Increase in carbon dioxide accelerates the performance of endurance exercise in rats.

Endurance exercise generates CO2 via aerobic metabolism; however, its role remains unclear. Exogenous CO2 by transcutaneous delivery promotes muscle fibre-type switching to increase endurance power in skeletal muscles. Here we determined the performance of rats running in activity wheels with/without transcutaneous CO2 exposure to clarify its effect on endurance exercise and recovery from muscle fatigue. Rats were randomised to control, training and CO2 groups. Endurance exercise included activity-wheel running with/without transcutaneous CO2 delivery. Running performance was measured after exercise initiation. We also analysed changes in muscle weight and muscle fibres in the tibialis anterior muscle. Running performance improved over the treatment period in the CO2 group, with a concomitant switch in muscle fibres to slow-type. The mitochondrial DNA content and capillary density in the CO2 group increased. CO2 was beneficial for performance and muscle development during endurance exercise: it may enhance recovery from fatigue and support anabolic metabolism in skeletal muscles.

Topical cutaneous CO2 application by means of a novel hydrogel accelerates fracture repair in rats.

BACKGROUND: We previously demonstrated that topical cutaneous application of CO2, by means of a hydrogel in which the CO2 readily dissolves, increases blood flow and oxygen dissociation from hemoglobin in the soft tissues surrounding bone. In the present study, we utilized a rat fracture model to test the hypothesis that application of this treatment to fractured limbs would accelerate fracture repair. METHODS: A closed femoral shaft fracture was created in each rat. Topical cutaneous application of CO2 by means of a hydrogel was performed five times a week for up to four weeks in the CO2/hydrogel group (n = 60). Sham treatments were performed in the control group (n = 60). Radiographic, histological, immunohistochemical, laser Doppler perfusion imaging, real-time polymerase chain reaction, and biomechanical assessments were performed. RESULTS: Radiographic fracture union was evident at week 3 in twelve (86%) of fourteen animals in the CO2/hydrogel group compared with five (36%) of fourteen in the control group (p < 0.05; 95% CI [confidence interval] for the difference in union rate, 2.26% to 99.64%). Histological assessment revealed promotion of endochondral ossification in the CO2/hydrogel group. Immunohistochemical assessment at week 2 showed significantly greater capillary density in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 161 to 258 per mm(2)). Laser Doppler perfusion imaging demonstrated that the blood flow in the fractured limb was significantly greater at weeks 2 and 3 in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 8.4% to 22.4% and 6.7% to 19.0%, respectively). Gene expression of chondrogenic, osteogenic, and angiogenic markers was significantly greater in the CO2/hydrogel group at several time points. Ultimate stress, extrinsic stiffness, and failure energy (relative to the contralateral limb) were significantly greater in the CO2/hydrogel group at week 3 (p < 0.05; 95% CI for the difference, 24.8% to 67.5%, 4.0 % to 22.7%, and 9.6% to 58.8%, respectively). There were no significant differences between the groups with respect to any outcome measure at week 4. CONCLUSIONS: Topical cutaneous application of CO2 by means of a hydrogel accelerated fracture repair in association with the promotion of angiogenesis, blood flow, and endochondral ossification. .

Inhibition of growth in a rabbit VX2 thigh tumor model with intraarterial infusion of carbon dioxide-saturated solution.

PURPOSE: To evaluate the efficacy of intraarterial infusion of CO2-saturated solution in rabbit VX2 thigh tumors. MATERIALS AND METHODS: Fourteen Japanese white rabbits had VX2 tumors implanted in the right femoral muscle 3 weeks before intraarterial infusion. Rabbits were divided into control and CO2 groups (n = 7 each). Fifty milliliters of solution (saline solution and CO2-saturated solution for the control and CO2 groups, respectively) was administered via a 24-gauge catheter in the ipsilateral iliac artery close to the feeding artery of the VX2 tumor. All rabbits were killed for tumor harvest on day 3 after the procedure. Tumor volume was evaluated with in vivo direct caliper measurement and contrast-enhanced computed tomography (CT). Tumor apoptotic changes were examined by DNA fragmentation assay and immunoblot analysis. The tumor growth ratio and apoptotic cell rate were analyzed. RESULTS: Body weight was equally increased in both groups, but the mean tumor growth ratio was significantly decreased in the CO2 group compared with the control group (-9.5% ± 7.9 vs 27.2% ± 6.6 and 4.1% ± 4.4 vs 35.7% ± 4.5 measured by calipers and contrast-enhanced CT, respectively; P < .01). Apoptotic activity in the CO2 group was higher than in the control group (number of apoptotic cells per area, 215.0 ± 58.7 vs 21.8 ± 5.4; adjusted relative density of cleaved caspase-3, 0.23 ± 0.07 vs 0.04 ± 0.01; P < .01). CONCLUSIONS: Intraarterial infusion of CO2-saturated solution inhibits rabbit VX2 thigh tumor growth by activation of apoptotic cell death through cleaved caspase-3 upregulation.

