Multicomponent hydrogels for the formation of vascularized bone-like constructs in vitro

Acta Biomater. 2020 Jun;109:82-94. doi: 10.1016/j.actbio.2020.03.025. Epub 2020 Apr 18.


The native extracellular matrix (ECM) is a complex gel-like system with a broad range of structural features and biomolecular signals. Hydrogel platforms that can recapitulate the complexity and signaling properties of this ECM would have enormous impact in fields ranging from tissue engineering to drug discovery. Here, we report on the design, synthesis, and proof-of-concept validation of a microporous and nanofibrous hydrogel exhibiting multiple bioactive epitopes designed to recreate key features of the bone ECM. The material platform integrates self-assembly with orthogonal enzymatic cross-linking to create a supramolecular environment comprising hyaluronic acid modified with tyramine (HA-Tyr) and peptides amphiphiles (PAs) designed to promote cell adhesion (RGDS-PA), osteogenesis (Osteo-PA), and angiogenesis (Angio-PA). Through individual and co-cultures of human adipose derived mesenchymal stem cells (hAMSCs) and human umbilical vascular endothelial cells (HUVECs), we confirmed the capacity of the HA-Tyr/RGDS-PA/Osteo-PA/Angio-PA hydrogel to promote cell adhesion as well as osteogenic and angiogenic differentiation in both 2D and 3D setups. Furthermore, using immunofluorescent staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), we demonstrated co-differentiation and organization of hAMSCs and HUVECs into 3D aggregates resembling vascularized bone-like constructs. STATEMENT OF SIGNIFICANCE: This body of work presents a new approach to develop more complex, yet functional, in vitro environments for cell culture while enabling a high level of control, tuneability, and reproducibility. The multicomponent self-assembling bioactive 2D and 3D hydrogels with nanofibrous architecture designed to recreate key molecular and macromolecular features of the native bone ECM and promote both osteogenesis and angiogenesis. The materials induce endothelial cells towards large vascular lumens and MSCs into bone cells on/within the same platform and form vascularized-bone like construct in vitro. This strategy looks encouraging for lifelike bone tissue engineering in vitro and bone tissue regeneration in vivo.

Keywords: 3D cell culture; Angiogenesis; Bone tissue engineering; Peptide nanofiber; Self-assembly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / cytology
  • Biomimetic Materials / chemical synthesis
  • Biomimetic Materials / chemistry*
  • Cell Adhesion / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Coculture Techniques / methods*
  • Elastic Modulus
  • Extracellular Matrix / chemistry
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hyaluronic Acid / chemistry
  • Hydrogels / chemical synthesis
  • Hydrogels / chemistry*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Neovascularization, Physiologic / drug effects*
  • Osteogenesis / drug effects*
  • Peptides / chemical synthesis
  • Peptides / chemistry
  • Porosity
  • Proof of Concept Study
  • Tyramine / chemistry


  • Hydrogels
  • Peptides
  • Hyaluronic Acid
  • Tyramine