Publications by authors named "Kwok-Sui Leung"

82 Publications

Fibrinolysis as a target to enhance osteoporotic fracture healing by vibration therapy in a metaphyseal fracture model.

Bone Joint Res 2021 Jan;10(1):41-50

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong.

Aims: Fibrinolysis plays a key transition step from haematoma formation to angiogenesis and fracture healing. Low-magnitude high-frequency vibration (LMHFV) is a non-invasive biophysical modality proven to enhance fibrinolytic factors. This study investigates the effect of LMHFV on fibrinolysis in a clinically relevant animal model to accelerate osteoporotic fracture healing.

Methods: A total of 144 rats were randomized to four groups: sham control; sham and LMHFV; ovariectomized (OVX); and ovariectomized and LMHFV (OVX-VT). Fibrinolytic potential was evaluated by quantifying fibrin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) along with healing outcomes at three days, one week, two weeks, and six weeks post-fracture.

Results: All rats achieved healing, and x-ray relative radiopacity for OVX-VT was significantly higher compared to OVX at week 2. Martius Scarlet Blue (MSB) staining revealed a significant decrease of fibrin content in the callus in OVX-VT compared with OVX on day 3 (p = 0.020). Mean tPA from muscle was significantly higher for OVX-VT compared to OVX (p = 0.020) on day 3. Mechanical testing revealed the mean energy to failure was significantly higher for OVX-VT at 37.6 N mm (SD 8.4) and 71.9 N mm (SD 30.7) compared with OVX at 5.76 N mm (SD 7.1) (p = 0.010) and 17.7 N mm (SD 11.5) (p = 0.030) at week 2 and week 6, respectively.

Conclusion: Metaphyseal fracture healing is enhanced by LMHFV, and one of the important molecular pathways it acts on is fibrinolysis. LMHFV is a promising intervention for osteoporotic metaphyseal fracture healing. The improved mechanical properties, acceleration of fracture healing, and safety justify its role into translation to future clinical studies. Cite this article:  2021;10(1):41-50.
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http://dx.doi.org/10.1302/2046-3758.101.BJR-2020-0185.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845465PMC
January 2021

Vibration and β-hydroxy-β-methylbutyrate treatment suppresses intramuscular fat infiltration and adipogenic differentiation in sarcopenic mice.

J Cachexia Sarcopenia Muscle 2020 04 28;11(2):564-577. Epub 2020 Jan 28.

Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, The People's Republic of China.

Background: Sarcopenia is an aging-induced deterioration of skeletal muscle mass and function. Low-magnitude high-frequency vibration (LMHFV) was shown to improve muscle functions and β-hydroxy-β-methylbutyrate (HMB) to increase muscle mass and strength. Muscle-derived stem cells (MDSCs) are progenitor cells important for muscle regeneration. We hypothesized that LMHFV and HMB could retard sarcopenia by reducing fat infiltration through inhibiting adipogenesis in MDSCs.

Methods: Senescence-accelerated mouse P8 male mice were randomized into control (CTL), HMB, LMHFV (VIB), and combined (COM) groups. Interventions started at age of month 7 and assessed at 1, 2, and 3 months post-intervention by densitometry, histology, and functional tests. In vitro, MDSCs isolated from gastrocnemius of senescence-accelerated mouse P8 mice were characterized, randomized into CTL, VIB, HMB, and COM groups, and assessed by oil red O staining, mRNA, and protein expression.

Results: At 2 months post-intervention, percentage lean mass of HMB, VIB, and COM groups were significantly higher than CTL group. Twitch, tetanic, and specific tetanic forces of COM group were higher, while specific twitch force of both VIB and COM groups were higher. Grip strength of HMB, VIB, and COM groups were higher. Histologically, both VIB and COM groups presented lower oil red O area than CTL group. Type I muscle fibre in CTL group was higher than HMB, VIB, and COM groups. MDSC were detected in situ by immunofluorescence stain with stem cell antigen-1 signals confirmed with higher β-catenin expression in the COM group. The observations were also confirmed in vitro, MDSCs in the HMB, VIB, and COM groups presented lower adipogenesis vs. the CTL group. β-Catenin mRNA and protein expressions were lower in the CTL group while their relationship was further validated through β-catenin knock-down approach.