Gentamycin-impregnated calcium phosphate cement for calcaneal osteomyelitis: a case report.

We report a case of chronic calcaneal osteomyelitis in a diabetic patient who was successfully treated with radical debridement and gentamycin-impregnated calcium phosphate cement. At 1.5-year follow-up, the patient could walk without any assistance. Calcium phosphate cement is an effective local antibiotic delivery system and a biocompatible material for filling the debrided space to facilitate bone formation.

Novel Surgical Treatment for Refractory Heel Ulcers in Werner's Syndrome.

Patients with Werner's syndrome frequently develop chronic leg ulcers that heal poorly. We present a patient who suffered from this rare syndrome and developed typical heel ulcers. Treatment of the ulcer is challenging, as flap options are limited over the lower third of the leg and skin grafting is not easy as there is a lack of healthy granulations. We successfully treated the ulcer with osteomyelitis by drilling the bone and applying an ultrathin split thickness skin graft with the thigh skin as the donor site.

Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells.

Osteosarcoma is the most common primary solid malignant bone tumor. Despite substantial improvements in surgery and chemotherapy, metastasis remains a major cause of fatal outcomes, and the molecular mechanisms of metastasis are still poorly understood. Hypoxia, which is common in malignant tumors including osteosarcoma, increases expressions of hypoxia inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2 and MMP-9, and can induce invasiveness. As we previously showed a novel transcutaneous CO2 application to decrease HIF-1α expression and induce apoptosis in malignant fibrous histiocytoma, we hypothesize that transcutaneous CO2 application could suppress metastatic potential of osteosarcoma by improving hypoxic conditions. Here, we examined the effects of transcutaneous CO2 application on apoptosis, and development of pulmonary metastasis using a highly metastatic osteosarcoma cell line, LM8. Transcutaneous CO2 application significantly decreased tumor growth and pulmonary metastasis in LM8 cells. Apoptotic activity increased, and intratumoral hypoxia was improved with decreased expressions of HIF-1α, MMP-2 and MMP-9, significantly, in the CO2-treated tumors. In conclusion, we found that transcutaneous CO2 application can induce tumor cell apoptosis and might suppress pulmonary metastasis by improvement of hypoxic conditions with decreased expressions of HIF-1α and MMPs in highly metastatic osteosarcoma cell. These findings strongly indicate that this novel transcutaneous CO2 therapy could be a therapeutic breakthrough for osteosarcoma patients.

Sacral Fracture Nonunion Treated by Bone Grafting through a Posterior Approach.

Nonunion of a sacral fracture is a rare but serious clinical condition which can cause severe chronic pain, discomfort while sitting, and significant restriction of the level of activities. Fracture nonunions reportedly occur most often after nonoperative initial treatment or inappropriate operative treatment. We report a case of fracture nonunion of the sacrum and pubic rami that resulted from non-operative initial treatment, which was treated successfully using bone grafting through a posterior approach and CT-guided percutaneous iliosacral screw fixation combined with anterior external fixation. Although autologous bone grafting has been the gold standard for the treatment of pelvic fracture nonunions, little has been written describing the approach. We utilized a posterior approach for bone grafting, which could allow direct visualization of the nonunion site and preclude nerve root injury. By this procedure, we were able to obtain the healing of fracture nonunion, leading to pain relief and functional recovery.

Analysis of circulating mesenchymal progenitor cells in arterial and venous blood after fracture.

