AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB025430444
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RESEARCH ARTICLE

3D-bioprinted active gingival hydrogel for periodontal soft tissue regeneration via TGF-β/ Smad and Wnt/β-Catenin-mediated extracellular matrix remodeling

Han Hu1† ,  Yue Liao1† ,  Jiachen Dong1 ,  Mengjun Sun1 ,  Xin Sun2 ,  Guodong Zhou3* ,  Zhongchen Song1*
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1 Department of Periodontology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, Shanghai, China
2 Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3 Department of Stomatology, Shanghai Yangpu District Kongjiang Hospital, Shanghai, China
†These authors contributed equally to this work.
IJB, 025430444 https://doi.org/10.36922/IJB025430444
Received: 26 October 2025 | Accepted: 4 December 2025 | Published online: 12 December 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Soft tissue management is essential in periodontal, orthodontic, and implant therapies, yet autologous grafts remain limited by donor-site morbidity, inconsistent tissue quality, and restricted availability. To address these challenges, we developed an active gingival hydrogel (AGH) composed of gelatin methacrylate, chondroitin sulfate methacrylate, and gingival fibroblasts, which was fabricated into cell-laden hydrogels using extrusion-based 3D bioprinting. The AGH exhibited excellent rheological performance, print fidelity, and interconnected porous microstructures that supported nutrient diffusion and cell migration. Gingival fibroblasts cocultured with the AGH showed robust adhesion, proliferation, and collagen matrix deposition, accompanied by significant upregulation of fibronectin and type I collagen. Mechanistic studies revealed that these effects were mediated through activation of the Wnt/β-catenin and transforming growth factor-β/Smad signaling pathways, which synergistically regulate extracellular matrix remodeling and epithelial keratinization. In vivo experiments demonstrated that AGH implantation significantly enhanced gingival thickness, collagen density, and neovascularization while reducing inflammatory infiltration, as verified by magnetic resonance imaging as well as histological and immunohistochemical analyses. Furthermore, coculture with gingival epithelial cells promoted upregulation of Krt10 and Krt14, indicating improved epithelial differentiation. Collectively, this study establishes a 3D-bioprinted active gingival hydrogel as a biomimetic and functional substitute for autologous grafts, offering a promising strategy for periodontal and peri-implant soft tissue regeneration.

Graphical abstract
Keywords
Bioprinting
Gingival fibroblast
Gingival phenotype
Soft tissue augmentation
Tissue engineering
Funding
This work was supported by the Biomaterials and Regenerative Medicine Institute Cooperative Research Project, Shanghai Jiao Tong University School of Medicine (Project No. 2022LHB04), and the Fundamental Research Program Funding of Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Project No. JYZZ210). The National Key Research and Development Program of China (2023YFC2413600).
Conflict of interest
The authors declare that they have no competing interests.
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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing
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