## 4 Discussion  
The most important finding of this study was that different results were found with respect to the loading conditions in a real knee joint model for mechano-biological tissue differentiation. Cartilage defects possess a very limited intrinsic healing capacity. [PERSON] et al. described 53,569 hyaline cartilage lesions in 19,827 patients that received total knee arthroplasty [28]. Similarly, a more recent prospective survey of 993 consecutive knee arthroscopies showed evidence of articular cartilage abnormality in 66% of the patients [29]. Several techniques for articular cartilage defect treatment have been described recently with various results and indications [24; 30]. Microfracture represents a widely used technique for the repair of symptomatic articular cartilage defects of the knee [31; 32]. The penetration of the subchondoral bone plate in these defects causes clot formation in the defect. This clot contains pluripotent, marrow-derived MSCs, which can induce fibrocartilage repair as they possess varying amounts of type II collagen [30]. However, the microfracture technique is limited for treating large-sized defects. Small defects can spontaneously undergo repair with the hyaline cartilage, while larger defects undergo repair only with fibrous tissue or fibrocartilage, which are biochemically and biomechanically different from normal hyaline cartilage [3]. A recent review paper indicated that osteochondral autograft transfer may achieve higher activity levels and a lower risk of failure compared to the microfracture technique for cartilage lesions greater than 3 cm\({}^{2}\), although there was no significant difference for lesions smaller than 3 cm\({}^{2}\) at midterm [33]. Therefore, degeneration may occur, which can subsequently progress to osteoarthritic changes [34]. Recently, MSCs have been recommended for use in the cell-based treatment of cartilage lesions. Chondrogenesis of MSCs was primarily reported by [PERSON] et al. [35] and a defined medium for the in-vitro chondrogenesis of MSCs was primarily reported by [PERSON] et al. [36], who used micromass culture with transforming growth factor-beta and dexamethasone. With regard to the in-vivo studies, the transplantation of MSCs into full-thickness articular cartilage defects has been attempted under various conditions. Some studies recently reported that adipose-derived MSCs therapy for young and even elderly patients with knee OA was effective with respect to cartilage healing, reducing pain and improving function [19; 20; 21]. Additionally, [PERSON] et al. demonstrated that the implantation of MSCs for knee OA resulted in improved clinical and second-look arthroscopic outcomes compared to those reported after an injection of MSCs [37]. Another recent study recommended that non-weight-bearing conditions with only toe-touching for 8 weeks may have similar effects to those achieved within the period used in other treatments for cartilage regeneration when MSCs were injected to OA patients [38]. However, the authors also stated that although this prolonged period of non-weight-bearing may enable some native repair, it decreased and delayed the recovery of knee function after injections  
Figure 7: Percentage of each tissue type formation in the axial loading and the stance-phase gait loading model after 40 iterations. as evidenced by an initial decline of the Knee Society Clinical Rating System function score [38]. Therefore, an optimal rehabilitation protocol for the injection and implantation of MSCs should be further investigated and determined. To date, the Prendergast mechano-regulation theory has been applied to a number of different scenarios of bone healing and cartilage regeneration and it has displayed tremendous promise as a theory that could accurately describe the course of mesenchymal tissue differentiation in response to a wide spectrum of mechanical conditions [12; 17; 18]. However, all of these studies performed simulations from a microfracture perspective [12; 17; 18; 39].