AccScience Publishing / CAR / Online First / DOI: 10.36922/CAR025400001
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REVIEW ARTICLE

Dual-crosslinked hydrogels for tissue engineering: A comprehensive systematic review and meta-analysis of emerging strategies

Muhammad Moazzam1,2*
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1 Department of Biomedical Engineering, School of Engineering and Digital Sciences, Nazarbayev University, Astana, Kazakhstan
2 Office of Research, Innovation and Commercialization (ORIC), Green International University, Lahore, Punjab, Pakistan
CAR, 025400001 https://doi.org/10.36922/CAR025400001
Received: 30 September 2025 | Revised: 21 December 2025 | Accepted: 9 January 2026 | Published online: 3 February 2026
© 2026 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

Advancements in tissue engineering rely on the development of more sophisticated scaffolds that can replicate the properties of native tissues and promote healing. This systematic review and meta-analysis, conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, synthesizes the latest research (2015–2025) on dual-crosslinked smart scaffolds—materials capable of both covalent and dynamic interactions—to evaluate their molecular mechanisms, mechanical performance, biological efficacy, and potential for clinical translation. The review reveals that combining dual-crosslinking chemistries—such as covalent Schiff bases, ionic interactions, and supramolecular bonds—synergistically enhances scaffold stability, stimuli-responsiveness, and bioactivity across various tissues, including bone, cartilage, skin, and vascular tissues. Quantitative data demonstrate degradation processes aligned with healing timelines, Young’s moduli tailored to specific environments, and tissue-relevant mechanical properties. Despite promising preclinical results showing improved cellular viability, differentiation, and functional tissue regeneration, the understanding of the underlying molecular interactions remains limited. Additionally, evaluation tools lack standardization, and incorporating complex chemistries into clinical practice continues to pose challenges. Future directions emphasize the rational design of stimuli-responsive, bioinspired, and adaptive systems, combined with computational modeling, to enable personalized regenerative therapies. Overcoming these scientific and translational hurdles is essential to realize the full potential of dual-crosslinked scaffolds in next-generation tissue engineering.

Graphical abstract
Keywords
Dual-crosslinked scaffolds
Smart biomaterials
Tissue engineering
Regenerative medicine
Stimuli-responsive hydrogels
Biomaterial design
Funding
None.
Conflict of interest
The author declares that he has no competing interests.
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