Ion-mediated progressively stiffening hydrogels for vascularized bone regeneration
Wenhuan Bu1, Jonathan I Dawson2, Richard O C Oreffo2
1Hospital of Stomatology, Jilin University, Changchun, 130021, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun, 130021, China; School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK; Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK.
Acta Biomaterialia
|October 17, 2025
Summary
This study introduces a dynamic hydrogel that mimics the extracellular matrix (ECM) by progressively stiffening over 48 hours. This biomaterial enhances cell interactions and promotes bone regeneration, offering a more physiologically relevant environment for tissue engineering.
Area of Science:
- Biomaterials Science
- Tissue Engineering
- Regenerative Medicine
- Extracellular Matrix Mechanics
Background:
- The extracellular matrix (ECM) exhibits dynamic mechanical properties crucial for tissue development, repair, and disease.
- Current synthetic biomaterials often lack the ability to replicate the gradual mechanical changes observed in the native ECM.
- Stiffness is a key parameter in biomaterial design, but mimicking dynamic stiffening remains a challenge.
Purpose of the Study:
- To develop a hydrogel platform capable of progressive stiffening, mimicking native ECM mechanical dynamics.
- To investigate the utility of this dynamic hydrogel as a substrate for in vitro cell culture and in vivo bone regeneration.
- To explore the impact of a progressively stiffening microenvironment on cell behavior and tissue repair.
Main Methods:
- Fabrication of a hydrogel platform by integrating tyramine derivative of hyaluronic acid (HAT) and Laponite® (Lap).
- Utilized cation diffusion from culture media to induce gradual secondary Lap-HAT cross-linking and progressive hydrogel stiffening (0.8 to 7.4 kPa over ~48 h).
- Assessed hydrogel performance in vitro using co-cultures of human bone marrow stromal cells (HBMSCs) and human umbilical vein endothelial cells (HUVECs), and in vivo using a critical-size rat cranial defect model.
Main Results:
- The hydrogel platform successfully demonstrated progressive stiffening from 0.8 kPa to 7.4 kPa within approximately 48 hours.
- In vitro studies showed that the progressively stiffening hydrogel altered cell morphology and enhanced HBMSC and HUVEC differentiation and communication.
- In vivo application in a rat cranial defect model resulted in promoted vascularized bone regeneration.
Conclusions:
- The developed dynamic hydrogel platform provides a physiologically relevant microenvironment by mimicking ECM progressive stiffening.
- This material enhances cellular interactions and promotes significant bone regeneration, demonstrating its potential in tissue engineering and regenerative medicine.
- The study highlights the importance of dynamic mechanical properties in biomaterials for improved in vitro and in vivo applications.