Mesenchymal progenitor cells (MPCs) play a critical role in fracture healing. Increasing evidence suggests that circulating MPCs in peripheral blood are mobilized during fracture healing and may contribute to fracture repair. However, to date, there have been no reports comparing the number of circulating MPCs in arterial blood (AB) with that in venous blood (VB) after fracture. In this study, we investigated the numbers of MPCs in AB, VB and bone marrow (BM) after fracture in rabbits via the colony-forming unit-fibroblasts (CFU-Fs) assay, and clarified the time-course change. After femoral fracture in one side, the number of BM-MPCs in the contralateral femur increased from day 1 to day 7. Correspondingly, the number of circulating MPCs in AB and VB increased. The number of circulating MPCs in AB was highest at post-fracture day 4, whereas that in VB was highest at post-fracture day 1, with significant difference compared to the control. Circulating MPCs in AB and VB after fracture may serve as new cell sources for bone tissue engineering. As the peaks of the number of circulating MPCs in AB and VB after fracture were different, our findings may provide new insights about when to collect circulating MPCs after fracture and from which blood to obtain them.

Transcutaneous application of carbon dioxide (CO2) induces mitochondrial apoptosis in human malignant fibrous histiocytoma in vivo.

Mitochondria play an essential role in cellular energy metabolism and apoptosis. Previous studies have demonstrated that decreased mitochondrial biogenesis is associated with cancer progression. In mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) regulates the activities of multiple nuclear receptors and transcription factors involved in mitochondrial proliferation. Previously, we showed that overexpression of PGC-1α leads to mitochondrial proliferation and induces apoptosis in human malignant fibrous histiocytoma (MFH) cells in vitro. We also demonstrated that transcutaneous application of carbon dioxide (CO(2)) to rat skeletal muscle induces PGC-1α expression and causes an increase in mitochondrial proliferation. In this study, we utilized a murine model of human MFH to determine the effect of transcutaneous CO(2) exposure on PGC-1α expression, mitochondrial proliferation and cellular apoptosis. PGC-1α expression was evaluated by quantitative real-time PCR, while mitochondrial proliferation was assessed by immunofluorescence staining and the relative copy number of mitochondrial DNA (mtDNA) was assessed by real-time PCR. Immunofluorescence staining and DNA fragmentation assays were used to examine mitochondrial apoptosis. We also evaluated the expression of mitochondrial apoptosis related proteins, such as caspases, cytochorome c and Bax, by immunoblot analysis. We show that transcutaneous application of CO(2) induces PGC-1α expression, and increases mitochondrial proliferation and apoptosis of tumor cells, significantly reducing tumor volume. Proteins involved in the mitochondrial apoptotic cascade, including caspase 3 and caspase 9, were elevated in CO(2) treated tumors compared to control. We also observed an enrichment of cytochrome c in the cytoplasmic fraction and Bax protein in the mitochondrial fraction of CO(2) treated tumors, highlighting the involvement of mitochondria in apoptosis. These data indicate that transcutaneous application of CO(2) may represent a novel therapeutic tool in the treatment of human MFH.

Technique to prepare the bed for autologous bone grafting in nonunion surgery.

This article describes a technique for preparing the bed for autologous bone grafting in nonunion surgery. The procedure is divided into 2 steps. First, both ends of the fracture fragments are chipped into small pieces using an osteotome and hammer without peeling off the periosteum, creating pathways into the bone marrow. Second, cancellous bone harvested from the iliac crest is grafted into the aperture created by the previous bone chipping treatment. The technique is easy to perform and is a promising approach for enhancing bone healing in nonunion and delayed union.

Mandibular hematoma cells as a potential reservoir for osteoprogenitor cells in fractures.

PURPOSE: We hypothesized that cells within the mandibular fracture hematoma played an important role in mandibular fracture healing. The objective of this study was to analyze cells in human mandibular fracture hematoma. PATIENTS AND METHODS: We isolated and analyzed human mandibular fracture hematoma cells (MHCs) and investigated whether MHCs had multilineage mesenchymal differentiation capacity in vitro, similar to bone marrow stromal cells (BMSCs). RESULTS: Cell-surface markers showed that the adherent MHCs expressed mesenchymal stem cell-related markers, namely CD29, CD44, CD105, and CD166, while lacking hematopoietic markers CD14, CD34, CD45, and CD133. The proliferative potential, osteogenic potential, and adipogenic potential of MHCs were comparable to those of BMSCs. In contrast, the chondrogenic potential of MHCs was inferior to that of BMSCs. CONCLUSIONS: The role of the mandibular fracture hematoma could be as a presumptive local reservoir for osteogenic progenitors and thus contribute to intramembranous bone healing. Our findings may provide new insights into the mechanism of intramembranous bone healing in membranous bone fractures.

