3D bioprinting lobule-like hepatorganoids with induced vascularization for orthotopic implantation

作者：Jianing Yan, Zhichao Ye, Yiwei Lu, Yang Yuan, Xiaofeng Wang, Tingting Yan, Jun Yin, Yifan Wang · 发表于：Materials Today Bio · 年份：2025 · DOI：10.1016/j.mtbio.2025.101515 · 被引用次数：12 · 研究领域：3D Printing in Biomedical Research、Liver physiology and pathology、Tissue Engineering and Regenerative Medicine

Orthotopic implantation in vivo is the ultimate target of tissue-engineering organoids research, aiming to achieve sustaining survival after implantation. However, the limited representation of a complex microenvironment in implanted accepter hampers a comprehensive understanding of long-term maintenance of tissue-engineering organoids, especially in liver. In this research, we developed a 3D bioprinting method using gelatin methacryloyl (GelMA) hydrogel to fabricate lobule-like hepatorganoids, which faithfully mimic the structure of hepatic lobules with lower level of hypoxia (lobule vs 60°, 90°, control; 0.4880 vs 1.009, 0.6778, 0.8704; p < 0.01), high secretion of albumin (lobule vs 60°, 90°, control; 13.47 vs 12.39, 12.65, 10.08 mg/L; p < 0.01) and urea (lobule vs 60°, 90°, control; 5.304 vs 5.233, 4.781, 4.358 mg/L; p < 0.01) in vitro; and promotion of angiogenesis and maintenance of activity following orthotopic implantation. Loaded with a prolonged released system of vascular endothelial growth factor (VEGF) and infused with human umbilical vein endothelial cells (HUVECs), we developed a fabricating method of vascularized lobule-like hepatorganoids (VLH) which possessed promoted vascularization. We identified GAS6/AXL and LAMB3/ITGA3 signaling pathway up-regulated in VLH, which was conducive to vascularization and proliferation. Furthermore, orthotopic implantation model indicated that VLH exhibited prolonged survival in vivo , with elevated level of serological biomar...