Conclusions: Our results showed that combined LMHFV and HMB interventions enhanced muscle strength and decreased percentage fat mass and intramuscular fat infiltration as compared with either treatment alone. Additive effect of LMHFV and HMB was demonstrated in β-catenin expression than either treatment in MDSCs and altered cell fate from adipogenesis to myogenesis, leading to inhibition of intramuscular lipid accumulation. Wnt/β-catenin signalling pathway was found to be the predominant regulatory mechanism through which LMHFV and HMB combined treatment suppressed MDSCs adipogenesis.
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http://dx.doi.org/10.1002/jcsm.12535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113529PMC
April 2020

One-year mortality in displaced intracapsular hip fractures and associated risk: a report of Chinese-based fragility fracture registry.

J Orthop Surg Res 2018 Sep 14;13(1):235. Epub 2018 Sep 14.

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, 5/F, Clinical Sciences Building, Shatin, New Territories, Hong Kong, SAR, China.

Background: The purpose of this registry-based retrospective study was to investigate the risk factors related to one-year mortality in displaced intracapsular fragility hip fracture patients.

Methods: Patients were screened from the Fragility Fracture Registry. Inclusion criterion was displaced intracapsular hip fracture patients with atypical or pathological fractures excluded. One-year mortality was investigated against risk factors including age, gender, past medical history, pre-fracture mobility (PFM), pre-operation ASA grade, delayed surgery over 48 h, post-surgical complications, and length of stay at acute orthopedic ward (LOS).

Results: A total of 1050 patients were included for further analysis. Gross one-year mortality was 14.9%. One-year mortality was significantly higher in patients who received non-operative treatment and those who received surgery but delayed over 48 h after admission (both p <  0.001). Male gender (OR = 2.708), advanced age (OR = 1.359), higher risk ASA grades (III to V) (OR = 1.990), past history of gastrointestinal disease (OR = 1.671), and renal impairment (OR = 1.984) were related to higher one-year mortality. The mortality of patients in PFM grade 3 and LOS group 3 was significantly higher (OR = 2.240 and 1.722, respectively).

Conclusions: Higher age, male gender, past gastrointestinal disease and renal impairment, ASA grade over 3, indoor confined pre-fracture ambulatory, and stay at hospital over 15 days were risk factors related to higher one-year mortality in surgically treated displaced intracapsular hip fracture patients. A multi-disciplinary approach is advised to patients identified with these risks factors and co-managed by orthopedic surgeons, geriatricians, and fracture liaison nurses.
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http://dx.doi.org/10.1186/s13018-018-0936-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137732PMC
September 2018

Ultrasound as a stimulus for musculoskeletal disorders.

J Orthop Translat 2017 Apr 5;9:52-59. Epub 2017 Apr 5.

Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.

Ultrasound is an inaudible form of acoustic sound wave at 20 kHz or above that is widely used in the medical field with applications including medical imaging and therapeutic stimulation. In therapeutic ultrasound, low-intensity pulsed ultrasound (LIPUS) is the most widely used and studied form that generally uses acoustic waves at an intensity of 30 mW/cm, with 200 ms pulses and 1.5 MHz. In orthopaedic applications, it is used as a biophysical stimulus for musculoskeletal tissue repair to enhance tissue regeneration. LIPUS has been shown to enhance fracture healing by shortening the time to heal and reestablishment of mechanical properties through enhancing different phases of the healing process, including the inflammatory phase, callus formation, and callus remodelling phase. Reports from studies reveal insights in the mechanism through which acoustic stimulations activate cell surface integrins that, in turn, activate various mechanical transduction pathways including FAK (focal adhesion kinase), ERK (extracellular signal-regulated kinase), PI3K, and Akt. It is then followed by the production of cyclooxygenase 2 and prostaglandin E2 to stimulate further downstream angiogenic, osteogenic, and chondrogenic cytokines, explaining the different enhancements observed in animal and clinical studies. Furthermore, LIPUS has also been shown to have remarkable effects on mesenchymal stem cells (MSCs) in musculoskeletal injuries and tissue regeneration. The recruitment of MSCs to injury sites by LIPUS requires the SDF-1 (stromal cell derived factor-1)/CXCR-4 signalling axis. MSCs would then differentiate differently, and this is regulated by the presence of different cytokines, which determines their fates. Other musculoskeletal applications including bone-tendon junction healing, and distraction osteogenesis are also explored, and the results are promising. However, the use of LIPUS is controversial in treating osteoporosis, with negative findings in clinical settings, which may be attributable to the absence of an injury entry point for the acoustic signal to propagate, strong attenuation effect of cortical bone and the insufficient intensity for penetration, whereas in some animal studies it has proven effective.
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http://dx.doi.org/10.1016/j.jot.2017.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822964PMC
April 2017

Inflammation and age-associated skeletal muscle deterioration (sarcopaenia).

