Discussion
tibial nonunion, nonunion, fracture, malignant tumors, fracture nonunion, femoral nonunion, injuries, trauma
MALIGNANT TUMORS, EVENTS, MINOR, FRACTURE NONUNION
This clinical trial revealed the efficacy and safety of CD34 + cell transplantation in patients with fracture nonunion. Harvesting, isolation, and transplantation of CD34 + cells were performed safely in all patients. No malignant tumors were identified during the study period. Mild-to-moderate events related to G-CSF administration and leukapheresis were frequent but transient. These outcomes indicated the feasibility and overall safety of CD34 + cell therapy in patients with fracture nonunion. In terms of efficacy, the results of this trial revealed that fracture nonunions heal fully and more rapidly with our novel regeneration therapy using autologous CD34 + cells than with the pre-existing standard treatment.Surgical intervention is the primary option for fracture nonunion treatment, and ABG is often performed. However, a certain proportion of patients do not achieve bone union even after ABG [This study had certain limitations. Although a randomized controlled trial is ideal to confirm the efficacy and safety of this cell therapy, we selected a nonrandomized, single-arm study. The principal reason for our selection was ethical issues with establishing placebo controls for patients with fracture nonunion, as a long-standing condition would interrupt daily activities. Additionally, the clinical background of the patients with fracture nonunion varied widely. Although we standardized the fracture location and limited this to the diaphysis of the tibia for comparison between the trial patients and historical controls, other factors, including the severity of the initial trauma, soft tissue condition, and duration of the nonunion, could not be standardized. Additionally, the heterogeneity of the fracture fixation devices used to fix the initial fracture and nonunion could be considered to have affected the healing time of the nonunion. Furthermore, the number of participants was small, and the study focused only on the tibia and femur.The results of the current clinical trial suggest the potential efficacy of CD34 + cell therapy for nonunion; however, here, ABG with CD34 + cell therapy was administered to all patients. Consequently, we could not evaluate the efficacy of CD34 + cell therapy alone for healing fracture nonunions. Nevertheless, we used a historical control group of patients treated with ABG for comparison; therefore, the differences in the treatment methods reflect the CD34 + cell-based therapy, and the result that the treated fracture nonunions healed faster than the control injuries could be attributed to the CD34 + cell therapy.In this cell therapy, G-CSF was systemically administered to patients to mobilize CD34 + cells from the BM to the PB. Animal studies have shown that G-CSF contributes to bone repair [Less than the full dose of CD34 + cells was administered to 4 patients with tibial nonunion and 3 patients with femoral nonunion. All these patients achieved bone union, suggesting no differences between patients given the full or reduced dose of CD34 + cells in terms of the primary outcome. In addition, no significant correlation was detected between the radiological healing period and the number of transplanted CD34 + cells in either tibial or femoral nonunion patients. However, the interval between the nonunion surgery and radiological healing differed among these patients. We speculate that this could be attributed to the small sample size and the relatively minor variation in cell dose in this study. Unfortunately, the number of patients was insufficient to statistically compare the effects between the full and lower doses. Hence, future studies should be conducted with a larger sample size of patients.