Brain Implantation of Tissue-Level-Soft Bioelectronics via Embryonic Development

Recording neural activities throughout brain development is critical to understanding how neurons self-assemble into an organ capable of learning, behavior, and cognition^1,2. However, the significant morphological changes occurring during brain development pose a challenge for implantable bioelectronics to continuously monitor neural activity throughout this process. To date, it has not been possible to perform the ideal experiment: recording brain-wide neural activity at the cellular level with millisecond temporal resolution in animals throughout brain development³.<br/>In this presentation, I will begin by introducing a class of bioelectronic devices and methods to integrate the device within the developing brain of vertebrate animals throughout embryogenesis. Specifically, I will introduce sub-micrometer-thick, tissue-level soft mesh electronics containing a stretchable electrode array that can be implanted into the embryo neural plate. During organogenesis, the neural plate undergoes a 2D-to-3D reorganization process², folding, proliferating, and expanding into the precursors of the nervous system. The endogenous forces involved in this process seamlessly and non-invasively distribute and integrate the sensor network across the 3D volume of the neural tube and brain, creating a “cyborg” embryo. I will also demonstrate that the presence of microelectronics had no discernible impact on embryo development or subsequent behaviors.<br/>Next, I will demonstrate how this technique enables tissue-wide, continuous recording of neuronal electrical activity during embryo development with millisecond temporal resolution. I will present an example of a cyborg frog embryo, illustrating the gradual development of localized neural activity in the frog brain: during the early stages of brain development, slow-wave synchronized electrical activities propagate across the neural tube from the forebrain to the midbrain. As development progresses, these synchronized signals gradually decouple, and calcium wave-like signals emerge, possibly indicating the increasing localization of brain activity. At last, isolated single-unit action potential-like spikes appear as the frog tadpole's brain function matures.<br/>Additionally, I will discuss our efforts to increase the channel count of the mesh electronics using electron-beam lithography. The new electronics with high-density, soft electrode arrays enable the simultaneous recording of more neurons during brain development. Activities from individual neurons can be captured by multiple electrodes, allowing for precise single-unit spike sorting. Together with new computational data analysis pipelines, this technology allows for the tracking of electrical activities from the same units throughout brain development.<br/>Finally, I will demonstrate the application of the mesh electronics across a broader range of animal models, including axolotl embryos, mouse embryos, and neonatal rats. Specifically, I will demonstrate the application to axolotl brain development, a unique model widely used for studying both brain development and regeneration. Continuous recording during embryonic brain development illustrates the evolution of well-isolated individual neurons and their positional migration. In addition, a spinal cord injury-regeneration experiment suggests similar neuronal activities involved in both development and regeneration. I will also demonstrate the successful implantation of the soft and stretchable mesh electronics in mouse embryos and neonatal rats, recording electrophysiological signals in the developing mammalian brain.<br/><br/><b>References:</b><br/>Sanes, D. H. et al. Development of the nervous system. (Academic Press, 2011).<br/>Smith, J. L. & Schoenwolf, G. C. Neurulation: coming to closure. Trends Neurosci. 20, 510-517 (1997).<br/>Randlett, O. et al. Whole-brain activity mapping onto a zebrafish brain atlas. Nat. Methods 12, 1039-1046 (2015).