Operative Management of Periarticular Medial Clavicle Fractures-Report of 10 Cases.

BACKGROUND:: The periarticular medial clavicle fracture is a rare injury and can be treated conservatively in the majority of cases. However, up to 8% of the patients develop symptomatic nonunion, and fracture dislocation correlates with the number of poor functional results. Operative treatment may be beneficial in these cases. Studies with large series of operated patients are still missing. METHODS:: We investigated 10 patients with operative treatment of periarticular medial clavicle fractures. Preoperative X-ray or computed tomography scan was obtained, and follow-up assessment was performed at determined intervals, including physical examination and X-ray evaluation of bone healing. Finally, functional assessment was carried out from September 2009 to July 2010 using the Disabilities of the Arm, Shoulder and Hand score. RESULTS:: All operated patients had displaced periarticular medial clavicle fractures. A direct surgical approach was performed, and denudation of the bone fragments was avoided. In 8 of 10 cases, we used locking plates, preferentially the T-locking plate. In 6 of 10 patients, three screws were placed in the medial fragment or the sternum. The arm was immobilized in a sling for 2 weeks to 3 weeks, followed by careful passive and increasing active motion exercises. In 9 of 10 operated patients, we observed fracture healing and good functional results. Two patients with paraplegia/tetraplegia were excluded from final assessment but demonstrated fracture healing. In one case, we observed early material loosening caused by misused locking system and wound infection. CONCLUSIONS:: Operative treatment can be considered for periarticular, dislocated medial-end clavicle fractures. Computed tomography scan can be useful for operative planning and is mostly performed in patients with multiple injuries. Locking plates, such as the T-locking plate or the pilon reconstruction plate, are preferred devices. For rigid fixation, at least three locking screws should be placed in the medial bone fragment. The plate can be removed 18 months after osteosynthesis.

A novel system for transcutaneous application of carbon dioxide causing an "artificial Bohr effect" in the human body.

BACKGROUND: Carbon dioxide (CO(2)) therapy refers to the transcutaneous administration of CO(2) for therapeutic purposes. This effect has been explained by an increase in the pressure of O(2) in tissues known as the Bohr effect. However, there have been no reports investigating the oxygen dissociation of haemoglobin (Hb) during transcutaneous application of CO(2)in vivo. In this study, we investigate whether the Bohr effect is caused by transcutaneous application of CO2 in human living body. METHODS: We used a novel system for transcutaneous application of CO(2) using pure CO(2) gas, hydrogel, and a plastic adaptor. The validity of the CO(2) hydrogel was confirmed in vitro using a measuring device for transcutaneous CO(2) absorption using rat skin. Next, we measured the pH change in the human triceps surae muscle during transcutaneous application of CO(2) using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) in vivo. In addition, oxy- and deoxy-Hb concentrations were measured with near-infrared spectroscopy in the human arm with occulted blood flow to investigate O2 dissociation from Hb caused by transcutaneous application of CO(2). RESULTS: The rat skin experiment showed that CO(2) hydrogel enhanced CO(2) gas permeation through the rat skin. The intracellular pH of the triceps surae muscle decreased significantly 10 min. after transcutaneous application of CO(2). The NIRS data show the oxy-Hb concentration decreased significantly 4 min. after CO(2) application, and deoxy-Hb concentration increased significantly 2 min. after CO(2) application in the CO(2)-applied group compared to the control group. Oxy-Hb concentration significantly decreased while deoxy-Hb concentration significantly increased after transcutaneous CO(2) application. CONCLUSIONS: Our novel transcutaneous CO(2) application facilitated an O(2) dissociation from Hb in the human body, thus providing evidence of the Bohr effect in vivo.

Negative pressure wound therapy for the treatment of infected wounds with exposed knee joint after patellar fracture.

