Alginate-methacrylate-RGD microspheres (Alg-MR-MS) for cell expansion and delivery in tissue engineering

  • Biomed Mater. 2026 Oct 20;21(5). doi: 10.1088/1748-605X/aeb214.
Alexandre Xavier Mendes  1  2 ,  Serena Duchi  2  3 ,  Carmine Onofrillo  2  3 ,  Ying Zhou  4 ,  Sanjeev Gambhir  5 ,  Adriana Teixeira do Nascimento  1  2 ,  Cathal O'Connell  2  6 ,  Steven Posniak  4 ,  Payal Mukherjee  7 ,  Gordon G Wallace  4 ,  Peter F Choong  3  8 ,  Simon E Moulton  1  2  9
Affiliations
  • 1. School of Engineering, Swinburne University of Technology, Melbourne, Victoria 3122, Australia.
  • 2. Aikenhead Centre for Medical Discovery, St Vincent's Hospital Melbourne, Melbourne, Victoria 3065, Australia.
  • 3. Department of Surgery, University of Melbourne, St Vincent's Hospital Melbourne, Melbourne, Victoria 3065, Australia.
  • 4. Intelligent Polymer Research Institute, Innovation Campus, University of Wollongong, Squires Way, North Wollongong, NSW 2500, Australia.
  • 5. ANFF Materials Node, Innovation Campus, Squires Way, University of Wollongong, NSW 2500, Australia.
  • 6. Department of Biomedical Engineering, School of Engineering, RMIT University, Melbourne, VIC 3000, Australia.
  • 7. Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia.
  • 8. Department of Orthopaedics, St Vincent's Hospital, Victoria, Australia.
  • 9. Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne, Victoria 3122, Australia.
PMID: 42849480 DOI: 10.1088/1748-605X/aeb214
Abstract

Clinically relevant cell numbers are essential for many tissue engineering applications, requiring scalable expansion platforms. Microcarrier-based bioreactor systems address this demand; however, conventional non-dissolvable carriers require harsh enzymatic or mechanical detachment, reducing cell viability and integrity. Although dissolvable microcarriers improve recovery, most are designed only for harvesting and lack functionality for downstream tissue engineering. Here, we present a sequential dual-crosslinkable alginate-methacrylate-RGD microsphere system (Alg-MR-MS) that integrates scalable cell expansion with scaffold formation in a single platform. The workflow involves: (1) microsphere fabrication via calcium-mediated ionic crosslinking; (2) three-dimensional cell expansion in a microcarrier culture system; (3) controlled phase change through calcium chelation with sodium citrate, enabling efficient cell recovery while preserving viability and phenotype; and (4) photocrosslinking to form a stable, cell-laden hydrogel suitable for bioprinting and tissue engineering. This sequential dual-crosslinking strategy supports expansion, dissolution, and structural stabilisation within one system. Human adipose-derived stem cells cultured on Alg-MR-MS showed ∼5-fold increased metabolic activity over 7 d, comparable to 2D controls, with high viability and strong attachment. Compared with other dissolvable carriers, Alg-MR-MS offers efficient expansion, rapid phase transition, and simplified single-step fabrication, bridging biomanufacturing and functional tissue engineering.

Keywords
cellular expansion; hydrogels; microspheres; tissue engineering.
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