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On-line Access: 2025-09-19
Received: 2024-09-25
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A hyaluronic acid-enhanced 3D-bioprinted osteosarcoma model reveals mechanisms of tumor metastasis and chemoresistance
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Hangyu Zhou (周航宇), Miaoben Wu (邬淼犇), Zekai Ding (丁泽铠), Wei Su (苏炜), Hankang Jiang (姜涵康), Kaixuan Chen (陈凯旋), Yibing Wu (吴屹冰), Enxing Yu (於恩兴), Yuye Huang (黄瑜烨), Qinghua Song (宋庆华) & Kailei Xu (徐开垒). A hyaluronic acid-enhanced 3D-bioprinted osteosarcoma model reveals mechanisms of tumor metastasis and chemoresistance[J]. Journal of Zhejiang University Science D, 2025, 8(5): 724-741.
@article{title=" A hyaluronic acid-enhanced 3D-bioprinted osteosarcoma model reveals
mechanisms of tumor metastasis and chemoresistance",
author="Hangyu Zhou (周航宇), Miaoben Wu (邬淼犇), Zekai Ding (丁泽铠), Wei Su (苏炜), Hankang Jiang (姜涵康), Kaixuan Chen (陈凯旋), Yibing Wu (吴屹冰), Enxing Yu (於恩兴), Yuye Huang (黄瑜烨), Qinghua Song (宋庆华) & Kailei Xu (徐开垒)",
journal="Journal of Zhejiang University Science D",
volume="8",
number="5",
pages="724-741",
year="2025",
publisher="Zhejiang University Press & Springer",
doi="10.1631/bdm.2400390"
}
%0 Journal Article
%T A hyaluronic acid-enhanced 3D-bioprinted osteosarcoma model reveals
mechanisms of tumor metastasis and chemoresistance
%A Hangyu Zhou (周航宇)
%A Miaoben Wu (邬淼犇)
%A Zekai Ding (丁泽铠)
%A Wei Su (苏炜)
%A Hankang Jiang (姜涵康)
%A Kaixuan Chen (陈凯旋)
%A Yibing Wu (吴屹冰)
%A Enxing Yu (於恩兴)
%A Yuye Huang (黄瑜烨)
%A Qinghua Song (宋庆华) & Kailei Xu (徐开垒)
%J Journal of Zhejiang University SCIENCE D
%V 8
%N 5
%P 724-741
%@ 1869-1951
%D 2025
%I Zhejiang University Press & Springer
%DOI 10.1631/bdm.2400390
TY - JOUR
T1 - A hyaluronic acid-enhanced 3D-bioprinted osteosarcoma model reveals
mechanisms of tumor metastasis and chemoresistance
A1 - Hangyu Zhou (周航宇)
A1 - Miaoben Wu (邬淼犇)
A1 - Zekai Ding (丁泽铠)
A1 - Wei Su (苏炜)
A1 - Hankang Jiang (姜涵康)
A1 - Kaixuan Chen (陈凯旋)
A1 - Yibing Wu (吴屹冰)
A1 - Enxing Yu (於恩兴)
A1 - Yuye Huang (黄瑜烨)
A1 - Qinghua Song (宋庆华) & Kailei Xu (徐开垒)
J0 - Journal of Zhejiang University Science D
VL - 8
IS - 5
SP - 724
EP - 741
%@ 1869-1951
Y1 - 2025
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/bdm.2400390
Abstract: Osteosarcoma, an aggressive bone cancer found most often in children and adolescents, remains difficult to treat, and little
improvement in survival rate has been observed over recent decades. The tumor microenvironment (TME), especially the extra
cellular matrix (ECM), is a critical factor determining cancer progression and chemotherapy resistance, yet traditional 2D
models generally fail to replicate its properties. Recent development of 3D-bioprinted tumor models has facilitated improved
simulation of the complexity of the TME, but specific models involving bioinks tailored to osteosarcoma remain underdevel
oped. Gelatin methacryloyl (GelMA) is a common bioink that can rapidly gel and contains Arg-Gly-Asp (RGD) sequences.
However, it lacks collagen’s triple-helix structure that is essential for ECM–cell communication. Hyaluronic acid (HA) is a
macromolecule that is aberrantly expressed in osteosarcoma by mechanisms that remain largely unexplored. In this study, we
developed a composite bioink containing GelMA, collagen, and HA, and applied it to 3D bioprint an in vitro osteosarcoma
model. We found that HA significantly enhanced osteosarcoma cell proliferation and chemoresistance, as well as the expres
sion of epithelial–mesenchymal transition and cancer stem cell markers. Furthermore, we found that HA abundance was
positively correlated with hypoxia and angiogenesis signaling pathways, and this occurred mainly via upregulation of
hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA) expression, thereby contributing to
increased chemoresistance. Overall, our study provides a protocol for building in vitro realistic 3D-bioprinted models for
studying osteosarcoma, highlights the role of HA in osteosarcoma progression, and offers a platform for developing new che
motherapy treatments.
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