IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59016-6.html
   My bibliography  Save this article

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

Author

Listed:
  • Bin Xue

    (Nanjing University
    Jinan Microecological Biomedicine Shandong Laboratory
    Nanjing University)

  • Zhengyu Xu

    (Nanjing University
    Nanjing University)

  • Lan Li

    (The Affiliated Hospital of Nanjing University Medical School
    Jiangsu Engineering Research Center for 3D Bioprinting)

  • 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
    Jiangsu Engineering Research Center for 3D Bioprinting)

  • Yi Cao

    (Nanjing University
    Jinan Microecological Biomedicine Shandong Laboratory
    Nanjing University
    Nanjing University)

  • Wei Wang

    (Nanjing University
    Nanjing University)

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.

Suggested Citation

  • 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 & Wei Wang, 2025. "Hydrogels with programmed spatiotemporal mechanical cues for stem cell-assisted bone regeneration," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59016-6
    DOI: 10.1038/s41467-025-59016-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59016-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-59016-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Mikhail Nikolaev & Olga Mitrofanova & Nicolas Broguiere & Sara Geraldo & Devanjali Dutta & Yoji Tabata & Bilge Elci & Nathalie Brandenberg & Irina Kolotuev & Nikolce Gjorevski & Hans Clevers & Matthia, 2020. "Homeostatic mini-intestines through scaffold-guided organoid morphogenesis," Nature, Nature, vol. 585(7826), pages 574-578, September.
    2. Xiaoyu Chen & Rui Li & Siu Hong Dexter Wong & Kongchang Wei & Miao Cui & Huaijun Chen & Yuanzhang Jiang & Boguang Yang & Pengchao Zhao & Jianbin Xu & Heng Chen & Chao Yin & Sien Lin & Wayne Yuk-Wai Le, 2019. "Conformational manipulation of scale-up prepared single-chain polymeric nanogels for multiscale regulation of cells," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    3. Matthias P. Lutolf & Penney M. Gilbert & Helen M. Blau, 2009. "Designing materials to direct stem-cell fate," Nature, Nature, vol. 462(7272), pages 433-441, November.
    4. Ovijit Chaudhuri & Justin Cooper-White & Paul A. Janmey & David J. Mooney & Vivek B. Shenoy, 2020. "Effects of extracellular matrix viscoelasticity on cellular behaviour," Nature, Nature, vol. 584(7822), pages 535-546, August.
    5. Daisy A. Robinton & George Q. Daley, 2012. "The promise of induced pluripotent stem cells in research and therapy," Nature, Nature, vol. 481(7381), pages 295-305, January.
    6. Boguang Yang & Kongchang Wei & Claudia Loebel & Kunyu Zhang & Qian Feng & Rui Li & Siu Hong Dexter Wong & Xiayi Xu & Chunhon Lau & Xiaoyu Chen & Pengchao Zhao & Chao Yin & Jason A. Burdick & Yi Wang &, 2021. "Enhanced mechanosensing of cells in synthetic 3D matrix with controlled biophysical dynamics," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    7. Nathaniel Huebsch & David J. Mooney, 2009. "Inspiration and application in the evolution of biomaterials," Nature, Nature, vol. 462(7272), pages 426-432, November.
    8. Linglan Fu & Lan Li & Qingyuan Bian & Bin Xue & Jing Jin & Jiayu Li & Yi Cao & Qing Jiang & Hongbin Li, 2023. "Cartilage-like protein hydrogels engineered via entanglement," Nature, Nature, vol. 618(7966), pages 740-747, June.
    9. Marc Robin & Elodie Mouloungui & Gabriel Castillo Dali & Yan Wang & Jean-Louis Saffar & Graciela Pavon-Djavid & Thibaut Divoux & Sébastien Manneville & Luc Behr & Delphine Cardi & Laurence Choudat & M, 2024. "Mineralized collagen plywood contributes to bone autograft performance," Nature, Nature, vol. 636(8041), pages 100-107, December.
    10. Elisa Laurenti & Berthold Göttgens, 2018. "From haematopoietic stem cells to complex differentiation landscapes," Nature, Nature, vol. 553(7689), pages 418-426, January.
    11. Zhong-Kai Cui & Soyon Kim & Jessalyn J. Baljon & Benjamin M. Wu & Tara Aghaloo & Min Lee, 2019. "Microporous methacrylated glycol chitosan-montmorillonite nanocomposite hydrogel for bone tissue engineering," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    12. Andrew C. Daly & Matthew D. Davidson & Jason A. Burdick, 2021. "3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yangteng Ou & Shixiang Cao & Yang Zhang & Hongjia Zhu & Chengzhi Guo & Wei Yan & Fengxue Xin & Weiliang Dong & Yanli Zhang & Masashi Narita & Ziyi Yu & Tuomas P. J. Knowles, 2023. "Bioprinting microporous functional living materials from protein-based core-shell microgels," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Woojin Choi & Utkarsh Mangal & Jae-Hun Yu & Jeong-Hyun Ryu & Ji‑Yeong Kim & Taesuk Jun & Yoojin Lee & Heesu Cho & Moonhyun Choi & Milae Lee & Du Yeol Ryu & Sang-Young Lee & Se Yong Jung & Jae-Kook Cha, 2024. "Viscoelastic and antimicrobial dental care bioplastic with recyclable life cycle," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Jinchang Zhu & Yi He & Yong Wang & Li-Heng Cai, 2024. "Voxelated bioprinting of modular double-network bio-ink