We have treated refractory fractures, including nonunion. Moreover, not only clinical treatments, but also clinical trials and basic researches, which could contribute to the treatment for refractory fractures, have been an important theme for us. Special clinics for refractory fractures are open for patients with refractory fractures, such as nonunion or osteomyelitis.
Our group has conducted a clinical research regarding "Clinical course of bone fractures, delayed union fractures, and osteomyelitis following trauma," with patients who were treated in our department after 2000.

Therapeutic osteogenesis and vasculogenesis by cell transplantation
To establish a novel therapy for nonunion fractures, our group performed a clinical research entitled "A Phase I/ II Clinical Trial: Autologous CD34+ Cell Transplantation for Bone and Vascular Healing in Patients with Non-Union Fracture" in cooperation with Foundation for Biomedical Research and Innovation, Institute of Biomedical Research and Innovation Hospital in Kobe from November 2009 to March 2012. In this research, CD34(+) cells, which contribute to osteogenesis and vasculogenesis, were collected form the peripheral blood of each patient and were transplanted to nonunion site in surgeries. All seven patients had bone union, and the therapy was shown to be safe and can treat nonunion in a shorter period compared with the conventional method (Kuroda R, et al. Stem Cells Trans Med 2014).
As a next step, an investigator-initiated clinical trial has been started in five institutions, including our department to obtain this treatment approved as a new medical technology by the Ministry of Health, Labour, and Welfare. We are searching for patients to participate in this trial. Fifteen patients with nonunion in the tibial diaphyses and 10 patients with nonunion in the femur are scheduled for this trial.

http://www.ibri-kobe.org/fracture/

Dr. Niikura from our department presented "Local transplantation of G-CSF-mobilized CD34+ cells for patients with femoral and tibial nonunion: Phase 1/2 clinical trial" in the 14th ECTES（European Congress of Trauma and Emergency Surgery） held on May 2013 in Lyon, and received Best Oral Presentation Award.

Fracture repair acceleration by CO2 application
A clinical trial has been done aiming to apply "CO2 therapy" for patients based on basic research with an animal, wherein we revealed that cutaneous application of CO2 accelerated fracture repair in association with blood flow promotion (Koga, Niikura, et al. J Bone Joint Surg Am 2014). This therapy can currently be performed only in our department. CO2 therapy for healthy humans has been found to increase blood flow and to make better influences for muscle. Moreover, the progression of rehabilitation, which is essential to bone fracture treatments, can possibly improve. The objective of this clinical trial study is the efficacy and safety of CO2 therapy by applying this therapy in addition to conventional therapy for fractures. CO2 therapy is expected to be established as new standard strategy for faster fracture union and is certainly accepted worldwide.
The clinical trial is currently temporarily finished, and this treatment cannot be performed. We will inform on this website when it becomes possible to start further clinical trials.

The theme of our basic research is acceleration of fracture repair and bone regeneration. Particularly, fracture repair with cells isolated from human pseudoarthrosis tissue and hematoma in fracture sites (please see below for details) is one of our main themes. The results of these researches were reported in domestic and international major conferences, such as the American Academy of Orthopaedic Surgeons (AAOS), Orthopaedic Research Society (ORS), International Society for Fracture Repair (ISFR), Japanese Orthopaedic Association (JOA), and Japanese Society for Fracture Repair (JSFR).

Effect of low-intensity pulse ultrasound (LIPUS) with fracture hematoma cells for fracture repair
LIPUS has an effect to promote fracture repair and is used as fracture repair device in the clinical setting. However, the mechanism of LIPUS for fracture repair has not been completely revealed yet, and we have investigated that with human cells existing fracture sites in molecular level. We found that hematomas at human fracture sites contain progenitor cells with multilineage capacity (Oe et al. J Bone Joint Surg Br. 2007). Following studies regarding the mechanism for this hematomas cells to contribute to fracture repair in reaction to LIPUS was published in international journals (Hasegawa et al. J Bone Joint Surg Br. 2009; Lee et al. J Orthop Trauma. 2013).
Dr. Niikura from our group presented "LIPUS contributes fracture repair with promoting bone and cartilage differentiation of cells derived from fracture hematoma" in the 38th JSFR (Japanese Society for Fracture Repair) held on June 2012, and received the Society Award.

Researches regarding cells in nonunion and pseudoarthrosis tissue
Our basic researches demonstrated that mesenchymal progenitor cells with osteogenic capacity exist in nonunion and pseudoarthrosis tissue and were published in international journals (Iwakura et al. J Orthop Res. 2009; Takahara et al. Injury. 2016), and those are highly evaluated in domestic and international scenes. These cells have been studied to develop a new therapeutic strategy for nonunion and to investigate the causes of nonunion. The research regarding the effect of LIPUS to nonunion or pseudoarthrosis cells was performed and published in 2013 (Koga et al. J Ultrasound Med. 2013).

Molecular biological investigation for the cause of nonunion with rat fracture model
Approximately 10% of bone fractures fail to heal and result in delayed union or nonunion, and those are difficult to treat, with significant problems in the clinical setting. The mechanism to develop nonunion is not fully known, and a further study has been required to establish better treatments. Gene expression in fracture sites were investigated over time with rat femoral fracture model and rat femoral nonunion model (Niikura et al. J Orthop Res. 2006; Koh et al. J Orthop Res. 2011). The possibility that microRNA as non-coding RNA might affect fracture repair or delayed union has been investigated (Waki et al. Bone Joint J. 2015; Waki et al, BMC Musculoskelet Disord. 2016).

Search and development of novel therapeutic strategy to promote fracture repair
Several researches are on-going to search and develop novel strategy for fracture repair to cure fractures faster and more certainly.

(1) Research has been being performed to study effectiveness of cutaneous application of CO2 for fracture repair (Koga, Niikura, et al. J Bone Joint Surg Am 2014).
Dr. Niikura from our group presented "Trial for promotion of fracture repair with cutaneous CO2 application" in the 39th JSFR (Japanese Society for Fracture Repair) held on June 2013, and received the Society Award.

(2) Research regarding the application of parathyroid hormone (PTH) 1-34, a new drug for osteoporosis with osteogenic function, for treatment for refractory fractures has been being performed. (Dogaki et al. J Tissue Eng Regen Med 2016)

(3) Regenerative therapy for refractory fractures with induced pluripotent stem cells (iPS cell), which is currently the biggest topic in the field of regenerative medicine, has been being investigated. (Dogaki et al. Int Orthop 2014)
Dr. Dogaki from our group presented "Efficient derivation of osteoprogenitor cells from induced pluripotent stem cells for bone regeneration" in the 1st AOTrauma Asia Pacific Scientific Congress held on May 2012 in Hong Kong and received the Best Poster Award.