Trabecular-Like Scaffold Dictates Osteogenesis via Fluid Shear Stress-Induced Metabolic Reprogramming through the CAV1-HIF-1α Axis

  • Research (Wash D C). 2026 Jun 16:9:1307. doi: 10.34133/research.1307.
Wang Gong  1  2  3 ,  Jing Zhang  1  2  3 ,  Xinyun Liu  4 ,  Sheng Zhou  1  2  3 ,  Keke Huang  1 ,  Jing Jin  1  2  3 ,  Jiasen Gu  5 ,  Jie Cui  5 ,  Ao Li  6 ,  Huixin Liang  1  2  3 ,  Peng Wang  1  2  3 ,  Qing Jiang  1  2  3
Affiliations
  • 1. State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.
  • 2. Branch of National Clinical Research Center for Orthopedics, Sports Medicine and Rehabilitation, Nanjing 210008, China.
  • 3. Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China.
  • 4. School of Stomatology, Xuzhou Medical University, Xuzhou 221004, China.
  • 5. College of Mechanical and Electrical Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, China.
  • 6. Department of Otolaryngology Head and Neck Surgery, Jiangsu Provincial Key Medical Discipline (Laboratory), Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
PMID: 42312216 DOI: 10.34133/research.1307
Abstract

The structural design of bone scaffolds determines the local fluid mechanical microenvironment; however, how such cues program stem cell metabolism to drive osteogenesis remains unclear. In this study, Voronoi-based trabecular-like scaffolds with tunable porosity were engineered to modulate fluid shear stress (FSS) while preserving a consistent topology. Computational fluid dynamics analyses confirmed that architectures with lower porosity generated higher FSS, enabling controlled investigation of mechano-metabolic coupling. Under dynamic culture conditions, bone marrow mesenchymal stem cells (BMSCs) cultured on high-FSS scaffolds exhibited enhanced osteogenic differentiation in vitro and promoted bone regeneration in vivo. Integrated transcriptomic, proteomic, and metabolomic analyses identified caveolin-1 (CAV1) as a prominent FSS-responsive membrane regulator. Mechanistically, CAV1 enhanced phosphatidylinositol 3-kinase (PI3K)-AKT signaling, stabilized hypoxia-inducible factor-1α (HIF-1α), and induced a glycolytic shift that supports the energetic and biosynthetic demands of osteogenesis. Pharmacological inhibition of PI3K, HIF-1α, or glycolysis abolished FSS-driven osteogenic responses, validating a CAV1-centered mechano-metabolic axis. These findings establish a direct link between scaffold microarchitecture and metabolic regulation of osteogenesis and provide design principles for mechanically instructive bone repair Materials.

Products