Bone Marrow-Derived Cell Therapies to Heal Long-Bone Nonunions: A Systematic Review and Meta-Analysis—Which Is the Best Available Treatment?

Abstract

Nonunions represent one of the major indications for clinical settings with stem cell-based therapies. The objective of this research was to systematically assess the current evidence for the efficacy of bone marrow-derived cell-based approaches associated or not with bone scaffolds for the treatment of nonunions. We searched MEDLINE (PubMed) and CENTRAL up to July 2019 for clinical studies focused on the use of cell-based therapies and bone marrow derivatives to treat bone nonunions. Three investigators independently extracted the data and appraised the risk of bias. We analysed 27 studies including a total number of 347 participants exposed to four interventions: bone marrow concentrate (BMAC), BMAC combined with scaffold (BMAC/Scaffold), bone marrow-derived mesenchymal stromal cells (BMSCs), and BMSC combined with scaffold (BMSC/Scaffold). Two controlled studies showed a positive trend in bone healing in favour of BMAC/Scaffold or BMSC/Scaffold treatment against bone autograft, although the difference was not statistically significant (RR 0.11, 95% CI -0.05; 0.28). Among single cohort studies, the highest mean pooled proportion of healing rate was reported for BMAC (77%; 95% CI 63%-89%; 107 cases, n=8) and BMAC/Scaffold treatments with (71%; 95% CI 50%-89%; 117 cases, n=8) at 6 months of follow-up. At 12 months of follow-up, an increasing proportion of bone healing was observed in all the treatment groups, ranging from 81% to 100%. These results indicate that BMAC or BMAC/Scaffold might be considered as the primary choice to treat nonunions with a successful healing rate at a midterm follow-up. Moreover, this meta-analysis highlighted that the presence of a scaffold positively influences the healing rate at a long-term follow-up. More case-control studies are still needed to support the clinical improvement of cell-based therapies against autografts, up to now considered as the gold standard for the treatment of nonunions.

Co-transfection with BMP2 and FGF2 via chitosan nanoparticles potentiates osteogenesis in human adipose-derived stromal cells in vitro

“…expansion can produce large numbers of cells, it also leads to the loss of stem cell characteristics and potential changes in the differentiation potential. 27,28 Compared with BMSCs, ADSCs have several advantages, such as a wide variety of sources, rich content, little trauma to the donor during harvesting, and in vitro amplification capability. 24,29 ADSCs have thus become an important source of seed cells for bone tissue engineering.…”

“… 23 , 24 Although BMSCs were the first to be found to have osteogenic potential and were thus considered as seed cells for bone tissue engineering, 25 , 26 the number of BMSCs in the bone marrow is limited, and although in vitro expansion can produce large numbers of cells, it also leads to the loss of stem cell characteristics and potential changes in the differentiation potential. 27 , 28 Compared with BMSCs, ADSCs have several advantages, such as a wide variety of sources, rich content, little trauma to the donor during harvesting, and in vitro amplification capability. 24 , 29 ADSCs have thus become an important source of seed cells for bone tissue engineering.…”

Arthroscopic Fixation of Knee Femoral Condyle Osteochondritis Dissecans Fragment With Bone Marrow Aspirate Concentrate

“…It is well established that BMAC augmentation is a valuable tool for the treatment of fracture nonunion. 19 , 20 It is also suggested that BMAC augmentation can lead to improved healing of focal chondral lesions and promote hyaline-like cartilage growth owing to the high concentration of growth factors present, including vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor 1, transforming growth factor β, and bone morphogenetic protein 2. 7 , 8 , 10 , 11 , 21 There have been several clinical studies supporting the use of BMAC for the treatment of cartilage lesions.…”

Implementation of Endogenous and Exogenous Mesenchymal Progenitor Cells for Skeletal Tissue Regeneration and Repair

“…Interestingly, upon comparative analysis, the study also identified evolutionary differences between mouse and human skeletogenesis [57]. Furthermore, the periosteum is considered to be the primary source of mesenchymal progenitor cells, giving rise to the fracture callus [88], but there is evidence that BM-MSCs and muscle progenitor cells also contribute to the bone repair process [63,89,90].…”