Bioactive hyaluronic acid hydrogels based on lysine dendrigrafts as crosslinkers: impact of stiffness and viscoelasticity on the osteogenic differentiation of mesenchymal stem cells
Abstract
Hyaluronic acid (HA) hydrogels are widely used as extracellular matrix mimics, but independently tuning stiffness, viscoelasticity and bioactive cue presentation within a single, fully covalent platform remains challenging. Here, we report generation 5 poly(L-lysine) dendrigrafts as highly multivalent crosslinkers for HA, yielding amide-linked networks with tunable mechanics and orthogonal post-gelation functionalisation. By varying HA concentration and the amine-to-carboxylate ratio, we established a simple formulation map in which dendrigraft content primarily controls storage modulus in the 15-32 kPa range, while HA loading modulates loss tangent and stress relaxation at nearly constant stiffness. The resulting hydrogels are predominantly elastic in small-strain oscillatory shear yet display substantial stress decay on time scales relevant to cell mechanosensing, with higher HA content enriching viscous dissipation without a proportional increase in modulus. Surface grafting with an RGDcontaining peptide and a BMP-2-mimetic peptide enabled robust co-presentation of integrin-binding and osteoinductive cues at receptor-relevant densities, independent of bulk composition. Human mesenchymal stem cells cultured on selected formulations exhibited enhanced spreading, reduced proliferation and a marker profile consistent with progression along the osteogenic lineage, including strong upregulation of the early osteocyte marker E11/podoplanin with relatively modest osteopontin accumulation. Human mesenchymal stem cells (MSCs) cultured on selected formulations exhibited enhanced spreading, reduced proliferation, and a marker profile consistent with progression along the osteogenic lineage, including strong upregulation of the early osteocyte marker E11/podoplanin with relatively modest osteopontin accumulation. In parallel, YAP analysis revealed a higher nuclear-tocytoplasmic (n/c) ratio on the softer gel despite its lower elastic stiffness, indicating that YAP nuclear localization in this system is not solely governed by substrate stiffness but is influenced by the viscoelastic properties of the matrix and associated mechanotransductive signaling. Together, these findings demonstrate that the hydrogels provide a cytocompatible, mechanically versatile and readily functionalised platform to decouple stiffness from viscoelastic dissipation and to probe how combined mechanical and biochemical signals regulate the osteoblast-to-osteocyte transition.
Related
- Matrix Viscoelasticity Regulates the Stemness and Multilineage differentiation of Primary Neural Progenitor-Stem Cells in 3D
- Enhanced 3D Osteogenic Differentiation of Encapsulated Human MSCs in Hyaluronic Acid Core Alginate Shell Capsules under Dynamic Culture Conditions
- Programmable DNA-Silk hydrogel with temporal mechanical reinforcement for mesenchymal stem cell differentiation and accelerated wound healing
- DNA methylation-based prediction of differentiation state at cell-type resolution reveals an age-associated epigenetic mesenchymal drift
- Quantifying punctate morphology in mesenchymal stem cells from single cell images provides a definitive quality assessment pipeline for direct correlation to osteogenic lineage differentiation
BibTeX
@article{apartsin2026bioactive,
title = {{Bioactive hyaluronic acid hydrogels based on lysine dendrigrafts as crosslinkers: impact of stiffness and viscoelasticity on the osteogenic differentiation of mesenchymal stem cells}},
author = {Evgeny Apartsin and Michele Valeo and Sébastien Marie and Fabien Granier and Marie-Christine Durrieu},
journal = {Materials Advances},
year = {2026},
month = jul,
doi = {10.1039/d6ma00379f},
url = {https://hal.science/hal-05770817v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Bioactive hyaluronic acid hydrogels based on lysine dendrigrafts as crosslinkers: impact of stiffness and viscoelasticity on the osteogenic differentiation of mesenchymal stem cells
AU - Evgeny Apartsin
AU - Michele Valeo
AU - Sébastien Marie
AU - Fabien Granier
AU - Marie-Christine Durrieu
PY - 2026
DA - 2026/07/13
JO - Materials Advances
DO - 10.1039/d6ma00379f
UR - https://hal.science/hal-05770817v1
AB - Hyaluronic acid (HA) hydrogels are widely used as extracellular matrix mimics, but independently tuning stiffness, viscoelasticity and bioactive cue presentation within a single, fully covalent platform remains challenging. Here, we report generation 5 poly(L-lysine) dendrigrafts as highly multivalent crosslinkers for HA, yielding amide-linked networks with tunable mechanics and orthogonal post-gelation functionalisation. By varying HA concentration and the amine-to-carboxylate ratio, we established a simple formulation map in which dendrigraft content primarily controls storage modulus in the 15-32 kPa range, while HA loading modulates loss tangent and stress relaxation at nearly constant stiffness. The resulting hydrogels are predominantly elastic in small-strain oscillatory shear yet display substantial stress decay on time scales relevant to cell mechanosensing, with higher HA content enriching viscous dissipation without a proportional increase in modulus. Surface grafting with an RGDcontaining peptide and a BMP-2-mimetic peptide enabled robust co-presentation of integrin-binding and osteoinductive cues at receptor-relevant densities, independent of bulk composition. Human mesenchymal stem cells cultured on selected formulations exhibited enhanced spreading, reduced proliferation and a marker profile consistent with progression along the osteogenic lineage, including strong upregulation of the early osteocyte marker E11/podoplanin with relatively modest osteopontin accumulation. Human mesenchymal stem cells (MSCs) cultured on selected formulations exhibited enhanced spreading, reduced proliferation, and a marker profile consistent with progression along the osteogenic lineage, including strong upregulation of the early osteocyte marker E11/podoplanin with relatively modest osteopontin accumulation. In parallel, YAP analysis revealed a higher nuclear-tocytoplasmic (n/c) ratio on the softer gel despite its lower elastic stiffness, indicating that YAP nuclear localization in this system is not solely governed by substrate stiffness but is influenced by the viscoelastic properties of the matrix and associated mechanotransductive signaling. Together, these findings demonstrate that the hydrogels provide a cytocompatible, mechanically versatile and readily functionalised platform to decouple stiffness from viscoelastic dissipation and to probe how combined mechanical and biochemical signals regulate the osteoblast-to-osteocyte transition.
SN - 2633-5409
ER -