A pH-Triggered, Self-Assembled, and Bioprintable Hybrid Hydrogel Scaffold for Mesenchymal Stem Cell Based Bone Tissue Engineering

Chen Zhao, Nader Taheri Qazvini, Monirosadat Sadati, Zongyue Zeng, Shifeng Huang, Ana Losada De La Lastra, Linghuan Zhang, Yixiao Feng, Wei Liu, Bo Huang, Bo Zhang, Zhengyu Dai, Yi Shen, Xi Wang, Wenping Luo, Bo Liu, Yan Lei, Zhenyu Ye, Ling Zhao, Daigui CaoLijuan Yang, Xian Chen, Aravind Athiviraham, Michael J. Lee, Jennifer Moriatis Wolf, Russell R. Reid, Matthew Tirrell, Wei Huang, Juan J. De Pablo, Tong Chuan He

Research output: Contribution to journalArticlepeer-review

111 Scopus citations


Effective bone tissue engineering can restore bone and skeletal functions that are impaired by traumas and/or certain medical conditions. Bone is a complex tissue and functions through orchestrated interactions between cells, biomechanical forces, and biofactors. To identify ideal scaffold materials for effective mesenchymal stem cell (MSC)-based bone tissue regeneration, here we develop and characterize a composite nanoparticle hydrogel by combining carboxymethyl chitosan (CMCh) and amorphous calcium phosphate (ACP) (designated as CMCh-ACP hydrogel). We demonstrate that the CMCh-ACP hydrogel is readily prepared by incorporating glucono δ-lactone (GDL) into an aqueous dispersion or rehydrating the acidic freeze-dried nanoparticles in a pH-triggered controlled-assembly fashion. The CMCh-ACP hydrogel exhibits excellent biocompatibility and effectively supports MSC proliferation and cell adhesion. Moreover, while augmenting BMP9-induced osteogenic differentiation, the CMCh-ACP hydrogel itself is osteoinductive and induces the expression of osteoblastic regulators and bone markers in MSCs in vitro. The CMCh-ACP scaffold markedly enhances the efficiency and maturity of BMP9-induced bone formation in vivo, while suppressing bone resorption occurred in long-term ectopic osteogenesis. Thus, these results suggest that the pH-responsive self-assembled CMCh-ACP injectable and bioprintable hydrogel may be further exploited as a novel scaffold for osteoprogenitor-cell-based bone tissue regeneration.

Original languageEnglish (US)
Pages (from-to)8749-8762
Number of pages14
JournalACS Applied Materials and Interfaces
Issue number9
StatePublished - Mar 6 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.


  • BMP9
  • amorphous calcium phosphate (ACP)
  • bone tissue engineering
  • carboxymethyl chitosan (CMCh)
  • hydrogels
  • mesenchymal stem cells
  • nanoparticles


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