (3D) tissues, profiling numerous genes in recorded cells, and performing multimodal computational analysis. However, none of the existing technologies fullfill these requirements.<br/>In this presentation, I will begin by introducing the development of soft, stretchable mesh nanoelectronics that mimic the physical and mechanical properties of biological tissues. We can distribute these stretchable tissue-like bioelectronics throughout the entire 3D organoids by their organogenetic processes. By establishing seamless and noninvasive connections between electrodes and cells, we can achieve long-term stable electrical contacts with progenitor or stem cells, capturing the emergence of single-cell action potentials. This facilitates continuous, long-term recording from various types of 3D organoids during their development.<br/>Next, I will demonstrate how this technique enables the long-term stable mapping of human 3D cardiac microtissues for the characterization of their functional maturation. Specifically, I will discuss an example in which stretchable mesh electronics were embedded with hiPSC-derived cardiomyocytes (hiPSC-CMs) and hiPSC-derived endothelial cells (hiPSC-ECs). By developing machine learning-based pseudotime trajectory inference of the long-term cardiomyocyte electrical signals from multiple samples, we can quantify the electrical phenotypic transition path during development. Our results showed that hiPSC-ECs drive remarkable hiPSC-CM electrical maturation via multiple intercellular pathways.<br/>Finally, I will discuss our efforts to combine in situ single-cell RNA sequencing with flexible bioelectronics, a methodology we term "in situ electro-seq". This technique allows us to link cell molecular gene expression with electrical activities. Specifically, I will discuss how in situ electro-seq enables systematic and simultaneous investigation of single-cell electrophysiology and gene expression across hiPSC-CMs during their development. Additionally, I will discuss the potential of using in situ electro-seq to create spatiotemporal multimodal maps in electrogenic tissues, thereby potentiating the discovery of cell types and gene programs responsible for electrophysiological function and dysfunction.