Sustained delivery of 3D-bioprinted stem cell-derived small extracellular vesicles promotes neural regeneration following traumatic brain injury via the CREB1/PGC-1α/FNDC5 axis.
10 affiliations
- 1Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, CN 410008, China.
- 2National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, CN 410008, China.
- 3Research Institute of Brain and Spinal Cord Injury, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- 4Department of Neurosurgery, Xiangya School of Medicine, Central South University, Changsha, 410008, Hunan, China.
- 5Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
- 6Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
- 7Research and Development Department, Huamei Biotech Co. Ltd., Shenzhen, 518107, China.
- 8Bio-Intelligent Manufacturing and Living Matter Bioprinting Center, Research Institute of Tsinghua University in Shenzhen, Tsinghua University, Shenzhen, China.
- 9Hunan Provincial Key Laboratory of Neurocritical Care, China.
- 10Department of Neurosurgery, National Regional Center for Neurological Diseases, Xiangya Hospital (Jiangxi), Central South University, Nanchang, Jiangxi, 330038, China.
Abstract
Clinical translation of stem cell-derived small extracellular vesicles (sEVs) for traumatic brain injury (TBI) is restricted by low yield in 2D culture and rapid in vivo clearance. To develop an in situ sustained delivery system (3D-sEVs@Gel) encapsulating 3D-bioprinted adipose stem cell (ADSC)-derived sEVs (3D-ADSC-sEVs) within GelMA (Gelatin methacryloyl) hydrogel for long-term functional repair after TBI. SEVs derived from coaxially bioprinted 3D-ADSCs were isolated, and a GelMA hydrogel-based delivery system was subsequently constructed. Following orthotopic transplantation of the 3D-sEVs@Gel system into the lesion site after TBI, functional recovery, neural stem cell (NSC) proliferation and lineage-associated responses, and the underlying molecular mechanisms were systematically evaluated through behavioral tests, immunofluorescence, multi-omics, and pharmacological inhibition. SEVs generated using the coaxial alginate-microfiber culture system exhibited an approximately eightfold higher yields and protein loading compared with those obtained from 2D culture. In vivo, 3D-sEVs@Gel prolonged local retention, reduced tissue loss, and significantly improved long-term sensorimotor coordination and spatial memory following TBI. In addition, treatment increased the numbers of proliferating cells co-expressing neural progenitor-, neuronal-, and oligodendroglial-lineage-associated markers within the examined neurogenic regions. Mechanistically, 3D-sEV treatment increased nuclear CREB1 levels in NSCs, promoting PGC-1α transcription and subsequent FNDC5 expression, thereby supporting endogenous neurogenesis and functional neural repair. The 3D-sEVs@Gel system promotes chronic neurological reconstruction post-TBI by modulating NSC proliferation and neural lineage-associated responses through the CREB1/PGC-1α/FNDC5 pathway, offering a promising cell-free strategy for neural repair and tissue engineering.
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BibTeX
@article{ai2026sustained,
title = {{Sustained delivery of 3D-bioprinted stem cell-derived small extracellular vesicles promotes neural regeneration following traumatic brain injury via the CREB1/PGC-1α/FNDC5 axis.}},
author = {Ying Ai and Qian Zhang and Tiange Chen and Lin Lin and Ziyang Chen and Ganzhi Liu and Jiacheng Liu and Zhuojing Dong and Yanpeng Jiao and Jingwei Zhang and Yi Zhang and Boxun Liu and Tao Xu and Xin Chen and Jinfang Liu and Liyang Zhang and Yuguo Xia},
journal = {Bioactive materials},
year = {2026},
month = oct,
doi = {10.1016/j.bioactmat.2026.10.030},
url = {https://europepmc.org/article/MED/42999541},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sustained delivery of 3D-bioprinted stem cell-derived small extracellular vesicles promotes neural regeneration following traumatic brain injury via the CREB1/PGC-1α/FNDC5 axis.
AU - Ying Ai
AU - Qian Zhang
AU - Tiange Chen
AU - Lin Lin
AU - Ziyang Chen
AU - Ganzhi Liu
AU - Jiacheng Liu
AU - Zhuojing Dong
AU - Yanpeng Jiao
AU - Jingwei Zhang
AU - Yi Zhang
AU - Boxun Liu
AU - Tao Xu
AU - Xin Chen
AU - Jinfang Liu
AU - Liyang Zhang
AU - Yuguo Xia
PY - 2026
DA - 2026/10/31
JO - Bioactive materials
DO - 10.1016/j.bioactmat.2026.10.030
UR - https://europepmc.org/article/MED/42999541
AB - Clinical translation of stem cell-derived small extracellular vesicles (sEVs) for traumatic brain injury (TBI) is restricted by low yield in 2D culture and rapid in vivo clearance. To develop an in situ sustained delivery system (3D-sEVs@Gel) encapsulating 3D-bioprinted adipose stem cell (ADSC)-derived sEVs (3D-ADSC-sEVs) within GelMA (Gelatin methacryloyl) hydrogel for long-term functional repair after TBI. SEVs derived from coaxially bioprinted 3D-ADSCs were isolated, and a GelMA hydrogel-based delivery system was subsequently constructed. Following orthotopic transplantation of the 3D-sEVs@Gel system into the lesion site after TBI, functional recovery, neural stem cell (NSC) proliferation and lineage-associated responses, and the underlying molecular mechanisms were systematically evaluated through behavioral tests, immunofluorescence, multi-omics, and pharmacological inhibition. SEVs generated using the coaxial alginate-microfiber culture system exhibited an approximately eightfold higher yields and protein loading compared with those obtained from 2D culture. In vivo, 3D-sEVs@Gel prolonged local retention, reduced tissue loss, and significantly improved long-term sensorimotor coordination and spatial memory following TBI. In addition, treatment increased the numbers of proliferating cells co-expressing neural progenitor-, neuronal-, and oligodendroglial-lineage-associated markers within the examined neurogenic regions. Mechanistically, 3D-sEV treatment increased nuclear CREB1 levels in NSCs, promoting PGC-1α transcription and subsequent FNDC5 expression, thereby supporting endogenous neurogenesis and functional neural repair. The 3D-sEVs@Gel system promotes chronic neurological reconstruction post-TBI by modulating NSC proliferation and neural lineage-associated responses through the CREB1/PGC-1α/FNDC5 pathway, offering a promising cell-free strategy for neural repair and tissue engineering.
SN - 2452-199X
ER -