The impact of mechanical bioreactors on human mesenchymal stromal cells utilized for articular cartilage repair

The rising global incidence of cartilage-related diseases, such as osteoarthritis, has intensified interest in regenerative strategies using human mesenchymal stromal cells (hMSCs). Mechanical cues are pivotal for hMSC chondrogenesis, and bioreactor systems, ranging from single-stimulus designs to advanced multiaxial platforms, provide controlled environments to study these effects. hMSC chondrogenic responses under mechanical loading are promising but highly variable, depending on factors such as TGF-β priming, scaffold stiffness, oxygen tension, and timing of stimulation. This review critically examines bioreactor design strategies for hMSC chondrogenesis, outlining technical advantages and limitations. The impact of physiological forces, including hydrostatic pressure, dynamic compression, and combined shear-compression loading, is analyzed alongside differences in study design and their relevance to replicating native cartilage architecture, where chondrons and their pericellular matrix govern load transmission. Comparisons with studies using native cartilage structures are included. The role of in silico models as complementary tools to reduce experimental time is highlighted. Finally, integrated approaches combining bioreactor design, experimental mechanobiology, and computational modeling are proposed to advance functional cartilage regeneration and accelerate clinical translation. STATEMENT OF SIGNIFICANCE: Classical testing protocols for novel biomaterials intended for cartilage repair and regeneration are typically performed statically, while the articulating joint is subject to complex load. Within this review we highlight the role of mechanics, a key biological driver, in chondrogenesis to provide an informative background to inform future biomaterials testing.