Engineering microcapsules to construct vascularized human brain organoids

Abstract Brain organoid is a promising technique with potential applications in developmental study, drug discovery and regenerative medicine, however, its practical values are restricted by poor flexibility, and lack of near-physiological structures or functions. Here, we present a multidisciplinary strategy to engineer novel vascularized human induced pluripotent stem cells (hiPSCs)-derived brain organoids system with biomimetic features using microfluidic hydrogel microcapsules. Due to the precise fluids control of microfluidic electrospray technology, its generated microcapsules enable the efficient encapsulation of hiPSCs-derived neural cells and formation of uniform human brain organoids. Through embedding microcapsules in hydrogel, vascularized brain organoids with structured organization and reasonable tissue size are established. We have found hiPSC-derived brain organoids with in vivo-like neural identity, brain region and layered cortex, as well as complex vascular networks, proving the capability to generate more relevant model of vascularized human brain. Thus, this biomimetic neural system could be injected for traumatic brain injury, and in vivo animal study has shown graft-to-host functional neural connectivity and neural regeneration, suggesting the organ-level functions for tissue repair. Our studies indicated that this simple, scalable and flexible system could be applied to develop biomimetic human tissues, which potentially advanced the organoid models for biomedical applications.