Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits.

Human brain organoids represent a remarkable platform for modeling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses reveal that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays reveal that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.

3D printing of interferon γ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI.

The reconstruction of neural function and recovery of chronic damage following traumatic brain injury (TBI) remain significant clinical challenges. Exosomes derived from neural stem cells (NSCs) offer various benefits in TBI treatment. Numerous studies confirmed that appropriate preconditioning methods enhanced the targeted efficacy of exosome therapy. Interferon-gamma (IFN-γ) possesses immunomodulatory capabilities and is widely involved in neurological disorders. In this study, IFN-γ was employed for preconditioning NSCs to enhance the efficacy of exosome (IFN-Exo, IE) for TBI. miRNA sequencing revealed the potential of IFN-Exo in promoting neural differentiation and modulating inflammatory responses. Through low-temperature 3D printing, IFN-Exo was combined with collagen/chitosan (3D-CC-IE) to preserve the biological activity of the exosome. The delivery of exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes, ensuring that they could exert long-term effects at the injury site. The 3D-CC-IE scaffold exhibited excellent biocompatibility and mechanical properties. Subsequently, 3D-CC-IE scaffold significantly improved impaired motor and cognitive functions after TBI in rat. Histological results showed that 3D-CC-IE scaffold markedly facilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis. Further mechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTOR signaling pathway. In summary, the results of this study indicated that 3D-CC-IE scaffold engaged in long-term pathophysiological processes, fostering neural function recovery after TBI, offering a promising regenerative therapy avenue.