J Orthop Translat 2017 Jul 3;10:94-101. Epub 2017 Jun 3.

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.

Ageing is accompanied by chronic inflammatory responses due to elevated circulatory inflammatory cytokine production. Several inflammatory cytokines have been shown to be responsible for a decrease in muscle mass. However, little is known about the possible relationship between inflammation and sarcopaenia. This review aims to summarise the existing evidence about inflammation and sarcopaenia. Sarcopaenia is defined as an age-related decrease of muscle mass and/or muscle strength; it is caused by multiple factors, such as skeletal muscle atrophy, neuromuscular junction degeneration, hormone imbalance, cytokine imbalance, protein synthesis and proteolysis. Several inflammatory cytokines have been considered to promote muscle loss; C-reactive protein levels are significantly upregulated in sarcopaenia and sarcopenic obesity, and high levels of interleukin-6 are associated with reduced muscle mass and muscle strength (the administration of interleukin-6 could lead to a reduction in muscle mass). Up-regulation of tumour necrosis factor-α expression is also related to the development of sarcopaenia. Signalling pathways, such as protein kinase B/mammalian target of rapamycin, Janus kinase/signal transducer and activator of transcription-5 and signal transducer and activator of transcription 3 signalling, involved in muscle metabolism are regulated by insulin-like growth factor-1, tumour necrosis factor-α and interleukin-6 respectively. In conclusion, the inflammatory cytokines produced during chronic inflammation due to ageing, may influence their respective related pathways, thus leading to age-related muscle deterioration.

The Translational Potential Of This Article: This review can provide more information for sarcopaenia medicine research in terms of anti-inflammation therapy.
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http://dx.doi.org/10.1016/j.jot.2017.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822997PMC
July 2017

Evaluation of a multidisciplinary rehabilitation programme for elderly patients with hip fracture: A prospective cohort study.

J Rehabil Med 2018 Feb;50(3):285-291

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, N/A Hong Kong, Hong Kong.

Objective: To investigate the effectiveness and cost of an 18-month multi-disciplinary Comprehensive Fragility Fracture Management Program (CFFMP) for fragility hip fracture patients.

Design: Prospective cohort study.

Patients: Elderly patients with hip fracture were recruited at their first postoperative follow-up in 2 district hospitals. The intervention group comprised patients from the hospital undergoing CFFMP, and the control group comprised patients from another hospital undergoing conventional care. CFFMP provided geri-orthopaedic co-management, physician consultations, group-exercise and vibration-therapy. Timed-up-and-go test (TUG), Elderly Mobility Scale (EMS), Berg Balance Scale (BBS) and fall risk screening (FS) were used to assess functional performance. Incidences of falls and secondary fractures, the cost of the programme and related healthcare resources were recorded.

Results: A total of 76 patients were included in the intervention group (mean age 77.9 years ((standard deviation; SD) 6.1) ) and 77 in the control group (79.9 (SD 7.2)), respectively. The re-fracture rate in the control group (10.39%) was significantly higher than in the intervention group (1.32%) (p = 0.034). The intervention group improved significantly in TUG, EMS and FS after a 1-year programme. The overall healthcare costs per patient in the intervention and control groups were US$22,450 and US$25,313, respectively.

Conclusion: Multi-disciplinary CFFMP is effective, with reduced overall cost, reduced length of hospital stay and reduced secondary fracture rate. The rehabilitation community service favours rehabilitation and improved quality of life of hip fracture patients.
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http://dx.doi.org/10.2340/16501977-2310DOI Listing
February 2018

Low-Magnitude High-Frequency Vibration Accelerated the Foot Wound Healing of n5-streptozotocin-induced Diabetic Rats by Enhancing Glucose Transporter 4 and Blood Microcirculation.

Sci Rep 2017 09 14;7(1):11631. Epub 2017 Sep 14.

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.

