3D-printed biomimetic scaffolds integrated with exosomes from injury-preconditioned hUCMSCs promote brain tissue repair via neuroprotection and neurogenesis.

Traumatic brain injury (TBI) results in severe neurological dysfunction, and effective morphological and functional recovery remains a challenge. Currently, safe and efficient strategies for neural regeneration and repair are lacking. Both human umbilical cord mesenchymal stem cell (hUCMSC)-derived exosomes and three-dimensional bioprinted scaffolds have exhibited application potential during neural repair. Nevertheless, the combined function of 3D-printed collagen/silk fibroin (3D-CS) scaffolds with injury-preconditioned exosomes obtained from hUCMSCs in the repair of traumatic brain injury remains unclear. Here, we demonstrate that exosomes produced from hUCMSCs preconditioned with brain trauma extracts have a neuroprotective effect on a craniocerebral trauma model in beagles. Notably, injury-preconditioned exosomes generated by hUCMSCs combined with 3D-CS scaffolds markedly promoted neuroregeneration and angiogenesis after TBI. Injury-preconditioned exosomes combined with 3D-CS scaffolds also alleviated both the pro-inflammatory factor-induced apoptosis and nerve apoptosis induced by injury in vivo. We further showed that the joint action of injury-preconditioned exosomes combined with 3D-CS scaffold-induced neurorepair ultimately promoted the recovery of neurological dysfunction after traumatic brain injury. In summary, this study reveals the cofunction of injury-preconditioned exosomes and 3D-CS scaffolds in response to traumatic brain injury and suggests a potential therapeutic strategy.