Predictors of fracture healing in patients with recalcitrant nonunions treated with autologous culture expanded bone marrow‐derived mesenchymal stromal cells

Abstract

The study reports the prospective outcome of treating severe recalcitrant fracture nonunion in patients with autologous bone marrow‐derived mesenchymal stromal cells (BMSC) from 2003 to 2010 and analyze predictors of union. Autologous BMSC were culture expanded and inserted at nonunion site with or without carriers in addition to surgical stabilization of the fracture. Radiological union was ascertained by musculoskeletal radiologists on plain radiographs and/or CT scans. A logistic regression analysis was performed with cell‐expansion parameters (cell numbers, cell doubling time) and known clinical factors (e.g., smoking and diabetes) as independent variables and fracture union as the dependent variable to identify the factors that influence bony healing. An Eq5D index score assessed the effect of treatment on general quality of health. A total of 35 patients (mean age 51+/−13 years) with established nonunion (median 2.9 years, 1–33) and, at least one failed nonunion surgery (median 4,1–14) received treatment. Fracture union was achieved in 21 patients (60%; 95%CI 44–75) at 2.6 years. Multiple penalized logistic regression revealed faster cell doubling time ( p = 0.07), absence of diabetes ( p = 0.003), less previous surgeries ( p = 0.008), and lower age at cell implantation ( p = 0.02) were significant predictors for fracture union. A significant increase in Eq5D index ( p = 0.01) was noted with a mean rise of the score by 0.34 units (95%CI 0.11–0.58) at 1 year following the study. In summary, the study revealed cell doubling time as a novel in vitro parameter in conjunction with age, multiple surgeries, and diabetes as being significant predictors of the fracture union. © 2018 The Authors. Journal of Orthopaedic Research ® Published by Wiley Periodicals, Inc. J Orthop Res 37:1303–1309, 2019.

Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue

“…A number of musculoskeletal conditions such as osteoporosis, osteomyelitis, osteosarcoma, diabetic fracture and congenital disorders such as osteogenesis imperfecta result in a compromise or delay in skeletal formation/repair [ 88 , 89 , 90 , 91 ]. While a majority of reports have utilized exogenous autologous or allogeneic MSC, other studies have attempted to recruit endogenous MSC through the administration of bioactive signals, including but not limited to BMP, parathyroid hormone (PTH), C-X-C Motif Chemokine Ligand 12 (CXCL12), VEGF, PDGF-Rβ, Interleukin 10 (IL-10), and Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 (Lgr5) signaling pathways, mediated by the above-mentioned biomimetic delivery methods [ 17 , 92 , 93 , 94 , 95 ].…”

Immunomodulatory Effects of MSCs in Bone Healing

“…Considering that a risk factor of suffering nonunions is diabetes or age, both chronic inflammatory conditions, and the increase levels of IL-6 detected in serum from nonunion patients, it is likely that an increased inflammatory process could be partially governing the pathophysiology of nonunions. Encouraged by the in vitro finding that osteogenic capacity of MSCs in nonunions is not affected, a recent prospective study treated nonunion patients with autologous expanded BM-MSCs [96]. Fracture union was observed in 21 patients from a total of 35 receiving cell therapy, and a faster in vitro MSC doubling time predicted the positive outcome of nonunions.…”

Therapeutic Efficacy and Safety of Osteoinductive Factors and Cellular Therapies for Long Bone Fractures and Non-Unions: A Meta-Analysis and Systematic Review

“…Although the international literature reports that MSCs suppressed lymphocyte reaction and induced immunosuppressive properties [61], our analysis demonstrated that adverse effects after MSC application were extremely uncommon [21,24,25]. Despite the fact that many studies reported increased healing outcomes after the administration of MSCs in patients with atrophic and hypertrophic non-unions, in critical-size bone defects as well as in depressed tibial plateau fractures [66][67][68][69][70], our metaanalysis did not reveal statistical differences in the healing process or in the prevention of refractures after MSC application compared to the control group. Contrariwise, our analysis confirmed the safety of MSCs application as their use was not associated with allergic reactions, deep infections, ectopic neo-formations and neoplastic transformations [71].…”