droplets," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Yuanxiong Cao & Jiayi Tan & Haoran Zhao & Ting Deng & Yunxia Hu & Junhong Zeng & Jiawei Li & Yifan Cheng & Jiyuan Tang & Zhiwei Hu & Keer Hu & Bing Xu & Zitian Wang & Yaojiong Wu & Peter E. Lobie & Sh, 2022. "Bead-jet printing enabled sparse mesenchymal stem cell patterning augments skeletal muscle and hair follicle regeneration," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    5. Qiang Shan & Xiang Li & Xia Chen & Zhouhao Zeng & Shaoqi Zhu & Kexin Gai & Weiqun Peng & Hai-Hui Xue, 2021. "Tcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    6. Chen Jiang & Alessia Centonze & Yura Song & Antonius Chrisnandy & Elisavet Tika & Saba Rezakhani & Zahra Zahedi & Gaëlle Bouvencourt & Christine Dubois & Alexandra Van Keymeulen & Matthias Lütolf & Al, 2024. "Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Hangchao Wang & Yali Yang & Chuan Gao & Tao Chen & Jin Song & Yuxuan Zuo & Qiu Fang & Tonghuan Yang & Wukun Xiao & Kun Zhang & Xuefeng Wang & Dingguo Xia, 2024. "An entanglement association polymer electrolyte for Li-metal batteries," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    8. Huimin He & Xi Wei & Bin Yang & Hongzhen Liu & Mingze Sun & Yanran Li & Aixin Yan & Chuyang Y. Tang & Yuan Lin & Lizhi Xu, 2022. "Ultrastrong and multifunctional aerogels with hyperconnective network of composite polymeric nanofibers," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    9. Matt D. G. Hughes & Sophie Cussons & Benjamin S. Hanson & Kalila R. Cook & Tímea Feller & Najet Mahmoudi & Daniel L. Baker & Robert Ariëns & David A. Head & David J. Brockwell & Lorna Dougan, 2023. "Building block aspect ratio controls assembly, architecture, and mechanics of synthetic and natural protein networks," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    10. Xianzhu Zhang & Wei Jiang & Chang Xie & Xinyu Wu & Qian Ren & Fei Wang & Xilin Shen & Yi Hong & Hongwei Wu & Youguo Liao & Yi Zhang & Renjie Liang & Wei Sun & Yuqing Gu & Tao Zhang & Yishan Chen & Wei, 2022. "Msx1+ stem cells recruited by bioactive tissue engineering graft for bone regeneration," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    11. Feipeng Chen & Xiufeng Li & Yafeng Yu & Qingchuan Li & Haisong Lin & Lizhi Xu & Ho Cheung Shum, 2023. "Phase-separation facilitated one-step fabrication of multiscale heterogeneous two-aqueous-phase gel," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    12. Israt Parveen & Kazi M. Maraz & Md. Iqbal Mahmud & Ruhul A. Khan*, 2019. "Seaweed Based Bio Polymeric Film and Their Application: A Review on Hydrocolloid Polysaccharides," Scientific Review, Academic Research Publishing Group, vol. 5(5), pages 93-102, 05-2019.
    13. Haonan He & Xianchi Zhou & Yuxian Lai & Rouye Wang & Hongye Hao & Xintian Shen & Peng Zhang & Jian Ji, 2025. "Chain entanglement enhanced strong and tough wool keratin/albumin fibers for bioabsorbable and immunocompatible surgical sutures," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    14. Kensuke Miyake & Junya Ito & Jun Nakabayashi & Shigeyuki Shichino & Kenji Ishiwata & Hajime Karasuyama, 2023. "Single cell transcriptomics clarifies the basophil differentiation trajectory and identifies pre-basophils upstream of mature basophils," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    15. Mina N. F. Morcos & Congxin Li & Clara M. Munz & Alessandro Greco & Nicole Dressel & Susanne Reinhardt & Katrin Sameith & Andreas Dahl & Nils B. Becker & Axel Roers & Thomas Höfer & Alexander Gerbaule, 2022. "Fate mapping of hematopoietic stem cells reveals two pathways of native thrombopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    16. Farshad Farshidfar & Kahn Rhrissorrakrai & Chaya Levovitz & Cong Peng & James Knight & Antonella Bacchiocchi & Juan Su & Mingzhu Yin & Mario Sznol & Stephan Ariyan & James Clune & Kelly Olino & Laxmi , 2022. "Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    17. Stefan Harmansa & Alexander Erlich & Christophe Eloy & Giuseppe Zurlo & Thomas Lecuit, 2023. "Growth anisotropy of the extracellular matrix shapes a developing organ," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    18. Zhengyu Xu & Jiajun Lu & Di Lu & Yiran Li & Hai Lei & Bin Chen & Wenfei Li & Bin Xue & Yi Cao & Wei Wang, 2024. "Rapidly damping hydrogels engineered through molecular friction," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    19. Zhao Wang & Jan Lauko & Amanda W. Kijas & Elliot P. Gilbert & Petri Turunen & Ramanathan Yegappan & Dongxiu Zou & Jitendra Mata & Alan E. Rowan, 2023. "Snake venom-defined fibrin architecture dictates fibroblast survival and differentiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    20. Qin-Yang Zeng & Gui-Xin Su & Ai-Sheng Song & Xin-Yu Mei & Zhi-Yue Xu & Yue Ying & Zhuo-Zhi Zhang & Xiang-Xiang Song & Guang-Wei Deng & Joel Moser & Tian-Bao Ma & Ping-Heng Tan & Xin Zhang, 2025. "High-quality-factor viscoelastic nanomechanical resonators from moiré superlattices," Nature Communications, Nature, vol. 16(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59016-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.