PURPOSE The aim of this study was to investigate the effect of product dose in autologous chondrocyte implantation (ACI) for the treatment of full-thickness cartilage defects of the knee and to assess its influence on clinical and morphological mid-term outcome. METHODS Seventy-five patients were included in this single-blind, randomised, prospective, controlled clinical trial. Patients were assigned randomly to three different dose groups [low (3-7 spheroids/cm2), medium (10-30 spheroids/cm2), or high (40-70 spheroids/cm2)] and assessed using standardised clinical and morphological scoring systems (KOOS, IKDC, MOCART) for 4 years following the intervention. RESULTS The analysis population comprised 75 patients (22 women, 53 men) aged 34 ± 9 years. Defect sizes ranged from 2 to 10 cm2 following intraoperative debridement. The assessment of the primary variable 'overall KOOS' showed a statistically significant improvement, compared with baseline, for each dose group, i.e., at baseline the mean 'overall KOOS' scores were 60.4 ± 13.6, 59.6 ± 15.4, and 51.1 ± 15.4 for the low-, medium-, and high-dose groups, respectively, and 57.0 ± 15.2 for 'all patients'. After 48 months those values improved to 80.0 ± 14.7, 84.0 ± 14.9, and 66.9 ± 21.5 in the respective dose groups and 77.1 ± 18.6 for 'all patients'. Pairwise comparisons of these dose groups did not reveal any statistically significant differences. Likewise, assessment of the subjective IKDC score revealed no statistically significant differences between the three dose groups up to the 48-month visit. However, between 12 and 48 months there was a low, but steady, improvement in the low-dose group and a substantial amelioration in the medium-dose group. The mean MOCART total scores 3 months after treatment were 59.8 ± 10.9, 64.5 ± 10.3, and 64.7 ± 9.4 for the low-, medium-, and high-dose groups, and 62.9 ± 10.3 for 'all patients'; 48 months after treatment these were 73.9 ± 13.1, 78.0 ± 12.4, and 74.3 ± 14.0 for the respective dose groups and 75.5 ± 13.1 for 'all patients'. CONCLUSIONS Results of this study confirm the efficacy and safety of the applied "advanced therapy medicinal product"; no dose dependence was found either for the incidence or for the severity of any adverse reactions. All doses applied in the present study led to significant clinical improvement over time and can therefore be regarded as effective doses. The influence of product doses in the range investigated seems to be low and can be neglected. Thus, the authorised dose range of 10-70 spheroids/cm2 confirmed by this clinical trial offers a broad therapeutic window for the surgeon applying the product, thereby reducing the risk of over- or underdosing. LEVEL OF EVIDENCE I.

中文翻译：

---

使用球体技术的基质相关自体软骨细胞植入的安全性和有效性与4年后球体剂量无关。

目的本研究的目的是研究产品剂量在自体软骨细胞植入（ACI）中治疗膝部全层软骨缺损的效果，并评估其对临床和形态学中期结局的影响。方法这项单盲，随机，前瞻性，对照临床试验纳入了75名患者。将患者随机分为三个不同的剂量组[低（3-7个球体/ cm2），中（10-30个球体/ cm2）或高（40-70个球体/ cm2）]，并使用标准化的临床和形态评分系统进行评估（KOOS，IKDC，MOCART）进行干预后的4年。结果分析人群包括75名患者（22名女性，53名男性），年龄34±9岁。术中清创后的缺损范围为2至10 cm2。与基线相比，每个剂量组的主要变量“总体KOOS”的评估显示出统计学上的显着改善，即在基线时，“总体KOOS”平均得分分别为60.4±13.6、59.6±15.4和51.1±15.4。低，中和高剂量组分别为“所有患者”和57.0±15.2。在48个月后，这些值分别在各个剂量组中分别提高到80.0±14.7、84.0±14.9和66.9±21.5，“所有患者”分别为77.1±18.6。这些剂量组的成对比较未显示任何统计学上的显着差异。同样，对主观IKDC评分的评估显示，直至48个月的随访，三个剂量组之间在统计学上均无统计学差异。但是，在12到48个月之间，低剂量组改善，中等剂量组明显改善。治疗后3个月，低，中，高剂量组的平均MOCART总分分别为59.8±10.9、64.5±10.3和64.7±9.4，“所有患者”为62.9±10.3。治疗后48个月，相应剂量组分别为73.9±13.1、78.0±12.4和74.3±14.0，“所有患者”分别为75.5±13.1。结论：本研究结果证实了“先进治疗药物”的有效性和安全性。没有发现任何不良反应的发生率或严重性与剂量有关。随着时间的推移，本研究中使用的所有剂量均导致临床显着改善，因此可以视为有效剂量。在所研究范围内的产品剂量影响似乎很小，可以忽略不计。因此，该临床试验确定的10-70椭球/ cm2的授权剂量范围为外科医生使用该产品提供了广阔的治疗窗口，从而降低了用药过量或不足的风险。证据级别I.