Early efficacy evaluation of mesenchymal stromal cells (MSC) combined to biomaterials to treat long bone non-unions

Abstract

Background and study aim: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture. Patients and methods: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in R This paper is part of a Supplement supported by The Orthopaedic Surgery and Traumatology Spanish Society (SECOT).

Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches

“…Thus, a more logical option for regeneration of bone is to revert to an earlier stage in the lineage, such as the pre-osteoblast or the MSC. In preclinical studies, and in limited clinical trials (Gomez-Barrena et al, 2015 , 2020 ; Lee et al, 2019 ; Hutchings et al, 2020 ), MSCs have been the target cell for isolation. As outlined above, MSCs are rare in the bone marrow; the approach most commonly used is expansion in vitro , and then injection or open grafting in a suitable carrier.…”

“…Given the above controversy, there have been many different methods for isolation of what the authors describe as mesenchymal stem cells (Kanczler et al, 2019 ) ( Figure 1 ). One such methodology for GMP compliant generation of bone marrow derived MSCs and expansion on a large scale for a multicenter study of fracture healing in Europe has been described in detail (Fekete et al, 2012 ; Rojewski et al, 2013 ; Gomez-Barrena et al, 2020 ). This and other studies using MSCs are ongoing.…”

A Review of Recent Developments in the Molecular Mechanisms of Bone Healing

“…A recent article showed that bone healing was efficaciously achieved in 28 patients with nonunions surgically treated with a combination of autologous expanded mesenchymal stromal cells from human bone marrow (hBM-MSCs) (between 100 × 10 6 and 200 × 10 6 expanded hBM-MSCs) combined with a bioceramic [MBCP + TM, a 100% synthetic (Biomatlante, Vigneux, France) bone substitute composed of 20% hydroxyapatite and 80% beta-tricalcium phosphate, in 1–2 mm granules]. The cell-biomaterial association was performed in the surgical room prior to implantation [ 5 ].…”

Osteonecrosis of the Femoral Head Safely Healed with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells in a Multicentric Trial with Minimum 5 Years Follow-Up

“…An aliquot of the starting material was removed to carry out controls, including cell count, viability, CFU-F-assay, and sterility. The entire manufacturing process was performed at each manufacturing site, following the same procedure described in ORTHO-1 CT (EudraCT 2011-005441-13) and ORTHOUNION CT (EudraCT 2015-000431-32) [ 14 , 15 ]. In brief, the culture was performed when the received BM, without any further manipulation, was seeded in alpha-MEM medium with 5% PL and 1 I.U./mL heparin, at the concentration of 50.000 WBC/cm 2 , in a culture chamber.…”