Delayed wound healing is a Type 2 diabetes mellitus (DM) complication caused by hyperglycemia, systemic inflammation, and decreased blood microcirculation. Skeletal muscles are also affected by hyperglycemia, resulting in reduced blood flow and glucose uptake. Low Magnitude High Frequency Vibration (LMHFV) has been proven to be beneficial to muscle contractility and blood microcirculation. We hypothesized that LMHFV could accelerate the wound healing of n5-streptozotocin (n5-STZ)-induced DM rats by enhancing muscle activity and blood microcirculation. This study investigated the effects of LMHFV in an open foot wound created on the footpad of n5-STZ-induced DM rats (DM_V), compared with no-treatment DM (DM), non-DM vibration (Ctrl_V) and non-DM control rats (Ctrl) on Days 1, 4, 8 and 13. Results showed that the foot wounds of DM_V and Ctrl_V rats were significantly reduced in size compared to DM and Ctrl rats, respectively, at Day 13. The blood glucose level of DM_V rats was significantly reduced, while the glucose transporter 4 (GLUT4) expression and blood microcirculation of DM_V rats were significantly enhanced in comparison to those of DM rats. In conclusion, LMHFV can accelerate the foot wound healing process of n5-STZ rats.
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http://dx.doi.org/10.1038/s41598-017-11934-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599683PMC
September 2017

An animal model of co-existing sarcopenia and osteoporotic fracture in senescence accelerated mouse prone 8 (SAMP8).

Exp Gerontol 2017 10 12;97:1-8. Epub 2017 Jul 12.

Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China. Electronic address:

Sarcopenia and osteoporotic fracture are common aging-related musculoskeletal problems. Recent evidences report that osteoporotic fracture patients showed high prevalence of sarcopenia; however, current clinical practice basically does not consider sarcopenia in the treatment or rehabilitation of osteoporotic fracture. There is almost no report studying the relationship of the co-existing of sarcopenia and osteoporotic fracture healing. In this study, we validated aged senescence accelerated mouse prone 8 (SAMP8) and senescence accelerated mouse resistant 1 (SAMR1) as animal models of senile osteoporosis with/without sarcopenia. Bone mineral density (BMD) at the 5th lumbar and muscle testing of the two animal strains were measured to confirm the status of osteoporosis and sarcopenia, respectively. Closed fracture was created on the right femur of 8-month-old animals. Radiographs were taken weekly post-fracture. MicroCT and histology of the fractured femur were performed at week 2, 4 and 6 post-fracture, while mechanical test of both femora at week 4 and 6 post-fracture. Results showed that the callus of SAMR1 was significantly larger at week 2 but smaller at week 6 post-fracture than SAMP8. Mechanical properties were significantly better at week 4 post-fracture in SAMR1 than SAMP8, indicating osteoporotic fracture healing was delayed in sarcopenic SAMP8. This study validated an animal model of co-existing sarcopenia and osteoporotic fracture, where a delayed fracture healing might be resulted in the presence of sarcopenia.
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http://dx.doi.org/10.1016/j.exger.2017.07.008DOI Listing
October 2017

The characterization of a full-thickness excision open foot wound model in n5-streptozotocin (STZ)-induced type 2 diabetic rats that mimics diabetic foot ulcer in terms of reduced blood circulation, higher C-reactive protein, elevated inflammation, and reduced cell proliferation.

Exp Anim 2017 Aug 11;66(3):259-269. Epub 2017 Apr 11.

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, 30-32 Ngan Shing Street, Shatin, Hong Kong, P.R. China.

Delayed foot wound healing is a major complication attributed to hyperglycemia in type 2 diabetes mellitus (DM) patients, and these wounds may develop into foot ulcers. There are at least two types of DM wound models used in rodents to study delayed wound healing. However, clinically relevant animal models are not common. Most models use type 1 DM rodents or wounds created on the back rather than on the foot. An open full-thickness excision wound on the footpad of type 2 DM rats is more clinically relevant, but such a model has not yet been characterized systematically. The objective of this study was to investigate and characterize how DM affected a full-thickness excision open foot wound in n5-streptozotocin (n5-STZ)-induced type 2 DM rats. We hypothesized that elevated inflammation, reduced blood circulation, and cell proliferation due to hyperglycemia could delay the wound healing of DM rats. The wounds of DM rats were compared with those of non-DM rats (Ctrl) at Days 1 and 8 post wounding. The wound healing process of the DM rats was significantly delayed compared with that of the Ctrl rats. The DM rats also had higher C-reactive protein (CRP) and lower blood circulation and proliferating cell nuclear antigen (PCNA) in DM wounds. This confirmed that elevated inflammation and reduced blood flow and cell proliferation delayed foot wound healing in the n5-STZ rats. Hence, this open foot wound animal model provides a good approach to study the process of delayed wound healing.
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http://dx.doi.org/10.1538/expanim.17-0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543247PMC
August 2017

Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial.

