Functional Tissue Engineering of Articular Cartilage through Dynamic Loading of Chondrocyte-Seeded Agarose Gels

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Articular cartilage is limited in its ability to regenerate and to repair as it is not supplied by blood vessels. In spite of the previous efforts in tissue engineering of articular cartilage, current cartilage replacements are only morphologically and biochemically similar to natural cartilage. Their mechanical functionality still needs to be ameliorated for better cartilage substitutes, which is the goal of the authors of this paper. The authors hypothesized that more mechanically functional cartilage can be engineered by subjecting the tissues to dynamic loading at physiological levels.

Three studies were used to test the hypothesis. In the first study, hydrogels made of agarose and alginate at various concentrations without cells were tested for their material properties by a loading device to assess which material is more suitable for use in scaffolds. In the second study, 2% agarose and 2% alginate hydrogels with chondrocytes and acellular controls were cultured without loading. Compositional analysis of sulfated glycosaminoglycan and confined compression testing were carried out for comparison. In the third study, chondrocyte-seeded 2% agarose gels were cultured in two conditions: unconfined compression loading and unloading. Sulfated glycosaminoglycan and hydroxyproline compositional analysis, as well as confined and unconfined stress relaxation testing, were performed at different times.

From the first study, subphysiological peak stresses of agarose gels were observed when they were subjected to physiological cartilage strain levels. The authors found it more reliable to evaluate the aggregate modulus from the equilibrium stress-strain response rather than the transient response. From the second study, the peak equilibrium aggregate modulus measured for the cell-seeded agarose gels was three-fold better than that for cell-seeded alginate gels; moreover, initial increase in sulfated glycosaminoglycan content lasts longer for cell-seeded agarose gels, suggesting that agarose be a better scaffold material. From the third study, the equilibrium modulus of cell-seeded agarose gels with dynamic loading measured at day 28 was 21-fold better than that measured at day 0; under unloading condition, agarose gels only showed a three-fold increase between the same time points. Lastly, the sulfated glycosaminoglycan content of loaded agarose gels remained accumulated at day 21 whereas that of unloaded hydrogels plateaued at day 14.

This paper was chosen because of its relevance to the class project on cartilage. I am amazed at the time period within which they were able to achieve an unprecedented 21-fold increase in the equilibrium modulus of the tissue. Moreover, their study provided a good example of how to design experiments with good controls.