Encapsulation and Controlled Release of Human Spinal Cord Organoid-Derived Extracellular Vesicles for Tissue...

Human induced pluripotent stem cells (hiPSCs) can differentiate into various types of central nervous system organoids which are valuable for applications in tissue engineering and injury repair. The secreted extracellular vesicles (EVs) of organoids, in particular the small-sized EV subset referred as exosomes (30-200 nm), have emerged as novel therapeutics in regenerative medicine. This study investigated the encapsulation and controlled release of human spinal cord organoid (hSCO)-derived EVs in viscoelastic hyaluronic acid (HA) hydrogels and assessed their impact on organoid patterning. A series of pH-responsive hydrogels were fabricated, leading to sustained EV release regulated by viscoelastic properties. The pH of these hydrogels decreased from 9 to 7 during incubation, which altered hydrogel viscoelasticity, thereby modulating EV release kinetics. In addition, EV-loaded hydrogels regulated key hSCO patterning markers such as DBX1 and ISL1. Furthermore, these EVs in hydrogels can cross a modeled blood-spinal cord barrier and provide cross-barrier capability for delivery. Taken together, the organoid-secreted EVs in viscoelastic HA hydrogels can be released at a controlled rate and have potential to regulate spinal cord organoid patterning. This study advances our knowledge of regulating intercellular communication and developing EV-based therapies for treating neurological disorders such as spinal cord injury.