Treatment of soft tissue defects with exposed bones and joints, resulting from trauma, infection, and surgical complications, represents a major challenge. The introduction of negative pressure wound therapy has changed many wound management practices. Negative pressure wound therapy has recently been used in the orthopedic field for management of traumatic or open wounds with exposed bone, nerve, tendon, and orthopedic implants. This article describes a case of a patient with a large soft tissue defect and exposed knee joint, in which negative pressure wound therapy markedly improved wound healing. A 50-year-old man presented with an ulceration of his left knee with exposed joint, caused by severe wound infections after open reduction and internal fixation of a patellar fracture. After 20 days of negative pressure wound therapy, a granulated wound bed covered the exposed bones and joint.To our knowledge, this is the first report of negative pressure wound therapy used in a patient with a large soft tissue defect with exposed knee joint. Despite the chronic wound secondary to infection, healing was achieved through the use of the negative pressure wound therapy, thus promoting granulation tissue formation and closing the joint. We suggest negative pressure wound therapy as an alternative option for patients with lower limb wounds containing exposed bones and joints when free flap transfer is contraindicated. Our result added to the growing evidence that negative pressure wound therapy is a useful adjunctive treatment for open wounds around the knee joint.

The effect of transcutaneous application of carbon dioxide (CO2) on skeletal muscle.

In Europe, carbon dioxide therapy has been used for cardiac disease and skin problems for a long time. However there have been few reports investigating the effects of carbon dioxide therapy on skeletal muscle. Peroxisome proliferators-activated receptor (PPAR)-gamma coactivator-1 (PGC-1α) is up-regulated as a result of exercise and mediates known responses to exercise, such as mitochondrial biogenesis and muscle fiber-type switching, and neovascularization via up-regulation of vascular endothelial growth factor (VEGF). It is also known that silent mating type information regulation 2 homologs 1 (SIRT1) enhances PGC-1α-mediated muscle fiber-type switching. Previously, we demonstrated transcutaneous application of CO(2) increased blood flow and a partial increase of O(2) pressure in the local tissue known as the Bohr effect. In this study, we transcutaneously applied CO(2) to the lower limbs of rats, and investigated the effect on the fast muscle, tibialis anterior (TA) muscle. The transcutaneous CO(2) application caused: (1) the gene expression of PGC-1α, silent mating type information regulation 2 homologs 1 (SIRT1) and VEGF, and increased the number of mitochondria, as proven by real-time PCR and immunohistochemistry, (2) muscle fiber switching in the TA muscle, as proven by isolation of myosin heavy chain and ATPase staining. Our results suggest the transcutaneous application of CO(2) may have therapeutic potential for muscular strength recovery resulting from disuse atrophy in post-operative patients and the elderly population.

Local transplantation of G-CSF-mobilized CD34(+) cells in a patient with tibial nonunion: a case report.

Although implantation of crude bone marrow cells has been applied in a small number of patients for fracture healing, transplantation of peripheral blood CD34(+) cells, the hematopoietic/endothelial progenitor cell-enriched population, in patients with fracture has never been reported. Here, we report the first case of tibial nonunion receiving autologous, granulocyte colony stimulating factor mobilized CD34(+) cells accompanied with autologous bone grafting. No serious adverse event occurred, and the novel therapy performed 9 months after the primary operation resulted in bone union 3 months later without any symptoms including pain and gait disturbance.

Nondestructive evaluation of cell numbers in bone marrow stromal cell/beta-tricalcium phosphate composites using ultrasound.

Composites of bone marrow stromal cells (BMSCs)/beta-tricalcium phosphate (beta-TCP) have been increasingly used as bone substitutes and studied as a bone graft model for bone tissue engineering. The number of seeded cells in the composites is a crucial factor for achieving successful bone tissue regeneration. In this study, we showed that the actual number of cells in BMSC/beta-TCP composites 24 h after seeding at densities of 1.0 x 10(6), 1.5 x 10(6), 2.0 x 10(6), and 1.0 x 10(7) cells/mL was 2.8 +/- 1.5 x 10(5), 3.4 +/- 2.3 x 10(5), 3.7 +/- 1.0 x 10(5), and 3.7 +/- 1.8 x 10(5), respectively, indicating that even when one regular cell-seeding concentration was applied to the beta-TCP, the actual number of cells in the individual BMSC/beta-TCP composites varied considerably. In clinical setting, it is important to choose composites containing an appropriate number of cells before implanting them to patients. In an attempt to searching for the practical tools that can nondestructively evaluate the actual number of cells in beta-TCP after cell seeding, we looked into ultrasound system and developed a nondestructive and quantitative ultrasound device. We successfully demonstrated for the first time that ultrasound amplitude effectively responded to the quantity of BMSC/beta-TCP composites after 24-h cell seeding, and was well correlated to the actual number of cells contained (r = 0.903). Using this ultrasound device, orthopedic surgeons can choose composites that contain favorable number of cells before implantation. Our device could be a valuable, convenient, and nondestructive tool for future bone tissue engineering.

