Instrumented brain organoids transplantation for chronic stroke treatment

About This Grant

Current stroke treatment targets acute phases of stroke with therapies administered in the first 48 hours after onset. There is still no restorative drug treatment beyond these two stages of stroke. Of the over 10 million strokes that occur annually in the United States, most survivors are left with functional deficits without any effective FDA-approved treatment to improve their conditions. Brain organoids hold great promises for stroke repair because they recapitulate various key features of the developing human central nervous system (CNS) in three-dimensional (3D) space. It has been shown that human brain organoids are able to survive and integrate into the developing brains of rodents. But it is a huge challenge for brain organoids to survive and extensively integrate in the adult brain for the treatment of chronic stroke. Electrical stimulations have been shown to improve growth and cell migration of brain organoids. However, a few critical limitations remain: First, conventional electrodes have a rigidity order of magnitude higher than that of the brain organoids or the brain, leading to chronic gliosis, disruption of the neural network, and incapability of providing stable electrical stimulation over time. Second, existing studies either rely on phenotypic observation with limited spatial and functional information or static histochemical comparison without temporal resolution. Third, there is no systematic study examining the effect electric stimulation of implanted cortical organoids (COs) on the recovery of chronic stroke. To address these issues, we propose the concept of microinstrumented cortical organoid therapy for stroke by employing a multidisciplinary approach that leverages advancements in flexible bioelectronics. This novel strategy integrates in vivo electrophysiology with intravital multiphoton imaging to create a dynamic platform for real-time monitoring and intervention in stroke recovery. Our central hypothesis is that microinstrumented COs with rationally designed FBDs will promote survival, migration, and integration of cells from engrafts with adult host brains in chronic stroke. We reason that electrical stimulation through FBDs increases the survival and integration of BOs into the ischemic brain. In Aim 1, we will perform rational design of FBDs for integration with COs and determine stimulation settings that promote survival, growth, and neural differentiation of COs under dual modality readout (electrophysiological recording and 2-photon imaging) in culture. In Aim 2, we will assess the repairing potential of electrical stimulation of transplanted microinstrumented COs in a chronic stroke model in mice. Overall, by integrating cutting-edge technologies, our proposal will develop a new method that is technology-directed but, importantly, also addresses a well-defined, unmet biomedical challenge. It paves the way for a much-needed breakthrough in treating patients with chronic stroke, particularly those severely paralyzed and facing a poor quality of life. We hope to obtain proof-of-concept results for laying a solid foundation for further research under other funding mechanisms, such as the R01.