Abstract：
BACKGROUND: Atrophic pseudoarthrosis is a serious complication with an incidence of 5-10 % of bone fractures located in the diaphysis of long bones. Standard treatments involve aggressive surgical procedures and re-interventions requiring the use of autografts from the iliac crest as a source of bone-forming biological activity (Standard of Care, SoC). In this context, regenerative ex vivo expanded osteogenic cell-based medicines could be of interest. Particularly, Mesenchymal Stromal Cells (MSC) offer new prospects to promote bone tissue repair in pseudoarthrosis by providing biological activity in an osteoconductive and osteoinductive environment.
METHODS: We conducted a phase IIa, prospective, randomised, parallel, two-arms, open-label with blinded assessor pilot clinical trial to compare SoC vs. a tissue-engineered product (TEP), composed of autologous bone marrow (BM)-derived MSCs loaded onto allogeneic decellularised, lyophilised spongy bone cubes, in a cohort of 20 patients with non-hypertrophic pseudoarthrosis of long bones. Patients were followed up for 12 months. Radiological bone healing was evaluated by standard X-ray and computed tomography (CT) scanning. Quality of life was measured using the EUROQOL-5D questionnaire.
RESULTS: Ten patients were randomized to TEP and 10 to SoC with iliac crest autograft. Manufacturing of TEP was feasible and reproducibly achieved. TEP implantation in the bone defect was successful in all cases and none of the 36 adverse events (AE) reported were related to the treatment. Efficacy analyses were performed in the Full Analysis Set (FAS) population, which included 17 patients after 3 patients withdrew from the study. The degree of consolidation, estimated by measuring Hounsfield units (HU) on CT, showed no significant differences between the two treatment groups at 12 months post treatment (main efficacy variable) (p = 0.4835) or at 6 months.
CONCLUSIONS: Although only a small number of patients were included in our study, it is notable that no significant differences were observed between the experimental treatment and SoC, thus suggesting TEP as an alternative where autograft is not available or contraindicated.
METHODS: We conducted a phase IIa, prospective, randomised, parallel, two-arms, open-label with blinded assessor pilot clinical trial to compare SoC vs. a tissue-engineered product (TEP), composed of autologous bone marrow (BM)-derived MSCs loaded onto allogeneic decellularised, lyophilised spongy bone cubes, in a cohort of 20 patients with non-hypertrophic pseudoarthrosis of long bones. Patients were followed up for 12 months. Radiological bone healing was evaluated by standard X-ray and computed tomography (CT) scanning. Quality of life was measured using the EUROQOL-5D questionnaire.
RESULTS: Ten patients were randomized to TEP and 10 to SoC with iliac crest autograft. Manufacturing of TEP was feasible and reproducibly achieved. TEP implantation in the bone defect was successful in all cases and none of the 36 adverse events (AE) reported were related to the treatment. Efficacy analyses were performed in the Full Analysis Set (FAS) population, which included 17 patients after 3 patients withdrew from the study. The degree of consolidation, estimated by measuring Hounsfield units (HU) on CT, showed no significant differences between the two treatment groups at 12 months post treatment (main efficacy variable) (p = 0.4835) or at 6 months.
CONCLUSIONS: Although only a small number of patients were included in our study, it is notable that no significant differences were observed between the experimental treatment and SoC, thus suggesting TEP as an alternative where autograft is not available or contraindicated.
摘要：
背景：萎缩性假性关节病是一种严重的并发症，其发生率为5-10％的位于长骨骨干的骨折。标准治疗涉及积极的外科手术和重新干预，需要使用来自the的自体移植物作为骨形成生物活性的来源（标准护理，SoC）。在这种情况下，再生离体扩增的基于成骨细胞的药物可能是令人感兴趣的。特别是,间充质基质细胞（MSC）通过在骨传导性和骨诱导性环境中提供生物活性，为促进假性关节炎中的骨组织修复提供了新的前景。
方法：我们进行了IIa阶段，prospective,随机化，平行,双臂，开放标签与盲化评估者试点临床试验比较SoC与组织工程产品（TEP），由自体骨髓（BM）衍生的MSC组成，冻干海绵状骨块，在20例非肥厚性长骨假性关节炎患者的队列中。随访12个月。通过标准X射线和计算机断层扫描（CT）扫描评估放射学骨愈合。使用EUROQOL-5D问卷测量生活质量。
结果：10例患者随机接受TEP治疗，10例患者随机接受SoC治疗。TEP的制造是可行且可重复的。在所有病例中，TEP在骨缺损中的植入均成功，并且没有报告的36起不良事件（AE）与治疗有关。在全分析集（FAS）人群中进行了疗效分析，其中包括17名患者，3名患者退出研究。巩固程度，通过在CT上测量亨氏单位(HU)来估计，在治疗后12个月（主要功效变量）（p=0.4835）或6个月时，两个治疗组之间没有显着差异。
结论：尽管我们的研究中只纳入了少数患者，值得注意的是，在实验处理和SoC之间没有观察到显著差异，因此建议TEP作为自体移植不可用或禁忌的替代方案。
方法：我们进行了IIa阶段，prospective,随机化，平行,双臂，开放标签与盲化评估者试点临床试验比较SoC与组织工程产品（TEP），由自体骨髓（BM）衍生的MSC组成，冻干海绵状骨块，在20例非肥厚性长骨假性关节炎患者的队列中。随访12个月。通过标准X射线和计算机断层扫描（CT）扫描评估放射学骨愈合。使用EUROQOL-5D问卷测量生活质量。
结果：10例患者随机接受TEP治疗，10例患者随机接受SoC治疗。TEP的制造是可行且可重复的。在所有病例中，TEP在骨缺损中的植入均成功，并且没有报告的36起不良事件（AE）与治疗有关。在全分析集（FAS）人群中进行了疗效分析，其中包括17名患者，3名患者退出研究。巩固程度，通过在CT上测量亨氏单位(HU)来估计，在治疗后12个月（主要功效变量）（p=0.4835）或6个月时，两个治疗组之间没有显着差异。
结论：尽管我们的研究中只纳入了少数患者，值得注意的是，在实验处理和SoC之间没有观察到显著差异，因此建议TEP作为自体移植不可用或禁忌的替代方案。
