Table 5.

Compilation of studies that investigated the response of chondrocytes subjected to multiaxial dynamic compressive loading regimes, including shear.

Reference	Study design/investigation	Cell source (n), scaffold, and preculture duration	Loading parameters	Results [PG = proteoglycans, Eeq = equilibrium, Edyn = dynamic, Ey = Young’s, and H(A) = aggregate]
Waldman et al. (2003)	Uniaxial compression versus shear	Adult bovine carpal-metacarpal chondrocytes on calcium phosphate ceramic surface precultured for 28 days	Frequency: 1 Hz Amplitude: 5% compress or 2% shear Duration: 400 cycles (6 min)/48 h for 28 days Max duration: 1.4 h	RNA: not assessed PG: ↑ only shear load Collagen: trended ↑ for only shear load Biomechanics: ↑ Eeq for both compressive and shear load
Grad et al. (2006)	Effect of unidirectional and multidirectional loading	3- to 4-month-old primary bovine chondrocytes in polyurethane scaffold precultured for 5 days	Frequency: 1 Hz Amplitude: 10% compress ±25° oscillation Duration: 2× 1 h/day for 5 days Max duration: 10 h	RNA: ↔ for dynamic compression only, ↑ in PRG4, ACAN, COMP, COL2, and TIMP3 shear/multiaxial relative to dynamic compression PG: ELISAs: ↔ COMP, PRG4, or HA for compression, ↑ COMP, PRG4, HA for multiaxial relative to dynamic compression Collagen: not assessed Biomechanics: not assessed
Waldman et al. (2007)	Effect of multiaxial loading	6- to 9-month-old primary bovine chondrocytes (n = 2–3 pooled) on calcium phosphate ceramic surface precultured for 28 days	Frequency: 0.5 Hz Amplitude: 2 or 5% compress and shear Duration: 400 cycles (6 min)/48 h for 6 days Max duration: 18 min	RNA: not assessed PG: ↑ only for 5% compression + 5% shear Collagen: ↑ only for 5% compression + 5% shear Biomechanics: ↑ in Eeq and G(shear), strain stiffening for compression + shear load
Wernike et al. (2007)	Additive effect of low oxygen environment to multiaxial loading	4- to 8-month-old primary bovine chondrocytes in polyurethane scaffold precultured for 6 days	Frequency: 0.5 Hz Amplitude: 10% compress ±25° oscillation Duration: 1 h/day, 6 days/week for 28 days Max duration: 28 h	RNA: ↓ COL1 in load and low oxygen at days 8 and 34, ↔ COL2, ACAN PG: ↓ with loading, but not compared with control Collagen: not quantified Biomechanics: not assessed
Bian et al. (2010)	Investigated immediate versus delayed loading and addition of shear	2- to 4-year-old expanded canine chondrocytes in 2% agarose hydrogel precultured for 0, 14, or 28 days	Frequency: 1 Hz Amplitude: 10% compress ±180° oscillation Duration: 3 h/day, 5 days/week for 42 days Max duration: 90 h	RNA: not assessed PG: ↔ any loading regime at any time point Collagen: ↔ any loading regime at any time Biomechanics: ↑ Ey continuous load at days 28 and 56, delayed load at day 56. ↑ Edyn all loading regimes at days 56, reduced μ (friction coefficient) for shear load
Shahin and Doran (2011)	Effect of dynamic loading after preculture in perfusion or shaking flasks with varied cell concentration and scaffold	16- to 20-week-old expanded human fetal epiphyseal chondrocytes (n = 3 pooled) in poly-glycolic acid (PGA) or PGA + 1.2% alginate scaffold precultured for 3 or 14 days	Frequency: 0.05 Hz Amplitude: 8.7% compress + 3 rpm revolution strain Duration: 10 min/day for 17 days Max duration: 2.8 h	RNA: not assessed PG: ↑ for all scaffold and cell density variations with loading and shaking flask preculture. Highest content with long preculture in perfusion Collagen: ↑ for all scaffold and cell density variations with loading. Highest content with long preculture in perfusion Biomechanics: not assessed
Wang et al. (2013)	Effect of cell expansion and passage on response to loading	3- to 4-month-old primary or expanded bovine chondrocytes (n = 3) in polyurethane scaffold precultured for 1 or 14 days	Frequency: 1 Hz Amplitude: 10% compress ±25° oscillation Duration: 10 min/day for 17 days Max duration: 2.8 h	RNA: ↑ COL2, COMP, ACAN, and PRG4 for continuous and delayed load and p0 and p3 chondrocytes PG: ↑ continuous and delayed loading Collagen: ↑ type II, ↔ type I on IHC Biomechanics: not assessed
Pourmohammadali et al. (2013)	Effect of perfusion and multiaxial loading	Primary bovine chondrocytes in 3% agarose hydrogel precultured for 7 days	Frequency: 8–14 mm/s Amplitude: 18% + shear flow Duration: 30 min/day for 21 days Max duration: 10.5 h	RNA: not assessed PG: ↔ perfusion ± compression and shear Collagen: not assessed Biomechanics: not assessed
Hilz et al. (2013)	Effect of low-frequency, low-energy electromagnetic fields combined with multiaxial loading	2- to 3-month-old primary bovine chondrocytes in polyurethane scaffold precultured for 7 days	Frequency: 1 Hz Amplitude: 10% compress ±25° oscillation Duration: 2× 1 h/day every other day for 21 days Max duration: 16 h	RNA: ↑ COL2/COL1 ratio, PRG4, ↔ MMP3, MMP13, COMP, and SOX9 PG: ↑ with load Collagen: ↑ type II, ↓ type I on Remmele score Biomechanics: not assessed
Neumann et al. (2015)	Response of chondroprogenitors to dynamic loading and/or BMP2	30- to 75-year-old expanded clonal human articular cartilage progenitor cells (n = 4) in polyurethane scaffold precultured for 3 days	Frequency: 1 Hz Amplitude: 10% compress ±25° oscillation Duration: 1 h/day, 6 days/week for 7 or 28 days Max duration: 24 h	RNA: ↑ COL1 (day 7), ACAN (days 7 and 28),↑ COLX (day 28 with BMP2); COL2 undetectable PG: ↑ with load, ↓ with addition of BMP2 Collagen: not assessed Biomechanics: not assessed