Department of Histology & Embryology, College of Basic Medical Sciences, Dalian Medical University, Liaoning 116044, China.
Biomedical Engineering Department, Tufts University, Medford, Massachusetts 02155, United States.
ACS Appl Mater Interfaces. 2022 Jan 12;14(1):201-213. doi: 10.1021/acsami.1c18215. Epub 2021 Dec 20.
Bioengineering functional hepatic tissue constructs that physiologically replicate the human native liver tissue is sought for clinical research and drug discovery. However, the intricate architecture and specific biofunctionality possessed by the native liver tissue remain challenging to mimic . In the present study, a versatile strategy to fabricate lobular-like silk protein scaffolds with radially aligned lamellar sheets, interconnected channels, and a converging central cavity was designed and implemented. A proof-of-concept study to bioengineer biomimetic hepatic lobules was conducted through coculturing human hepatocytes and primary endothelial cells on these lobular-like scaffolds. Relatively long-term viability of hepatocyte/endothelial cells was found along with cell alignment and organization . The hepatocytes showed special epithelial polarity and bile duct formation, similar to the liver plate, while the aligned endothelial cells generated endothelial networks, similar to natural hepatic sinuses. This endowed the three-dimensional (3D) tissue constructs with the capability to recapitulate hepatic-like parenchymal-mesenchymal growth patterns . More importantly, the cocultured hepatocytes outperformed monocultures or monolayer cultures, displaying significantly enhanced hepatocyte functions, including functional gene expression, albumin (ALB) secretion, urea synthesis, and metabolic activity. Thus, this functional unit with a biomimetic phenotype provides a novel technology for bioengineering biomimetic hepatic lobules , with potential utility as a building block for bioartificial liver (BAL) engineering or as a robust tool for drug metabolism investigation.
生物工程功能性肝组织构建体，旨在生理上复制人体天然肝组织，用于临床研究和药物发现。然而，天然肝组织所具有的复杂结构和特定生物功能仍然难以模拟。本研究设计并实施了一种通用策略，用于制造具有放射状排列的层片状片、相互连接的通道和汇聚中央腔的小叶状丝蛋白支架。通过在这些小叶状支架上共培养人肝细胞和原代内皮细胞，进行了生物工程仿生肝小叶的概念验证研究。发现肝细胞/内皮细胞具有相对长期的活力，同时还具有细胞排列和组织。肝细胞表现出特殊的上皮极性和胆管形成，类似于肝板，而排列整齐的内皮细胞则形成类似于天然肝窦的内皮网络。这使三维（3D）组织构建体具有重现肝样实质-间质生长模式的能力。更重要的是，共培养的肝细胞比单培养或单层培养表现出显著增强的肝细胞功能，包括功能基因表达、白蛋白（ALB）分泌、尿素合成和代谢活性。因此，这种具有仿生表型的功能性单位为生物工程仿生肝小叶提供了一种新的技术，具有作为生物人工肝（BAL）工程构建模块的潜在用途，或作为药物代谢研究的强大工具。