Ankle arthrodesis using antegrade intramedullary nail for salvage of nonreconstructable tibial pilon fractures.

The treatment of nonreconstructable tibial pilon fractures for which the optimal timing for reduction and fixation has been missed is challenging. Ankle arthrodesis may be a treatment option in such cases. We treated 2 patients with nonreconstructable tibial pilon fractures using ankle arthrodesis with an antegrade intramedullary nail. Our method included exposing of the ankle joint through a lateral approach; excising the distal fibula, comminuted fragments, and remaining articular cartilage; inserting an intramedullary nail in an antegrade fashion from the proximal tibia into the talus; insertion of 2 interlocking screws in the talus and the proximal tibia; and autologous bone grafting using the excised distal fibula. At latest follow-up at 2 and 1 year respectively, fusion was complete, and both patients were pain free and could walk without support. When ankle arthrodesis is performed for a tibial pilon fracture, an intramedullary nail is thought to be superior to a plate, which is bulky and may impede soft tissue healing. Moreover, insertion of an intramedullary nail in an antegrade fashion can preserve the subtalar joint, and is therefore preferred over placement in a retrograde fashion. Ankle arthrodesis using this technique can be a useful salvage procedure for a nonreconstructable tibial pilon fracture.

Human hypertrophic nonunion tissue contains mesenchymal progenitor cells with multilineage capacity in vitro.

Hypertrophic nonunion usually results from insufficient fracture stabilization. Therefore, most hypertrophic nonunions simply require the stabilization of the nonunion site. However, the reasons why union occurs without treating the nonunion site directly is not well understood biologically. In this study, we hypothesized that the intervening tissue at the hypertrophic nonunion site (nonunion tissue) could serve as a reservoir of mesenchymal progenitor cells and investigated whether the cells derived from nonunion tissue had the capacity for multilineage mesenchymal differentiation. After nonunion tissue was obtained, it was cut into strips and cultured. Homogenous fibroblastic adherent cells were obtained. Flow cytometry revealed that the adherent cells were consistently positive for mesenchymal stem cell related markers CD13, CD29, CD44, CD90, CD105, CD166, and negative for the hematopoietic markers CD14, CD34, CD45, and CD133, similar to control bone marrow stromal cells. In the presence of lineage-specific induction factors, the adherent cells differentiated in vitro into osteogenic, chondrogenic, and adipogenic cells. These results demonstrated for the first time that hypertrophic nonunion tissue contains multilineage mesenchymal progenitor cells. This suggests that hypertrophic nonunion tissue plays an important role during the healing process of hypertrophic nonunion by serving as a reservoir of mesenchymal cells that are capable of transforming into cartilage and bone forming cells.

Circulating endothelial/skeletal progenitor cells for bone regeneration and healing.

An emerging strategy in the regeneration and repair of bone is to use stem cells, including bone marrow mesenchymal stem cells, which are the most investigated and reliable source for tissue engineering, as well as circulating skeletal stem/progenitor cells, which are receiving abundant attention in regenerative medicine due to their ease of isolation and high osteogenic potential. Because failures in fracture healing are largely due to poor vascularization among many environmental factors, we highlight the first proof-of-principle experiments that elucidated the collaborative multi-lineage differentiation of circulating CD34 positive cells - a cell-enriched population of endothelial/hematopoietic progenitor cells - into not only endothelial cells but also osteoblasts. These cells develop a favorable environment for fracture healing via vasculogenesis/angiogenesis and osteogenesis, ultimately leading to functional recovery from fracture. This review will also highlight current concepts of circulating stem/progenitor cell-based therapy and their potential application for bone repair.