---
title: "Alginate Injectable Hydrogels for MSC Delivery: Comparing Ionic Crosslinking Strategies"
id: "pubmed-42607716"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42607716"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42607716/"
doi: "10.1088/1748-605X/ae9ae6"
published_at: "2026-09-02T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Alginate Injectable Hydrogels for MSC Delivery: Comparing Ionic Crosslinking Strategies
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42607716
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42607716/)
- **DOI:** [10.1088/1748-605X/ae9ae6](https://doi.org/10.1088%2F1748-605X%2Fae9ae6)
- **Published At:** 2026-09-02T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- This comparative study evaluated three **ionic crosslinking** strategies for alginate-based injectable hydrogels used to deliver human adipose-derived **mesenchymal stem cells (MSCs)**: internal gelation (CaCO3/GDL), external gelation (CaCl2), and combined (double) gelation. - Materials were characterized for microstructure, weight variation, viscoelastic (rheological) behavior, protein diffusion, and early in vitro biological outcomes including metabolic activity, DNA content, and post-injection viability. - Rheological testing showed storage moduli spanning roughly 10^2–10^3 Pa depending on crosslinking approach; internally gelled matrices were softer and more deformable with a wider linear viscoelastic region, whereas externally and double-crosslinked gels were stiffer but more brittle. - Microstructure differed by gelation method: internally crosslinked hydrogels displayed larger, more interconnected pores; external gelation produced denser networks; double-crosslinked systems resembled stiffer, less porous structures. - Protein diffusion and weight-change (swelling/variation) behaviors were assessed to inform delivery and retention properties; specific quantitative values were not reported in the abstract. - Early in vitro cell assays demonstrated that crosslinking strategy significantly influenced early cell fate: internally-crosslinked hydrogels supported higher cell viability and metabolic activity and maintained superior post-injection survival (>95%). - Double-crosslinked hydrogels exhibited lower post-syringe viability consistent with higher stiffness and limited deformation tolerance, indicating a trade-off between mechanical integrity and cell tolerance to injection stresses. - The authors conclude that crosslinking choice requires balancing mechanical strength and handling during syringe delivery against early biological performance; the results offer practical, design-oriented guidance for selecting alginate crosslinking approaches in minimally invasive MSC delivery systems. - Keywords highlighted by the source include **alginate hydrogel**, **cell delivery**, **injectable hydrogels**, and **ionic crosslinking**.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Advanced Materials Research Group, Academic Center for Education, Culture and Research (ACECR), Mashhad, Khorasan Razavi, Iran. * 2 Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR), Mashhad, Khorasan Razavi, Iran. * 3 Hudson Institute of Medical Research, Clayton, Australia. * 4 Department of Surgery, Mashhad Branch, Islamic Azad University, Mashhad, Iran. * PMID: **42607716** * DOI: [ 10.1088/1748-605X/ae9ae6 ](https://doi.org/10.1088/1748-605x/ae9ae6) Item in Clipboard Comparative Study # Engineering injectable alginate hydrogels for mesenchymal stem cell delivery: comparative evaluation of ionic crosslinking strategies and early _in vitro_ outcomes Mahsa Haghbin et al. Biomed Mater. 2026. Show details Display options Display options Format Abstract PubMed PMID Biomed Mater Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Biomed+Mater%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Biomed+Mater%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42607716/) . 2026 Sep 2;21(5). doi: 10.1088/1748-605X/ae9ae6. ### Authors [Mahsa Haghbin](https://pubmed.ncbi.nlm.nih.gov/?term=Haghbin+M&cauthor_id=42607716)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-1 "Advanced Materials Research Group, Academic Center for Education, Culture and Research \(ACECR\), Mashhad, Khorasan Razavi, Iran."), [Mahboubeh Kazemi Noughabi](https://pubmed.ncbi.nlm.nih.gov/?term=Kazemi+Noughabi+M&cauthor_id=42607716)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-2 "Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research \(ACECR\), Mashhad, Khorasan Razavi, Iran."), [Zahra Esmaeili](https://pubmed.ncbi.nlm.nih.gov/?term=Esmaeili+Z&cauthor_id=42607716)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-2 "Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research \(ACECR\), Mashhad, Khorasan Razavi, Iran."), [Hamid Reza Bidkhori](https://pubmed.ncbi.nlm.nih.gov/?term=Bidkhori+HR&cauthor_id=42607716)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-2 "Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research \(ACECR\), Mashhad, Khorasan Razavi, Iran.")