|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.
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
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.
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
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.
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
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
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
(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.
|Trauma Division /
(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,
(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,
(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,
(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,
(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
(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
(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
(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,
(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
(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
(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,
(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)
(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,
(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
(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
(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.