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

ACS Appl Mater Interfaces. 2019 Mar 6;11(9):8749-8762. doi: 10.1021/acsami.8b19094. Epub 2019 Feb 25.


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.

Keywords: BMP9; amorphous calcium phosphate (ACP); bone tissue engineering; carboxymethyl chitosan (CMCh); hydrogels; mesenchymal stem cells; nanoparticles.

MeSH terms

  • Biocompatible Materials / chemistry
  • Biocompatible Materials / pharmacology
  • Bioprinting*
  • Bone Regeneration
  • Bone and Bones / physiology
  • Calcium Phosphates / chemistry
  • Cell Adhesion / drug effects
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Chitosan / analogs & derivatives
  • Chitosan / chemistry
  • Growth Differentiation Factors / genetics
  • Growth Differentiation Factors / metabolism
  • Humans
  • Hydrogels / chemical synthesis
  • Hydrogels / chemistry*
  • Hydrogen-Ion Concentration
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Nanoparticles / chemistry
  • Osteogenesis / drug effects
  • Tissue Engineering*
  • Tissue Scaffolds / chemistry*


  • Biocompatible Materials
  • Calcium Phosphates
  • Growth Differentiation Factors
  • Hydrogels
  • amorphous calcium phosphate
  • carboxymethyl-chitosan
  • Chitosan