## 4 Discussion
This finding also confirms consistency of repair in improved collagen-based organization and content, which are necessary components for long-term durability of cartilage since collagen breakdown is considered to be a critical step in the progression of osteoarthritis [33; 34]. It may be considered a limitation of the study that ChondroMimetic was used as back-fill treatment for the majority of osteochondral defects (13/15) in the study, particularly since it is generally believed that mosaicplasty donor sites are: (1) not exposed to weight bearing forces; and (2) ultimately filled with a fibrocartilage through self-repair processes and are asymptomatic [35]. To the contrary, donor sites experience high loads with daily activities, depending on their size and location, from 1.3 times up to 7.8 times body weight [36]. Furthermore, [PERSON] et al. [37] reviewed 21 original mosaicplasty studies comprising 1726 patients and found that donor site morbidity reportedly occurs in 5.9-16.9% of cases and manifests through crepitation and knee stiffness, instability during activities of daily living, and persistent pain. The fact that in this study no adverse events or symptoms were reported to be related to donor sites or ChondroMimetic implants over the 7.9 year follow-up, and modified Cincinnati and KOOS scores demonstrated a high level of satisfaction, demonstrates that ChondroMimetic treatment was safe and may suggest some clinical benefit, further supported by the MRI-assessed high quality cartilage repair. Furthermore, the regeneration of bone and cartilage to near-native levels of fill and biochemical structure suggest that Chondromimetic may fit into an algorithm for treatment of full-thickness, primary cartilage lesions. Indeed, two full weight bearing primary defects on the medial femoral condyles were treated in this study with ChondroMimetic and demonstrated similarly high degrees of total defect fill (mean: 95.85%) and high quality repair tissue with T2 relaxation times comparable to native cartilage (means: 46.7 ms vs. 47.7 ms, respectively), in addition to satisfactory clinical benefit. A true study limitation was the lack of an active control group, such as microfracture, which has been suggested by current regulatory guidance [38]. But use of an ipsilateral native cartilage control ROI for quantitative structural outcomes provided an appropriate internal control for making a determination of quality and durability of cartilage repair. Also, the small sample size of the study could limit the interpretation of the results. However, the low variance in both clinical and structural quantitative MRI outcomes nonetheless supports a consistency in repair that would likely be maintained with a larger sample size. Long-term follow-up studies can also present challenges that limit interpretation of study outcomes. For example, here, 14 procedures were conducted in the index knee of 12 subjects over the 8-year follow-up period. However, it can be concluded that it is highly unlikely that these procedures had any effect on the assessments conducted for this study. In 2 cases, the procedures were not knee related (e.g., lung biopsy). The other 12 included: (1) hyaluronic acid injections in 4 subjects performed at least 12 months prior to the extension study visit, and therefore would be expected to have lost any therapeutic effect; (2) microfracture of new primary lesions in 3 subjects, although this would represent a worst case scenario since the procedure could worsen the pain at the time of the extension study visit, or simply decrease the new pain associated with the new lesion back to baseline levels; and (3) second-look arthroscopy in 5 subjects, conducted 1-2 years post-operative by the investigator and unrelated to the study (e.g., to remove bone material from an HTO; to remove malleolar screws from ankles).