Academic Journal
Diels-Alder Click Chemistry as a Dynamic-Covalent Crosslinking Method in Spheroid-Encapsulating Hydrogels for Cartilage Engineering.
| Title: | Diels-Alder Click Chemistry as a Dynamic-Covalent Crosslinking Method in Spheroid-Encapsulating Hydrogels for Cartilage Engineering. |
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| Authors: | van de Looij SM; Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands., Vasilopoulou AG; Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands.; Regenerative Medicine Center Utrecht, Utrecht, the Netherlands., Spauwen L; Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands.; Regenerative Medicine Center Utrecht, Utrecht, the Netherlands.; HU University of Applied Sciences Utrecht, Utrecht, the Netherlands., van den Dikkenberg A; Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands., Korpershoek JV; Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands.; Department of Orthopedic Surgery, Mayo Clinic Rochester, Rochester, Minnesota, USA., de Ruijter M; Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands.; Regenerative Medicine Center Utrecht, Utrecht, the Netherlands.; Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands., Malda J; Department of Orthopedics, University Medical Center Utrecht, Utrecht, the Netherlands.; Regenerative Medicine Center Utrecht, Utrecht, the Netherlands.; Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands., van Ravensteijn BGP; Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands., Vermonden T; Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands.; Regenerative Medicine Center Utrecht, Utrecht, the Netherlands. |
| Source: | Advanced healthcare materials [Adv Healthc Mater] 2026 May; Vol. 15 (17), pp. e05013. Date of Electronic Publication: 2026 Feb 20. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 101581613 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2192-2659 (Electronic) Linking ISSN: 21922640 NLM ISO Abbreviation: Adv Healthc Mater Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Weinheim : Wiley-VCH, 2012- |
| MeSH Terms: | Hydrogels*/chemistry , Click Chemistry*/methods , Tissue Engineering*/methods , Spheroids, Cellular*/cytology , Spheroids, Cellular*/metabolism , Cartilage, Articular*/cytology , Cartilage*, Tissue Scaffolds/chemistry ; Gelatin/chemistry ; Hyaluronic Acid/chemistry ; Polyethylene Glycols/chemistry ; Animals ; Chondrogenesis ; Hydrogen-Ion Concentration |
| Abstract: | In cartilage tissue engineering, there is a growing interest in dynamic hydrogels that promote spheroid fusion and cartilaginous matrix deposition, while maintaining sufficient stability for long-term construct maturation. In this study, Diels-Alder click chemistry is employed as a dynamic-covalent crosslinking method to create hydrogels composed of hyaluronic acid, gelatin, and PEG. By adjusting the pH during crosslinking, the tuneability of hydrogel stiffness and stability at pH values around the physiological pH of native cartilage is demonstrated. This pH modulation does not compromise hydrogel functionality, as encapsulated equine articular cartilage progenitor cell spheroids remain viable and functional for a culture period of 28 days. The hydrogel environment supports the deposition of cartilaginous extracellular matrix components, including collagens and sulphated glycosaminoglycans. Enhanced chondrogenesis and deposition of collagen type II are observed at higher spheroid concentrations, corresponding to inter-spheroid distances of 100-150 µm following hydrogel swelling, compared to lower concentrations at a distance of >500 µm. To further improve construct robustness, the hydrogel constructs can be reinforced on day 1 with a melt electrowritten scaffold, increasing the compressive modulus 100-fold by day 28 compared to non-reinforced constructs, highlighting the potential of this system for engineering cartilage implants. (© 2026 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.) |
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| Grant Information: | Dutch Research Council (NWO); NWO/VICI 18673 Nederlandse Organisatie voor Wetenschappelijk Onderzoek; NWA.1389.20.192 Nederlandse Organisatie voor Wetenschappelijk Onderzoek |
| Contributed Indexing: | Keywords: Diels‐Alder click‐chemistry; cartilage engineering; cell‐encapsulation; hydrogels; multicellular cartilage spheroids |
| Substance Nomenclature: | 0 (Hydrogels) 9000-70-8 (Gelatin) 9004-61-9 (Hyaluronic Acid) 3WJQ0SDW1A (Polyethylene Glycols) |
| Entry Date(s): | Date Created: 20260220 Date Completed: 20260708 Latest Revision: 20260813 |
| Update Code: | 20260813 |
| PubMed Central ID: | PMC13175297 |
| DOI: | 10.1002/adhm.202505013 |
| PMID: | 41717958 |
| Database: | MEDLINE |
| ISSN: | 2192-2659 |
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| DOI: | 10.1002/adhm.202505013 |