Local transplantation of granulocyte colony stimulating factor-mobilized CD34+ cells for patients with femoral and tibial nonunion: pilot clinical trial

Abstract

Most bone fractures typically heal, although a significant proportion (5%-10%) of fractures fail to heal, resulting in delayed union or persistent nonunion. Some preclinical evidence shows the therapeutic potential of peripheral blood CD34(+) cells, a hematopoietic/endothelial progenitor cell-enriched population, for bone fracture healing; however, clinical outcome following transplantation of CD34(+) cells in patients with fracture has never been reported. We report a phase I/IIa clinical trial regarding transplantation of autologous, granulocyte colony stimulating factor-mobilized CD34(+) cells with atelocollagen scaffold for patients with femoral or tibial fracture nonunion (n = 7). The primary endpoint of this study is radiological fracture healing (union) by evaluating anteroposterior and lateral views at week 12 following cell therapy. For the safety evaluation, incidence, severity, and outcome of all adverse events were recorded. Radiological fracture healing at week 12 was achieved in five of seven cases (71.4%), which was greater than the threshold (18.1%) predefined by the historical outcome of the standard of care. The interval between cell transplantation and union, the secondary endpoint, was 12.6 ± 5.4 weeks (range, 8-24 weeks) for clinical healing and 16.1 ± 10.2 weeks (range, 8-36 weeks) for radiological healing. Neither deaths nor life-threatening adverse events were observed during the 1-year follow-up after the cell therapy. These results suggest feasibility, safety, and potential effectiveness of CD34(+) cell therapy in patients with nonunion.

Keywords: CD34+ cells; Clinical trial; G-CSF; Nonunion; Peripheral blood.

Figure 1.

Schema of the treatment procedure. Abbreviations: G-CSF, granulocyte colony stimulating factor; VEGF, vascular endothelial growth factor.

Figure 2.

Procedure of CD34⁺ cell transplantation. Following refreshing fibrous tissue at the nonunion site and the surrounding cortical bone and grafting autologous iliac bone, CD34⁺ cells dissolved in 3 ml of atelocollagen gel were locally administered into the fracture site.

Figure 3.

Preoperative and postoperative radiographs in all cases. All cases achieved union at final follow-up. Radiological fracture healing at week 12, the primary endpoint of this study, was achieved in five of seven cases. Two cases without fracture healing at week 12 (case 2 and case 3) had femoral fractures in which, ultimately, radiological healing was observed at weeks 19 and 36. Circles indicate the site of fracture.