【Research and Results】Trauma

神戸大学医学部整形外科 Kobe University Orthopaedic Surgery

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黒田良祐 教授 Prof. Ryosuke Kuroda

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整形外科教室の歩み Department of Orthopaedic Surgery

研究・業績 Research and Results

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  Research and Results
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Greeting
Staff
 
Research and Results Sports & Lower Extremity Spine Adults Reconstruction
Orthopaedic Oncology Upper Extremity Trauma Reumatology

Trauma Division /
Research
Results

【Clinical Research】

 
  ▲Trauma Division
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.



難治骨折診

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/index.html

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.

【Basic Research】

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.


Greeting
Staff
 
Research and Results Sports & Lower Extremity Spine Adults Reconstruction
Orthopaedic Oncology Upper Extremity Trauma Reumatology

Trauma Division /
Results
Research

Original Article

(1) Thrombin-antithrombin III complex tests: A useful screening tool for postoperative venous thromboembolism in lower limb and pelvic fractures. Lee SY, Niikura T, Iwakura T, Sakai Y, Kuroda R, Kurosaka M. J Orthop Surg [In press]

(2) Akahane S, Sakai Y, Ueha T, Nishimoto H, Inoue M, Niikura T, Kuroda R. Transcutaneous carbon dioxide application accelerates muscle injury repair in rat models. Int Orthop. 2017 [Epub ahead of print]

(3) Shoda E, Kitada S, Sasaki Y, Hirase H, Niikura T, Lee SY, Sakurai A, Oe K, Sasaki T. Proposal of new classification of femoral trochanteric fracture by three-dimensional computed tomography and relationship to usual plain X-ray classification. J Orthop Surg (Hong Kong). 25(1):2309499017692700, 2017

(4) Niikura T, Lee SY, Iwakura T, Sakai Y, Kuroda R, Kurosaka M. Antibiotic-impregnated calcium phosphate cement as part of a comprehensive treatment for patients with established orthopaedic infection. J Orthop Sci. 21(4):539-45, 2016

(5) Takahara S, Niikura T, Lee SY, Iwakura T, Okumachi E, Kuroda R, Kurosaka M. Human pseudoarthrosis tissue contains cells with osteogenic potential. Injury. 47(6):1184-90, 2016

(6) Waki T, Lee SY, Niikura T, Iwakura T, Dogaki Y, Okumachi E, Oe K, Kuroda R, Kurosaka M. Profiling microRNA expression during fracture healing. BMC Musculoskelet Disord. 16;17:83, 2016

(7) Dogaki Y, Lee SY, Niikura T, Koga T, Okumachi E, Nishida K, Kuroda R, Kurosaka M. Effects of parathyroid hormone 1-34 on osteogenic and chondrogenic differentiation of human fracture haematoma-derived cells in vitro. J Tissue Eng Regen Med. 10(10):E365-E371, 2016

(8) Waki T, Lee SY, Niikura T, Iwakura T, Dogaki Y, Okumachi E, Kuroda R, Kurosaka M. Profiling microRNA expression in fracture nonunions: Potential role of microRNAs in nonunion formation studied in a rat model. Bone Joint J 97-B(8):1144-51, 2015

(9) Okumachi E, Lee SY, Niikura T, Iwakura T, Dogaki Y, Waki T, Takahara S, Ueha T, Sakai Y, Kuroda R, Kurosaka M. Comparative analysis of rat mesenchymal stem cells derived from slow and fast skeletal muscle in vitro. Int Orthop 39(3):569-76, 2015

(10) Chinzei N, Hiranaka T, Niikura T, Tsuji M, Kuroda R, Doita M, Kurosaka M. Comparison of the Sliding and Femoral Head Rotation among Three Different Femoral Head Fixation Devices for Trochanteric Fractures. Clin Orthop Surg 7(3):291-7, 2015

