**Background:** Articular cartilage has limited self-healing capacity due to avascularity, and current treatments primarily address symptoms rather than degeneration. Functional tissue engineering combines cells, scaffolds, biochemical factors, and biomechanical stimuli to repair cartilage damage. Hydrogels are attractive scaffold materials due to their high water content, biocompatibility, and ability to encapsulate cells while mimicking native extracellular matrix. This review summarizes the role of biomechanical stimuli on cell-encapsulated hydrogels for cartilage regeneration, covering signaling pathways, hydrogel design considerations, and key factors affecting cellular responses.
**Methods:** The authors conducted a narrative review of the literature on biomechanical stimulation of cell-encapsulated hydrogels for cartilage tissue engineering. They discuss biochemical and biomechanical signaling pathways, hydrogel types (natural and synthetic), 3D culture microenvironments, and factors affecting cellular responses including cell type, pre-culture conditioning, cell density, growth factors, load magnitude/frequency, and type/number of applied biomechanical forces. The review includes two summary tables: Table 1 lists examples of cell-encapsulating hydrogels with cross-linking methods and stimulation types; Table 2 details 14 studies with specific parameters including preculture time, mechanical stimuli type, frequency, magnitude, duration, cell types, and responses.
**Key Results:** The review synthesizes findings from multiple studies:
- Cell type matters: Luo et al. found porcine bone marrow-derived stem cells (BMSCs) were superior to fat pad-derived stem cells (FPSCs) for cartilage matrix formation with suppressed hypertrophy. Carroll et al. showed hydrostatic pressure (10 MPa, 1 Hz, 4 h/day, 5 days/week for 5 weeks) enhanced sGAG in both cell types but collagen accumulation was greater in BMSCs.
- Pre-culture conditioning: McDermott et al. demonstrated that human MSCs in fibrin hydrogels with 0, 2, 4, or 6 weeks of chondrogenic priming before dynamic compression (1 Hz, 10% strain, 2 h/day, 5 days/week for 2 weeks) showed enhanced COL2A1 and ACAN mRNA expression with >2 weeks priming, while immediate loading without priming increased COL10A1 and suppressed SOX9.
- Growth factors: Ge et al. showed that dynamic compression (10 kPa, 0.25 Hz, 1 h/day till day 28) of human SMSCs in agarose upregulated pro-chondrogenic genes, but TGF-β3 therapy caused much greater upregulation. Aisenbrey et al. found the combination of TGF-β3 and dynamic compression (5% peak-to-peak strain, 1 Hz, 1 h/day for 3 weeks) was the best condition for stable chondrogenesis in iPS-MPs.
- Load magnitude: Kowsari-Esfahan et al. identified 10% strain (among 0, 5, 10, 15, 20%) as optimal for inducing chondrogenesis in encapsulated ADSCs in alginate hydrogel. Natenstedt et al. reported 5–10 MPa at 1 Hz for a week or more as optimal for cartilage tissue.
- Combined forces: Cochis et al. found that combining shear (±25° at 1 Hz) and compression (10–20%, 1 Hz) in MSC-laden methyl-cellulose/polyurethane scaffolds led to high collagen II expression and low collagen X expression. A study using shear stress combined with oscillating hydrostatic pressure showed greater GAG and collagen secretion compared to shear stress alone, with suppression of collagen X, collagen I, and β1 integrin.
- In vivo studies: Lin et al. used methacrylated hyaluronic acid hydrogel encapsulating bone marrow-derived MSCs with dynamic loading (10% peak compressive sinusoidal strain at 1 Hz, 4 h/day, 5 days/week for 14 days) in a CartiGen Bioreactor. Constructs implanted subcutaneously in nude mice for 30 days showed promoted neocartilage production, and rat osteochondral defects showed improved healing after 8 weeks. Dufour et al. demonstrated that perfusion bioreactor treatment (2.5 μL/s for 21 days) of human chondrocytes in fibrin hydrogel before implantation caused integration with native tissue and secretion of type II and type VI collagen.
**Clinical Implications:** The review establishes that biomechanical stimulation is a critical tool for cartilage tissue engineering, with the potential to enhance chondrogenesis, suppress hypertrophy, and improve mechanical properties of engineered constructs. However, no current model completely mimics the complex structure of articular cartilage. The authors note that agarose hydrogel is most commonly used in biomechanical loading studies because chondrocyte phenotype can be preserved in agarose culture, but more complex and advanced biomaterials should be considered. Few studies have attempted to replicate implantable cartilage constructs for clinical use. Future directions include optimizing loading parameters (initiation time, duration), developing hybrid bioreactors for multiple loading types, and advancing cell-based therapy through chondrogenic preconditioning combined with implantable scaffolds and biomechanical stimulation for load-bearing applications.