Bioengineering researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a soft, thin, stretchable bioelectronic device that can be implanted into a tadpole embryo's neural plate, the early-stage, flat structure that folds to become the 3D brain and spinal cord.
The researchers demonstrated that the device could integrate seamlessly into the brain as it develops and record electrical activity from single brain cells with millisecond precision, with no impact on normal tadpole embryo development or behavior.
These so-called cyborg tadpoles offer a glimpse into a future in which profound mysteries of the brain could be illuminated, and diseases that manifest in early development could be understood, treated, or cured.
"Autism, bipolar disorder, schizophrenia – these all could happen at early developmental stages," said Jia Liu, Assistant Professor of Bioengineering at SEAS. "There is just no ability currently to measure neural activity during early neural development. Our technology will really enable an uncharted area."
The research is published in Nature .
In vertebrate embryos, the folding and expansion of the neural plate into the neural tube, which is the precursor to the brain and spinal cord, involves complex morphological changes over millisecond time scales, Liu said. By integrating their stretchable device into the neural plate, the researchers showed they could stably and continuously monitor brain activity during each subsequent embryonic stage.
In the past, scientists have used patch-clamp or metal electrodes inserted into mature brains to record electrical activity of single neurons with high resolution. Further breakthroughs in tissue-like microelectronics from Liu's previous work have made single-cell brain recording even less invasive. Yet in fully developed brains, neurons connect with each other at nanometer resolutions; no matter how soft and small brain probes are, implanting them requires at least some neuronal damage, Liu said.
"If we can fully leverage the natural development process, we will have the ability to implant a lot of sensors across the 3D brain noninvasively, and at the same time, monitor how brain activity gradually evolves over time," Liu said. "No one has ever done this before."
This research builds on a multi-year effort to create soft, flexible, non-invasive bioelectronics for brains, which have the consistency of tofu. In previous studies, the team embedded electrode arrays into petri dishes of stem cells. The thin electrodes stretched and folded with growing tissue and created cyborg heart and brain organoids .
Though the organoid studies were successful, integrating nanoelectronics into amphibian embryos posed new challenges, according to Liu. "It turns out tadpole embryos are much softer than human stem cell-derived tissue," he said. "We ultimately had to change everything, including developing new electronic materials."
The researchers made a new type of implant out of fluorinated elastomers , which are as soft as biological tissue but can be engineered into highly resilient electronic components that can withstand nanofabrication processes and house multiple sensors for recording brain activity.
The fluorinated elastomer, called perfluoropolyether-dimethacrylate, is intellectual property protected by Harvard's Office of Technology Development, which licensed the technology to the start-up company Axoft for further development. Liu co-founded Axoft in 2021, and the company is focused on the development of scalable, soft bioelectronics for brain-machine interface applications.
The study's first author is Harvard postdoctoral fellow Hao Sheng. Co-authors were Ren Liu, Qiang Li, Zuwan Lin, Yichun He, Thomas S. Blum, Hao Zhao, Xin Tang, Wenbo Wang, Lishuai Jin, Zheliang Wang, Emma Hsiao, Paul Le Floch, Hao Shen, Ariel J. Lee, Rachael Alice Jonas-Closs, James Briggs, Siyi Liu, Daniel Solomon, Xiao Wang, Jessica L. Whited, and Nanshu Lu.
The research received federal support from the National Institutes of Health / National Institutes of Mental Health under grant No. 1RF1MH123948; the National Science Foundation / Emerging Frontiers in Research and Innovation under grant No. 2422348; and the National Institutes of Health / National Institute of Child Health and Human Development under grant No. 1R01HD115272.