(11) Chinzei N, Hiranaka T, Niikura T, Fujishiro T, Hayashi S, Kanzaki N, Hashimoto S, Sakai Y, Kuroda R, Kurosaka M. Accurate and Easy Measurement of Sliding Distance of Intramedullary Nail in Trochanteric Fracture. Clin Orthop Surg 7(2):152-7, 2015

(12) Niikura T, Sakai Y, Lee SY, Iwakura T, Kuroda R, Kurosaka M. Rate of venous thromboembolism after complex lower-limb fracture surgery without pharmacological prophylaxis. J Orthop Surg (Hong Kong) 23(1):37-40, 2015

(13) Niikura T, Sakai Y, Lee SY, Iwakura T, Nishida K, Kuroda R, Kurosaka M. D-dimer levels to screen for venous thromboembolism in patients with fractures caused by high-energy injuries. J Orthop Sci 20(4):682-8, 2015

(14) Sakata R, Iwakura T, Reddi AH. Regeneration of Articular Cartilage Surface: Morphogens, Cells, and Extracellular Matrix Scaffolds. Tissue Eng Part B Rev 21(5):461-73, 2015

(15) Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Outcome of fixation for nonunion of extremities. J Orthop Surg (Hong Kong) 22(3):309-12, 2014

(16) Koga T, Niikura T, Lee SY, Okumachi E, Ueha T, Iwakura T, Sakai Y, Miwa M, Kuroda R, Kurosaka M. Topical Cutaneous CO2 Application by Means of a Novel Hydrogel Accelerates Fracture Repair in Rats. J Bone Joint Surg Am 17;96(24):2077-84, 2014

(17) Niikura T, Sakurai A, Oe K, Shibanuma N, Tsunoda M, Maruo A, Shoda E, Lee SY, Sakai Y, Kurosaka M. Clinical and radiological results of locking plate fixation for periprosthetic femoral fractures around hip arthroplasties: a retrospective multi-center study. J Orthop Sci 19(6):984-90, 2014

(18) Dogaki Y, Lee SY, Niikura T, Iwakura T, Okumachi E, Waki T, Kakutani K, Nishida K, Kuroda R, Kurosaka M. Efficient derivation of osteoprogenitor cells from induced pluripotent stem cells for bone regeneration. Int Orthop 38(9):1779-85, 2014

(19) Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Treatment results of a periprosthetic femoral fracture case series: treatment method for vancouver type b2 fractures can be customized. Clin Orthop Surg 6(2):138-45, 2014

(20) Niikura T, Sugimoto M, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Tactile surgical navigation system for complex acetabular fracture surgery. Orthopedics 37(4):237-42, 2014

(21) Imai Y, Hasegawa T, Takeda D, Akashi M, Lee SY, Niikura T, Shibuya Y, Kurosaka M, Komori T. The osteogenic activity of human mandibular fracture haematoma-derived cells is stimulated by low-intensity pulsed ultrasound in vitro. Int J Oral Maxillofac Surg 43(3):367-72, 2014

(22) Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Comparison of radiographic appearance and bone scintigraphy in fracture nonunions. Orthopedics 37(1):e44-50, 2014

(23) Kuroda R, Matsumoto T, Niikura T, Kawakami Y, Fukui T, Lee SY, Mifune Y, Kawamata S, Fukushima M, Asahara T, Kawamoto A, Kurosaka M. Local transplantation of granulocyte colony stimulating factor-mobilized CD34+ cells for patients with femoral and tibial nonunion: pilot clinical trial. Stem Cells Transl Med 3(1):128-34, 2014

(24) Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Causative factors of fracture nonunion: the proportions of mechanical, biological, patient-dependent, and patient-independent factors. J Orthop Sci 19(1):120-4, 2014

(25) Iwakura T, Sakata R, Reddi AH. Induction of chondrogenesis and expression of superficial zone protein in synovial explants with TGF-β1 and BMP-7. Tissue Eng Part A 19(23-24):2638-44, 2013

