Increased connectivity of hiPSC-derived neural networks in multiphase granular hydrogel scaffolds

Chia-chen Hsu, Julian H. George, Sharlayne Waller, Cyril Besnard, David A Nagel, Eric J Hill, Michael D. Coleman, Alexander M. Korsunsky, Zhanfeng Cui, Hua Ye

Research output: Contribution to journalArticlepeer-review


To reflect human development, it is critical to create a substrate that can support long-term cell survival, differentiation, and maturation. Hydrogels are promising materials for 3D cultures. However, a bulk structure consisting of dense polymer networks often leads to suboptimal microenvironments that impedes nutrient exchange and cell-to-cell interaction. Herein, granular hydrogel-based scaffolds were used to support 3D human induced pluripotent stem cell (hiPSC)-derived neural networks. A custom designed 3D printed toolset was developed to extrude hyaluronic acid hydrogel through a porous nylon fabric to generate hydrogel granules. Cells and hydrogel granules were combined using a weaker secondary gelation step, forming self-supporting cell laden scaffolds. At three and seven days, granular scaffolds supported higher cell viability compared to bulk hydrogels, whereas granular scaffolds supported more neurite bearing cells and longer neurite extensions (65.52 ± 11.59 μm) after seven days compared to bulk hydrogels (22.90 ± 4.70 μm). Long-term (three-month) cultures of clinically relevant hiPSC-derived neural cells in granular hydrogels supported well established neuronal and astrocytic colonies and a high level of neurite extension both inside and beyond the scaffold. This approach is significant as it provides a simple, rapid and efficient way to achieve a tissue-relevant granular structure within hydrogel cultures.
Original languageEnglish
Pages (from-to)358-372
Number of pages15
JournalBioactive Materials
Early online date15 Jul 2021
Publication statusPublished - Mar 2022

Bibliographical note

© 2021 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY license (

Funding: This study was supported by funding from the Biotechnology and Biological Sciences Research Council (BB/H008527/1) ( uk), China Regenerative Medicine International (CRMI), Jiangsu In-dustrial Technology Research Institute (JITRI), and Engineering and Physical Sciences Research Council (EPSRC EP/P005381/1 and EP/ V007785/1).


  • Microgel
  • Hydrogel
  • Hyaluronan
  • iPSC
  • Neural tissue engineering
  • 3D printing


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