Pseudoarthrosis is a relatively frequent complication of fractures, in which the lack of mechanical stability and biological stimuli results in the failure of bone union, most frequently in humerus and tibia. Treatment of recalcitrant pseudoarthrosis relies on the achievement of satisfactory mechanical stability combined with adequate local biology. Herein we present two cases of atrophic pseudoarthrosis that received a tissue-engineering product (TEP) composed of autologous bone marrow-derived mesenchymal stromal cells (BM-MSC) combined with deantigenized trabecular bone particles from a tissue bank. The feasibility of the treatment and osteogenic potential of the cell-based medicine was first demonstrated in an ovine model of critical size segmental tibial defect. Clinical-grade autologous BM-MSC were produced following a good manufacturing practice-compliant bioprocess. Results were successful in one case, with pseudoarthrosis resolution, and inconclusive in the other one. The first patient presented atrophic pseudoarthrosis of the humeral diaphysis and was treated with osteosynthesis and TEP resulting in satisfactory consolidation at month 6. The second case presented a recalcitrant pseudoarthrosis of the proximal tibia and the Masquelet technique was followed before filling the defect with the TEP. This patient presented a neuropathic pain syndrome unrelated to the treatment that forced the amputation of the extremity 3 months later. In this case, the histological analysis of the tissue formed at the defect site provided evidence of neovascularization but no overt bone remodelling activity. It is concluded that the use of expanded autologous BM-MSC to treat pseudoarthrosis was demonstrated to be feasible and safe, provided that no clinical complications were reported, and early signs of effectiveness were observed.

Current methods for diagnosis of bone healing after treatment of trauma injuries rely on clinical findings and the use of imaging methodologies that provide conclusive results but only at mid/long-term post-intervention. In this Perspective we present and discuss incipient evidence on biomarkers that may serve for monitoring the progression of bone healing as well as predicting eventual nonunion outcomes.

Background Pseudoarthrosis or non-union is a complication with an incidence of 5–10% of bone fractures, most frequently located in the diaphysis of long bones. The management of this complication is addressed by means of complex surgical procedures and is a concern for orthopaedic and trauma surgeons nowadays. The use of biomarkers for diagnosing patients at risk of non-union would help us to establish special measures for early corrective treatment. Methods Prospective exploratory pilot study with a cohort of 20 patients diagnosed of non-hypertrophic pseudoarthrosis of long bones who were treated surgically with either autologous bone graft or a Tissue Engineering Product composed of bone marrow-derived Mesenchymal Stromal Cells. Patients were followed for 12 months and plasma blood samples were obtained to determine circulating levels of Transforming Growth Factor Beta 1 and Beta 2 (TGF-β1 and TGF-β2, respectively) at inclusion, and at 1 week, 2 weeks, and months 1, 2, 3, 6 and 12 after surgery. Radiological bone healing was evaluated by the Tomographic Union Score (TUS). Results Basal levels of TGF-β1 and TGF-β2 were determined in the twenty patients (26,702 ± 14,537 pg/mL and 307.8 ± 83.1 pg/mL, respectively). Three of them withdrew from the study, so complete follow-up was conducted on 17 patients (9 successfully healed vs. 8 that did not heal). Statistically significant differences between the bone healing group and the non-union group were found at month 12 for both TGF-β1 ( p = 0.005) and TGF-β2 ( p = 0.02). Conclusions TGF-β1 and TGF-β2 are biomarkers that correlate with clinical evidence of bone regeneration and may be used to monitor patients, although early predictive value after intervention needs to be further studied in combination with other molecules.

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