Hydrogels with programmed spatiotemporal mechanical cues for stem cell-assisted bone regeneration

Bin Xue (), Zhengyu Xu, Lan Li, Kaiqiang Guo, Jing Mi, Haipeng Wu, Yiran Li, Chunmei Xie, Jing Jin, Juan Xu, Chunping Jiang, Xiaosong Gu, Meng Qin, Qing Jiang (), Yi Cao () and Wei Wang ()
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Bin Xue: Nanjing University
Zhengyu Xu: Nanjing University
Lan Li: The Affiliated Hospital of Nanjing University Medical School
Kaiqiang Guo: Nanjing University
Jing Mi: The Affiliated Hospital of Nanjing University Medical School
Haipeng Wu: Nanjing University
Yiran Li: Nanjing University
Chunmei Xie: The Affiliated Hospital of Nanjing University Medical School
Jing Jin: The Affiliated Hospital of Nanjing University Medical School
Juan Xu: The Affiliated Hospital of Nanjing University Medical School
Chunping Jiang: Jinan Microecological Biomedicine Shandong Laboratory
Xiaosong Gu: Jinan Microecological Biomedicine Shandong Laboratory
Meng Qin: Nanjing University
Qing Jiang: The Affiliated Hospital of Nanjing University Medical School
Yi Cao: Nanjing University
Wei Wang: Nanjing University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Hydrogels are extensively utilized in stem cell-based tissue regeneration, providing a supportive environment that facilitates cell survival, differentiation, and integration with surrounding tissues. However, designing hydrogels for regenerating hard tissues like bone presents significant challenges. Here, we introduce macroporous hydrogels with spatiotemporally programmed mechanical properties for stem cell-driven bone regeneration. Using liquid-liquid phase separation and interfacial supramolecular self-assembly of protein fibres, the macroporous structure of hydrogels provide ample space to prevent contact inhibition during proliferation. The rigid protein fibre-coated pore shell provides sustained mechanical cues for guiding osteodifferentiation and protecting against mechanical loads. Temporally, the hydrogel exhibits tunable degradation rates that can synchronize with new tissue deposition to some extent. By integrating localized mechanical heterogeneity, macroporous structures, surface chemistry, and regenerative degradability, we demonstrate the efficacy of these stem cell-encapsulated hydrogels in rabbit and porcine models. This marks a substantial advancement in tailoring the mechanical properties of hydrogels for stem cell-assisted tissue regeneration.

Date: 2025
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DOI: 10.1038/s41467-025-59016-6

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