Percutaneous administration of allogeneic bone-forming cells for the treatment of delayed unions of fractures: a pilot study

Abstract

Background 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. Methods 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 × 106 to 100 × 106 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. Results 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. Conclusion 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. Trial registration 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.

Cellular therapies for bone repair: current insights

“…With concerns about potential donor-site morbidity, the use of allogenic MSCs remains an option, though they also have associated concerns regarding disease transmission and immunogenicity. To investigate the role of allogenic MSCs, Jayankura et al percutaneously injected allogenic MSCs (ALLOB, Bone Therapeutics) into 22 patients with long-bone nonunion [ 42 ]. Using this technique, they achieved union in 20/22 patients at 6 months, although they did note increased in anti-human leukocyte antigen antibodies in 23% of patients, albeit with no clinical hypersensitivity reactions.…”

Stem Cells and Acellular Preparations in Bone Regeneration/Fracture Healing: Current Therapies and Future Directions

“…Additionally, none of the 21 patients analyzed required revision/rescue surgery by the 6-month post-op timepoint. However, by the 18-month timepoint, 2 out of21 patients required revision surgery [ 122 ].…”

Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review

“…Pain Visual Analog scale was significantly lower in the MSC group NCT02580695 [ 126 ] OA N/A 29 1 × 10 6 cell UC-MSC N/A No Visual analog scale showed decreased pain. MSC Decreased WOMAC score NCT03800810 [ 127 ] Bone fracture Percutaneous 22 50–100 × 10 6 cell BMSC I/II No TUS, GDE score was improved and pain at palpation at the fracture site was reduced NCT02020590 [ 128 ] Bone fracture Intramedullary I.V 20 4 × 10 7 cells 2 × 10 8 cells WJ-MSC I/IIa No VAS, ODI, and SF-36 scores significantly improved. Promoted bone architecture N/A [ 129 ] Mandibular lesions Intralesional 20 N/A BMSC N/A No Increase in bone density with respect to the baseline levels.…”

“…In a pilot study by Jayankura and coworkers, allogeneic BMSCs were applied to treat 22 participants with bone fractures [ 128 ]. All participants received percutaneous implantation of autologous BMSCs (5 to 10 × 10 7 cells) into the fracture area.…”