[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-3 "Hudson Institute of Medical Research, Clayton, Australia."), [Nasser Sanjar Mousavi](https://pubmed.ncbi.nlm.nih.gov/?term=Sanjar+Mousavi+N&cauthor_id=42607716)[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-4 "Department of Surgery, Mashhad Branch, Islamic Azad University, Mashhad, Iran."), [Halimeh Hassanzadeh](https://pubmed.ncbi.nlm.nih.gov/?term=Hassanzadeh+H&cauthor_id=42607716)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-2 "Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research \(ACECR\), Mashhad, Khorasan Razavi, Iran."), [Alireza Sadeghi-Avalshahr](https://pubmed.ncbi.nlm.nih.gov/?term=Sadeghi-Avalshahr+A&cauthor_id=42607716)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42607716/#short-view-affiliation-1 "Advanced Materials Research Group, Academic Center for Education, Culture and Research \(ACECR\), Mashhad, Khorasan Razavi, Iran.") ### Affiliations * 1 Advanced Materials Research Group, Academic Center for Education, Culture and Research (ACECR), Mashhad, Khorasan Razavi, Iran. * 2 Stem Cells and Regenerative Medicine Research Group, Academic Center for Education, Culture and Research (ACECR), Mashhad, Khorasan Razavi, Iran. * 3 Hudson Institute of Medical Research, Clayton, Australia. * 4 Department of Surgery, Mashhad Branch, Islamic Azad University, Mashhad, Iran. * PMID: **42607716** * DOI: [ 10.1088/1748-605X/ae9ae6 ](https://doi.org/10.1088/1748-605x/ae9ae6) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Injectable hydrogels are widely investigated as carriers for mesenchymal stem cells (MSCs); however, the influence of ionic crosslinking strategy on injectability-relevant properties and early _in vitro_ cell responses remains insufficiently defined from a design perspective. In this study, alginate-based hydrogels were prepared using three ionic crosslinking approaches-internal (CaCO3/ glucono-delta-lactone (GDL)), external (CaCl2), and combined gelation-and comparatively evaluated as delivery matrices for human adipose-derived MSCs. The hydrogels were characterized in terms of microstructural features, weight variation behavior, viscoelastic properties, protein diffusion, and early biological performance. Rheological analysis revealed a broad range of mechanical responses, with storage moduli varying from approximately 102-103Pa depending on the crosslinking mechanism. Internally-gelled hydrogels exhibited a softer, more deformable network and a wider linear viscoelastic region, while externally and double-crosslinked hydrogels showed increased stiffness but more brittle behavior. Microstructural observations indicated larger and more interconnected pores in internally crosslinked systems compared to the denser networks formed via external gelation._In vitro_ biological assessments, including metabolic activity, DNA quantification, and post-injection viability, demonstrated that the crosslinking strategy significantly affected early cell fate. Notably, internally-crosslinked hydrogels supported higher cell viability and metabolic activity while maintaining superior post-injection cell survival (>95%), whereas double-crosslinked hydrogels showed lower viability following syringe delivery consistent with their higher stiffness and lower deformation tolerance. Overall, this comparative study highlights the trade-offs between mechanical integrity, handling during syringe delivery, and early biological performance in ionically-crosslinked alginate hydrogels. The findings provide practical design-oriented guidance for selecting alginate crosslinking strategies in injectable MSCs delivery systems where minimally invasive administration and early cell survival are critical considerations. **Keywords:** alginate hydrogel; cell delivery; design guidelines; injectable hydrogels; ionic crosslinking; mesenchymal stem cells. © 2026 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Similar articles * [ The calcium silicate/alginate composite: preparation and evaluation of its behavior as bioactive injectable hydrogels. ](https://pubmed.ncbi.nlm.nih.gov/23796407/) Han Y, Zeng Q, Li H, Chang J.Han Y, et al.Acta Biomater. 2013 Nov;9(11):9107-17. doi: 10.1016/j.actbio.2013.06.022. Epub 2013 Jun 21.Acta Biomater. 2013.PMID: 23796407 * [ Personality Theories. ](https://pubmed.ncbi.nlm.nih.gov/42475469/) Gallios JM, Iyer V, Kaylor LE.Gallios JM, et al.2026 Jun 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–.2026 Jun 20. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–.PMID: 42475469Free Books & Documents. * [ Regulation of the fate of dental-derived mesenchymal stem cells using engineered alginate-GelMA hydrogels. ](https://pubmed.ncbi.nlm.nih.gov/28639378/) Ansari S, Sarrion P, Hasani-Sadrabadi MM, Aghaloo T, Wu BM, Moshaverinia A.Ansari S, et al.J Biomed Mater Res A. 2017 Nov;105(11):2957-2967. doi: 10.1002/jbm.a.36148. Epub 2017 Jul 14.J Biomed Mater Res A. 2017.PMID: 28639378Free PMC article. * [ Innovative advances and future perspectives in injectable hydrogels for wound healing: a comprehensive review. ](https://pubmed.ncbi.nlm.nih.gov/42063092/) Fahimirad S, Tabatabaei ZG, Farahpour MR, Mahmoudian F.Fahimirad S, et al.Biomed Eng Online. 2026 Apr 30;25(1):80. doi: 10.1186/s12938-026-01541-6.Biomed Eng Online. 2026.PMID: 42063092Free PMC article.Review. * [ The promise of injectable hydrogels in dental bone regeneration. ](https://pubmed.ncbi.nlm.nih.gov/41986226/) Sakhrani SS, Khan SS.Sakhrani SS, et al.Dent Mater. 2026 Sep;42(9):1497-1519. doi: 10.1016/j.dental.2026.04.002. Epub 2026 Apr 14.Dent Mater. 2026.PMID: 41986226Review. 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