AccScience Publishing / IJB / Online First / DOI: 10.36922/IJB025370372
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RESEARCH ARTICLE

Hyaluronic acid-based self-healing hydrogels with enhanced hydrolytic stability for 3D bioprinting in tissue engineering

Minhyung Kong1 ,  Hyun Seung Kim1 ,  Jiwon Hwang1 ,  Joon Seo Park1 ,  In Young Lee1 ,  Kuen Yong Lee1,2*
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1 Department of Bioengineering, Hanyang University, Seoul, Republic of Korea
2 Institute for Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul, Republic of Korea
IJB, 025370372 https://doi.org/10.36922/IJB025370372
Received: 9 September 2025 | Accepted: 1 October 2025 | Published online: 2 October 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

Hyaluronic acid (HA)-based hydrogels have gained significant interest for many biomedical applications because of their biocompatibility and degradability as glycosaminoglycans. However, it is challenging to control their mechanical properties and degradation rates. In this study, we investigated the potential of carbodihydrazide-modified HA (HA-CDH) and oxidized diol-modified HA (odHA) to form hydrogels. We modulated the mechanical stiffness of the HA-CDH/odHA hydrogels by adjusting the degree of CDH substitution and polymer composition in the gels. These hydrogels exhibited improved hydrolytic stability under physiological conditions, which was attributed to the presence of multiple delocalized electron arrangements within the hydrazone bonds. Notably, the enzymatic degradability of these hydrogels was unaffected by the hydrazone bonds. We developed self-healing HA-CDH/odHA hydrogels using free adipic acid dihydrazide and utilized them to fabricate various three-dimensional (3D) structures via 3D printing. We integrated resonance-stabilized hydrazone chemistry with self-healing behavior in HA-based hydrogels, enabling both slow degradation and direct extrusion-based 3D bioprinting of cell-laden constructs without secondary networks or post-crosslinking treatments. Furthermore, we investigated the effect of enhanced mechanical stiffness on in vitro cell differentiation and observed significant gene expression levels that were indicative of chondrogenic and osteogenic differentiation within hydrogels with increased stiffness. These findings could help elucidate the effect of the physical properties of natural polysaccharide-based hydrogels on cell phenotype modulation and expand their applications in tissue engineering.  

Graphical abstract
Keywords
3D bioprinting
Hydrazide-modified hyaluronate
Hydrolytic degradation
Oxidized hyaluronate
Resonance structure
Self-healing
Funding
This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIT) (RS-2024-00355200).
Conflict of interest
The authors declare 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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