Trabecular-Like Scaffold Dictates Osteogenesis via Fluid Shear Stress-Induced Metabolic Reprogramming through the...

Area of Science:

• Biomaterials Engineering
• Stem Cell Biology
• Mechanobiology

Background:

• The microenvironment of bone scaffolds impacts stem cell behavior, but the link between fluid mechanics and stem cell metabolism driving bone formation is not fully understood.
• Understanding how mechanical cues from scaffold architecture regulate cell metabolism is crucial for developing effective bone regenerative therapies.

Purpose of the Study:

• To engineer bone scaffolds that modulate fluid shear stress (FSS) and investigate its effect on bone marrow mesenchymal stem cell (BMSC) metabolism and osteogenesis.
• To elucidate the mechano-metabolic signaling pathways involved in FSS-induced osteogenic differentiation.

Main Methods:

• Fabrication of Voronoi-based trabecular-like scaffolds with tunable porosity.
• Computational fluid dynamics (CFD) to analyze FSS distribution.
• In vitro culture of BMSCs under dynamic conditions with varying FSS.
• In vivo bone regeneration studies.
• Integrated multi-omics (transcriptomic, proteomic, metabolomic) analyses.
• Pharmacological inhibition of key signaling pathways (PI3K-AKT, HIF-1α) and glycolysis.

Main Results:

• Scaffolds with lower porosity generated higher FSS, promoting enhanced osteogenic differentiation of BMSCs in vitro and bone regeneration in vivo.
• Caveolin-1 (CAV1) was identified as a key mediator of FSS response.
• CAV1 signaling activates PI3K-AKT, stabilizes HIF-1α, and promotes glycolysis, supporting osteogenesis.
• Inhibition of PI3K-AKT, HIF-1α, or glycolysis abrogated FSS-driven osteogenic effects.

Conclusions:

• Scaffold microarchitecture-induced FSS directly regulates BMSC metabolism to drive osteogenesis through a CAV1-centered mechano-metabolic axis.
• These findings provide insights into designing mechanically instructive biomaterials for bone repair.