Abstract
Cartilage defects generally do not heal and may result in osteoarthritis (OA) development. Unfortunately, current treatment strategies result in repair tissue with insufficient structural and mechanical properties as compared to native cartilage, and, therefore, are thought to provide merely a temporary alleviation of symptoms and insufficient protection against osteoarthritis (OA)
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development. This composes a strong driving force for the rapid development of the field of regenerative medicine and the application of such strategies to the treatment of cartilage defects. The first clinical studies have reported promising results. As a result, cartilage regeneration techniques, such as ACI, are increasingly applied, although microfracturing is still considered the treatment of choice for articular cartilage defects by many surgeons as the full scope of information needed for final evaluation of the efficacy of cartilage regeneration techniques remains to be provided in prospective randomized clinical trials. Furthermore, a discrepancy in reliability and reproducibility of cartilage regeneration techniques has been observed when comparing the outcome of culture techniques and animal models with clinically applied ACI. This suggests that we need to explore the boundary conditions that determine these discrepancies. In this thesis, we have clearly demonstrated the superior structural repair resulting from ACI as compared to the traditionally used microfracturing technique. However, one should realize that these beneficial results were found under strict trial conditions with accurately defined in- and exclusion criteria based on previously reported trials. Still, we found that ACI resulted in morphologically variable regeneration tissue-quality, which led us to the subject of this thesis: “exploring the boundaries of successful cartilage regeneration”. In our effort to acquire adequate regenerative conditions, we established that in future clinically applied ACI, chondrocytes should be expanded under growth factor supplemented conditions. Furthermore, upon refining the surgical techniques, scaffold materials should not only be considered for practical reasons, but also because they may significantly enhance the process of chondrogenesis. Further optimization may be attained by in vitro and in vivo experiments comparing the influence of different scaffold materials on cartilage regeneration by expanded and implanted chondrocytes. Besides the culture conditions, we demonstrated the importance of selecting patients with sufficient donor tissue quality. Until the substantial differences in chondrogenic potency between healthy and OA chondrocytes can be overcome, ACI should not be implemented for the treatment of early OA. In addition, effort should be put into elucidating the transition from cartilage defects towards the development of OA and how this affects donor tissue characteristics, as this increases insight into adequate treatment timing and patient selection. Lastly, we have demonstrated that transferring clinically relevant variables, such as SF from injured knee joints, to the “controlled” environment of in vitro experiments significantly alters the process of cartilage regeneration. Therefore, exploring the variables of this environment will likely elucidate mediators unfavorable to in vivo cartilage regeneration. These mediators may provide feasible targets for optimization of joint homeostasis by pre-treating a damaged joint before implementing ACI. Among others, IL-1B might be such a target, as this pro-inflammatory cytokine has proven to be of key importance during wound repair throughout different tissue types in the human body. The biological efficacy of a newly developed autologous form of IL-1ra was demonstrated by clinical improvement found in patients with symptomatic knee OA. Whether this treatment modality actually results in improved cartilage regeneration remains to be proven. In conclusion, the aim of this thesis was to establish the position and to determine the boundary conditions of cartilage regeneration techniques for the treatment of articular cartilage defects. Based on our results, ACI should now be considered a first approach rather than a last resort for the treatment of articular cartilage defects. Still, we have demonstrated the significant impact of clinically relevant parameters on the outcome of these treatment strategies. Clarifying and targeting the mediators that account for the observed detrimental effects, have the potential to provide the key in our ongoing effort to enhance the clinical outcome of cartilage regeneration techniques.
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