(26) Koga T, Lee SY, Niikura T, Koh A, Dogaki Y, Okumachi E, Akisue T, Kuroda R, Kurosaka M. Effect of low-intensity pulsed ultrasound on bone morphogenetic protein 7-induced osteogenic differentiation of human nonunion tissue-derived cells in vitro. J Ultrasound Med 32(6):915-22, 2013

(27) Iwakura T, Lee SY, Miwa M, Sakai Y, Niikura T, Oe K, Matsumoto T, Kuroda R, Kurosaka M. Analysis of circulating mesenchymal progenitor cells in arterial and venous blood after fracture. J Tissue Eng Regen Med 7(6):501-4, 2013

(28) Koga T, Niikura T, Lee SY, Dogaki Y, Okumachi E, Nishida K, Kuroda R, Kurosaka M. In vitro hypertrophy and calcification of human fracture haematoma-derived cells in chondrogenic differentiation. Int Orthop 37(5):961-7, 2013

(29) Iwakura T, Inui A, Reddi AH. Stimulation of superficial zone protein accumulation by hedgehog and Wnt signaling in surface zone bovine articular chondrocytes. Arthritis Rheum 65(2):408-17, 2013

(30) Lee SY, Koh A, Niikura T, Oe K, Koga T, Dogaki Y, Kurosaka M. Low-intensity pulsed ultrasound enhances BMP-7-induced osteogenic differentiation of human fracture hematoma-derived progenitor cells in vitro. J Orthop Trauma 27(1):29-33, 2013

(31) Inui A, Iwakura T, Reddi AH. Human stem cells and articular cartilage regeneration. Cells 1(4):994-1009, 2012

(32) Niikura T, Lee SY, Oe K, Koh A, Koga T, Dogaki Y, Okumachi E, Sakai Y, Akisue T, Kuroda R, Kurosaka M. Incidence of venous thromboembolism in fractures around and below the knee with physical prophylaxis. Orthopedics 35(10):e1476-82, 2012

(33) Niikura T, Lee SY, Oe K, Koh A, Koga T, Dogaki Y, Okumachi E, Kurosaka M. Venous thromboembolism in Japanese patients with fractures of the pelvis and/or lower extremities using physical prophylaxis alone. J Orthop Surg (Hong Kong) 20(2):196-200, 2012

(34) Niikura T, Miwa M, Lee SY, Oe K, Iwakura T, Sakai Y, Koh A, Koga T, Dogaki Y, Okumachi E, Kurosaka M. Technique to prepare the bed for autologous bone grafting in nonunion surgery. Orthopedics 35(6):491-5, 2012

(35) Niikura T, Lee SY, Oe K, Koh A, Koga T, Dogaki Y, Okumachi E, Kurosaka M. Incidence of venous thromboembolism in pelvic and acetabular fractures in the Japanese population. J Orthop Sci 17:233-8, 2012

(36) Hasegawa T, Miwa M, Sakai Y, Niikura T, Lee SY, Oe K, Iwakura T, Kurosaka M, Komori T. Mandibular hematoma cells as a potential reservoir for osteoprogenitor cells in fractures. J Oral Maxillofac Surg 70(3):599-607, 2012

(37) Sakai Y, Miwa M, Oe K, Ueha T, Koh A, Niikura T, Iwakura T, Lee SY, Tanaka M, Kurosaka M. A novel system for transcutaneous application of carbon dioxide causing an "artificial bohr effect" in the human body. PLoS One 6:e24137, 2011

(38) Koh A, Niikura T, Lee SY, Oe K, Koga T, Dogaki Y, Kurosaka M. Differential gene expression and immunolocalization of insulin-like growth factors and insulin-like growth factor binding proteins between experimental nonunions and standard healing fractures. J Orthop Res 29:1820-6, 2011

