Service d'Orthopédie - Traumatologie, Cliniques Universitaires de Bruxelles - Université Libre de Bruxelles, Hôpital Erasme, Route de Lennik 808, 1070, Brussels, Belgium.
Klinik für Orthopädie und Unfallchirurgie, Universität zu Lübeck, Ratzeburger Allee 160, 23568, Lübeck, Germany.
Stem Cell Res Ther. 2021 Jun 26;12(1):363. doi: 10.1186/s13287-021-02432-4.
Overall, 5-10% of fractures result in delayed unions or non-unions, causing major disabilities and a huge socioeconomic burden. Since rescue surgery with autologous bone grafts can cause additional challenges, alternative treatment options have been developed to stimulate a deficient healing process. This study assessed the technical feasibility, safety and preliminary efficacy of local percutaneous implantation of allogeneic bone-forming cells in delayed unions of long bone fractures.
In this phase I/IIA open-label pilot trial, 22 adult patients with non-infected delayed unions of long bone fractures, which failed to consolidate after 3 to 7 months, received a percutaneous implantation of allogeneic bone-forming cells derived from bone marrow mesenchymal stem cells (ALLOB; Bone Therapeutics) into the fracture site (50 × 10 to 100 × 10 cells). Patients were monitored for adverse events and need for rescue surgery for 30 months. Fracture healing was monitored by Tomographic Union Score (TUS) and modified Radiographic Union Score. The health status was evaluated using the Global Disease Evaluation (GDE) score and pain at palpation using a visual analogue scale. The presence of reactive anti-human leukocyte antigen (HLA) antibodies was evaluated.
During the 6-month follow-up, three serious treatment-emergent adverse events were reported in two patients, of which two were considered as possibly treatment-related. None of the 21 patients in the per-protocol efficacy population needed rescue surgery within 6 months, but 2/21 (9.5%) patients had rescue surgery within 30 months post-treatment. At 6 months post-treatment, an improvement of at least 2 points in TUS was reached in 76.2% of patients, the GDE score improved by a mean of 48%, and pain at palpation at the fracture site was reduced by an average of 61% compared to baseline. The proportion of blood samples containing donor-specific anti-HLA antibodies increased from 8/22 (36.4%) before treatment to 13/22 (59.1%) at 6 months post-treatment, but no treatment-mediated allogeneic immune reactions were observed.
This pilot study showed that the percutaneous implantation of allogeneic bone-forming cells was technically feasible and well tolerated in patients with delayed unions of long bone fractures. Preliminary efficacy evidence is supporting the further development of this treatment.
NCT02020590 . Registered on 25 December 2013. ALLOB-DU1, A pilot Phase I/IIa, multicentre, open proof-of-concept study on the efficacy and safetyof allogeneic osteoblastic cells (ALLOB®) implantation in non-infected delayed-union fractures.
总体而言，5-10%的骨折会导致延迟愈合或不愈合，导致严重残疾和巨大的社会经济负担。由于自体骨移植的挽救性手术可能会带来额外的挑战，因此已经开发出替代治疗方案来刺激受损的愈合过程。本研究评估了局部经皮植入同种异体成骨细胞治疗长骨骨折延迟愈合的技术可行性、安全性和初步疗效。
在这项 I/IIA 期开放性标签试验中，22 名非感染性长骨骨折延迟愈合的成年患者（骨折后 3-7 个月未愈合）接受同种异体成骨细胞（骨髓间充质干细胞来源的 ALLO；Bone Therapeutics）经皮植入骨折部位（50×10 至 100×10 个细胞）。在 30 个月内监测患者的不良事件和挽救性手术的需要。通过 Tomographic Union Score（TUS）和改良的 Radiographic Union Score 监测骨折愈合情况。使用 Global Disease Evaluation（GDE）评分评估健康状况，使用视觉模拟评分法评估触诊时的疼痛。评估了反应性抗人白细胞抗原（HLA）抗体的存在。
在 6 个月的随访期间，2 名患者报告了 3 例严重的治疗相关不良事件，其中 2 例被认为与治疗可能相关。21 名符合方案疗效人群中的 21 名患者在 6 个月内均无需挽救性手术，但在治疗后 30 个月内有 2/21（9.5%）名患者需要挽救性手术。治疗后 6 个月时，76.2%的患者 TUS 至少改善 2 分，GDE 评分平均改善 48%，触诊时骨折部位的疼痛平均减轻 61%。与治疗前相比，在治疗后 6 个月时，8/22（36.4%）份血样中含有供体特异性抗 HLA 抗体，13/22（59.1%）份血样中含有供体特异性抗 HLA 抗体，但未观察到治疗介导的同种异体免疫反应。
这项初步研究表明，长骨骨折延迟愈合患者经皮植入同种异体成骨细胞在技术上是可行的，且耐受性良好。初步疗效证据支持进一步开发这种治疗方法。
NCT02020590。于 2013 年 12 月 25 日注册。ALLOB-DU1，一项关于非感染性延迟愈合骨折中同种异体成骨细胞（ALLOB®）植入的疗效和安全性的多中心、开放性 I/IIa 期试验。
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