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Integrated Bone Formation Through In Vivo Endochondral Ossification Using Mesenchymal Stem Cells
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Biomimetic Gradient Hydrogels Regulate Osteochondral Regeneration Microenvironment Remodeling via Spatiotemporal

Xiaolian Niu1,2, Shengzhao Xiao3, Di Huang2

  • 1Key Laboratory For Biomechanics and Mechanobiology of Ministry of Education, Key Laboratory of Innovation and Transformation of Advanced Medical Devices of Ministry of Industry and Information Technology, National Medical Innovation Platform for Industry-Education Integration in Advanced Medical Devices (Interdiscipline of Medicine and Engineering), Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 8, 2026
PubMed
Summary

This study introduces a novel gradient hydrogel scaffold (GHZF4) that mimics natural tissue structures to improve osteochondral repair. The advanced scaffold effectively recruits cells and releases growth factors, promoting functional tissue regeneration without cells.

Keywords:
angiogenesis‐osteogenesis couplingcontinuous gradient scaffoldimmunomodulationosteochondral regenerationspatiotemporal programming

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Area of Science:

  • Biomaterials Science
  • Tissue Engineering
  • Regenerative Medicine

Background:

  • Osteochondral defects present significant challenges due to limitations in current repair strategies, including poor mechanical properties and lack of controlled biological factor delivery.
  • Existing scaffolds often fail to replicate the complex hierarchical structure and dynamic environment of native osteochondral tissue, hindering effective regeneration.
  • There is a critical need for advanced biomaterials that can guide cellular behavior and promote coordinated healing processes for osteochondral repair.

Purpose of the Study:

  • To develop and evaluate an electric field-driven continuous gradient hydrogel (GHZF4) for functional osteochondral repair.
  • To investigate the scaffold's ability to mimic native tissue gradients and spatiotemporally control the release of bioactive factors.
  • To assess the efficacy of GHZF4 in promoting cell recruitment, vascularization, osteogenesis, and chondrogenesis in vitro and in vivo.

Main Methods:

  • Fabrication of a nanofiber-reinforced gradient hydrogel (GHZF4) using spatiotemporal programming and electric field-induced alignment.
  • Incorporation of ZIF-8 nanocarriers for controlled release of platelet-derived growth factor-BB (PDGF-BB), bone morphogenetic protein-2 (BMP-2), and transforming growth factor-β3 (TGF-β3).
  • In vitro studies involving macrophage polarization, stem cell recruitment, angiogenesis, and osteochondral differentiation assays; in vivo studies using rat and rabbit osteochondral defect models.

Main Results:

  • GHZF4 successfully constructed compositional, structural, and mechanical gradients mimicking native osteochondral tissue.
  • The scaffold demonstrated controlled release of PDGF-BB and BMP-2 for osteogenesis and TGF-β3 for chondrogenesis.
  • In vitro results showed enhanced M2 macrophage polarization, stem cell recruitment, angiogenesis, and osteochondral differentiation.
  • In vivo studies in rat and rabbit models confirmed seamless integration and functional repair, supported by micro-CT, nanoindentation, and histological analyses.
  • Transcriptomic analysis indicated upregulation of key signaling pathways involved in immunomodulation, angiogenesis, and osteochondral differentiation.

Conclusions:

  • The developed nanofunctionalized gradient hydrogel scaffold (GHZF4) represents a promising cell-free strategy for functional osteochondral repair.
  • Spatiotemporal programming and gradient design effectively couple critical repair processes, addressing limitations of conventional scaffolds.
  • GHZF4 demonstrates significant potential for enhancing tissue integration and promoting comprehensive regeneration of osteochondral defects.