Bioelectronics for Cellular Electrophysiology during Tissue Development

Abstract

Gaining insights from high spatiotemporal resolution electrophysiology studies of developmental biosystems, such as developing brains or organoids, is pivotal. These studies play a fundamental role in understanding the progression of biosystem development into functional entities and in uncovering the mechanisms underlying diseases that may arise during these processes. However, the technological aspect presents a substantial challenge. Achieving high spatiotemporal resolution in electrical signal acquisition often requires integrating bioelectronics with the biosystem. As developmental biosystems frequently undergo rapid volumetric expansion and significant changes in tissue morphology, conventional microelectronics encounter limitations when attempting to investigate such dynamically changing environments accurately, compatibly, and durably. The thesis commences with an exploration of the use of hydrogel as a neural interface (Chapter 1). Given its water-rich and tissue-like nature, hydrogel was investigated for its potential to accommodate tissue morphology changes. Our initial prototypes validated its effectiveness as a neural interface, although temporal resolution was lacking. Consequently, our attention shifted towards the emerging field of "tissue-like" mesh electronics, fueled by advancements in materials science, electronics, and bioengineering. We conceived the notion of integrating mesh electronics with biosystems during their developmental progression, not only to uniformly distribute bioelectronics across the system but also to record electrophysiological dynamics throughout the developmental phases. This concept was first put to the test in cardiac organoids (Chapter 2). We describe the creation of cyborg organoids: three-dimensional assemblies of flexible, stretchable mesh nanoelectronics orchestrated by the cell-cell attraction forces inherent in the 2D-to-3D tissue reconfiguration during organogenesis. The exploration of this idea extended to embryo systems (Chapter 3). We introduce a micrometer-thick, tissue-level soft mesh microelectrode array that seamlessly integrates into the neural plate of embryos (including frog, axolotl, and mouse) through the inherent 2D-to-3D tissue reconfiguration during organogenesis. Guided by the expansion and folding processes intrinsic to organogenesis, the stretchable mesh electrode array undergoes deformation, stretching, and dispersion throughout the entirety of the brain, achieving full integration within the complex 3D tissue structure. The resulting cyborg organoids and embryos, with their capacity for micrometer-scale, microsecond-resolution recording throughout the entirety of the developmental timeline, hold the potential to unveil novel opportunities within the realm of developmental biology.