title: 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.
authors.affiliation: Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan; Unit of Regenerative Medicine and Group of Vascular Regeneration Research, Institute of Biomedical Research and Innovation, Kobe, Japan; Department of Cell Therapy Development, Foundation for Biomedical Research and Innovation, Kobe, Japan; Translational Research Informatics Center, Kobe, Japan; Department of Regenerative Medicine Science, Tokai University School of Medicine, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kuroda
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Niikura
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Fukui
authors.forename: Sang Yang
authors.initials: SY
authors.lastname: Lee
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mifune
authors.forename: Shin
authors.initials: S
authors.lastname: Kawamata
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kurosaka
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000628:therapy*; D017102:Fracture Healing; D005599:Fractures, Ununited / Q000000981:diagnostic imaging / Q000628:therapy*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011859:Radiography; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013978:Tibial Fractures / Q000000981:diagnostic imaging / Q000628:therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D016179:Granulocyte Colony-Stimulating Factor
keywords: CD34+ cells; Clinical trial; G-CSF; Nonunion; Peripheral blood