(39) Oe K, Ueha T, Sakai Y, Niikura T, Lee SY, Koh A, Hasegawa T, Tanaka M, Miwa M, Kurosaka M. The effect of transcutaneous application of carbon dioxide (CO2) on skeletal muscle. Biochem Biophys Res Commun 407:148-52, 2011


Case Report

(1) Lee SY, Niikura T, Iwakura T, Kuroda R, Kurosaka M. Treatment of ununited femoral neck fractures in young adults using low-intensity pulsed ultrasound: Report of 2 cases. Int J Surg Case Rep. 21:59-62, 2016

(2) Niikura T, Lee SY, Sakai Y, Kuroda R, Kurosaka M. Rare non-traumatic periprosthetic femoral fracture with features of an atypical femoral fracture: a case report. J Med Case Rep 6;9:103, 2015

(3) Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Retrograde intramedullary nailing for the treatment of femoral medial condyle fracture nonunion. Strategies Trauma Limb Reconstr 10(2):117-22, 2015

(4) Iwakura T, Lee SY, Niikura T, Miwa M, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Gentamycin-impregnated calcium phosphate cement for calcaneal osteomyelitis: a case report. J Orthop Surg (Hong Kong) 22(3):437-9, 2014

(5) Lee SY, Niikura T, Iwakura T, Sakai Y, Kuroda R, Kurosaka M. Bicondylar hoffa fracture successfully treated with headless compression screws. Case Rep Orthop 139897, 2014.

(6) Lee SY, Niikura T, Iwakura T, Kurosaka M. Traumatic subchondral fracture of the femoral head in a healed trochanteric fracture. BMJ Case Rep bcr2014205161, 2014

(7) Lee SY, Niikura T, Iwakura T, Sakai Y, Kuroda R, Kurosaka M. Complete traumatic backout of the blade of proximal femoral nail antirotation: a case report. Orthop Traumatol Surg Res 100(4):441-3, 2014

(8) Takahara S, Oe K, Fujita H, Sakurai A, Iwakura T, Lee SY, Niikura T, Kuroda R, Kurosaka M. Missed massive morel-lavallee lesion. Case Rep Orthop 920317, 2014.

(9) Iwakura T, Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Breakage of a third generation gamma nail: a case report and review of the literature. Case Rep Orthop 172352, 2013.

(10) Lee SY, Niikura T, Sakai Y, Miwa M, Nishida K, Kuroda R, Kurosaka M. Sacral Fracture Nonunion Treated by Bone Grafting through a Posterior Approach. Case Rep Orthop 932521, 2013

(11) Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Nonunion with breakage of gamma nail and subsequent fracture in the ipsilateral femur. Case Rep Med 534570, 2013

(12) Niikura T, Lee SY, Sakai Y, Nishida K, Kuroda R, Kurosaka M. Radiation-associated fracture nonunion of the clavicle treated with locking plate fixation and autologous bone grafting. Case Rep Med 407349, 2012

(13) Niikura T, Lee SY, Matsumoto T, Fukui T, Kawakami Y, Akisue T, Kuroda R, Kurosaka M. Backout of the helical blade of proximal femoral nail antirotation and accompanying fracture nonunion. Orthopaedics 35:e1264-6, 2012

(14) Lee SY, Niikura T, Miwa M, Sakai Y, Oe K, Fukazawa T, Kawakami Y, Kurosaka M. Negative pressure wound therapy for the treatment of infected wounds with exposed knee joint after patellar fracture: a case report. Orthopedics 14;34(6):2011

(15) Kuroda R, Matsumoto T, Miwa M, Kawamoto A, Mifune Y, Fukui T, Kawakami Y, Niikura T, Lee SY, Oe K, Shoji T, Kuroda T, Horii M, Yokoyama A, Ono T, Koibuchi Y, Kawamata S, Fukushima M, Kurosaka M, Asahara T. Local transplantation of G-CSF-mobilized CD34+ cells in a patient with tibial nonunion: a case report. Cell Transplant. 2011;20(9):1491-6

 
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