Together with biomechanical stresses biochemical and genetic
Together with biomechanical stresses, biochemical and genetic factors participate in the progression and development of AC in OA. They contribute to decomposing chondrocyte-ECM interactions, in turn modifying cell metabolism . Matrix gene expression of chondrocytes is altered in OA as it presents collagen molecules (type X, III, VI) that are normally missed in adult normal AC .
In the initial stages of OA, chondrocytes tend to repair the matrix loss with no positive result since the synthesis of catabolic cytokines and matrix degrading PTK0796 increases . Unfortunately, it induces the leakage of proteoglycans and the breakdown of type II collagen, which start at the cartilage surface. Consequently, the water concentration increases implying a critical reduction of the tensile strength of the ECM . Other important enzymes involved in the degradation of articular cartilage in OA are the matrix metalloproteinases (MMPs). Previous studies have shown that tissue specific MMPs 1,8 and 13 (collagenases I, II and III, respectively) are involved in OA. The posterior step is aggrecan degradation produced by aggrecanases 1 and 2, which are family of the ADAMs (a desintegrin and metalloproteinases) attached to type 1 thrombospondin (TS1) .The cascade of initial steps results in a partial or total degradation of the AC (Fig. 2), that is in charge of reducing articular erosion. Therefore, shear stresses produced by friction between the adjacent bones of the articulation increases . Growth of bone spurs thereby progresses during disease development, which will lead to articular inflammation and joint pain . In this state, the presence of interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α)  induces the synthesis of other inflammatory factors like cyclooxygenases (COX-1, COX-2) , the phosphorylation of mitogen-activated protein kinase (MAPK) , as well as the degrades I-kBs activating Nuclear Factor-Kappa B (NF-kB) .
Key mechanical factors in cartilage tissue engineering of OA In the last decades, several tissue engineering (TE) cartilage products like the matrix-associated autologous chondrocyte implantation (MACI), Hyalograft® C, NeoCart®, NOVOCART® 3D, Cartipatch®, etc. have tried to mimic articular cartilage . But, current bioengineered neocartilage is far from being optimal in comparison with its mature counterpart (Fig. 1C). In part, this is because it is a challenge to create a construct that collects the anisotropy and homogeneity in its structure giving rise to the characteristic mechanical properties of the AC . Thus, the main challenge for taking the tissue engineered cartilage (Fig. 1F) to the clinic is to design biomechanical properties of the final implant which are close to native tissue. In addition, autologous chondrocytes are not the best cellular source for making this autologous explant, since the percentage of these cells inside the articular cartilage is <5% among other drawbacks. In addition, during the time of in vitro expansion, monolayer cell cultures present an overexpression of type I collagen and versican in lieu of type II collagen and aggrecan production . This process by itself, results in a reorganization of the microfilament structure of the three-dimensional (3D) ECM, implying that biomechanical stresses of the microstructure can change, which are crucial for the correct tissue performance . On the other hand, mesenchymal stem cells (MSCs) have demonstrated a real potential in differentiating healthy chondrocytes . In addition, MSCs promote the resilience of chondrocytes when they are co-cultured in vitro . But not everything in the field of MSCs is an advantage. Nowadays, there is no stablished cell therapy approach approved for therapeutic interventions , although, the use of MSCs derived from the umbilical cord for AC treatment has been approved within the last year. Even more, the differentiation potential of MSCs is age-dependent, being a limitational factor for autologous implants .