BMJ 2016 Oct 25;355:i5351. Epub 2016 Oct 25.

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, L8S 4K1, Canada.

Objective:  To determine whether low intensity pulsed ultrasound (LIPUS), compared with sham treatment, accelerates functional recovery and radiographic healing in patients with operatively managed tibial fractures.

Design:  A concealed, randomized, blinded, sham controlled clinical trial with a parallel group design of 501 patients, enrolled between October 2008 and September 2012, and followed for one year.

Setting:  43 North American academic trauma centers.

Participants:  Skeletally mature men or women with an open or closed tibial fracture amenable to intramedullary nail fixation. Exclusions comprised pilon fractures, tibial shaft fractures that extended into the joint and required reduction, pathological fractures, bilateral tibial fractures, segmental fractures, spiral fractures >7.5 cm in length, concomitant injuries that were likely to impair function for at least as long as the patient's tibial fracture, and tibial fractures that showed <25% cortical contact and >1 cm gap after surgical fixation. 3105 consecutive patients who underwent intramedullary nailing for tibial fracture were assessed, 599 were eligible and 501 provided informed consent and were enrolled.

Interventions:  Patients were allocated centrally to self administer daily LIPUS (n=250) or use a sham device (n=251) until their tibial fracture showed radiographic healing or until one year after intramedullary fixation.

Main Outcome Measures:  Primary registry specified outcome was time to radiographic healing within one year of fixation; secondary outcome was rate of non-union. Additional protocol specified outcomes included short form-36 (SF-36) physical component summary (PCS) scores, return to work, return to household activities, return to ≥80% of function before injury, return to leisure activities, time to full weight bearing, scores on the health utilities index (mark 3), and adverse events related to the device.

Results:  SF-36 PCS data were acquired from 481/501 (96%) patients, for whom we had 2303/2886 (80%) observations, and radiographic healing data were acquired from 482/501 (96%) patients, of whom 82 were censored. Results showed no impact on SF-36 PCS scores between LIPUS and control groups (mean difference 0.55, 95% confidence interval -0.75 to 1.84; P=0.41) or for the interaction between time and treatment (P=0.30); minimal important difference is 3-5 points) or in other functional measures. There was also no difference in time to radiographic healing (hazard ratio 1.07, 95% confidence interval 0.86 to 1.34; P=0.55). There were no differences in safety outcomes between treatment groups. Patient compliance was moderate; 73% of patients administered ≥50% of all recommended treatments.

Conclusions:  Postoperative use of LIPUS after tibial fracture fixation does not accelerate radiographic healing and fails to improve functional recovery.Study registration ClinicalTrialGov Identifier: NCT00667849.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080447PMC
http://dx.doi.org/10.1136/bmj.i5351DOI Listing
October 2016

Value of Measuring Bone Microarchitecture in Fracture Discrimination in Older Women with Recent Hip Fracture: A Case-control Study with HR-pQCT.

Sci Rep 2016 Sep 27;6:34185. Epub 2016 Sep 27.

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.

We aimed to determine whether loss of volumetric bone mineral density (vBMD) and deterioration of microarchitecture imaged by high-resolution peripheral quantitative computed tomography at the distal radius/tibia provided additional information in fracture discrimination in postmenopausal women with recent hip fracture. This case-control study involved 24 postmenopausal Chinese women with unilateral femoral neck fracture (average [SD] age: 79.6[5.6]) and 24 age-matched women without any history of fracture. Each SD decrease in T-score at femoral neck (FN) was associated with a higher fracture risk (odds ratio: 6.905, p = 0.001). At the distal radius, fracture women had significantly lower total vBMD (-17.5%), fewer (-20.3%) and more unevenly spaced (81.4%) trabeculae, and thinner cortices (-14.0%) (all p < 0.05). At the distal tibia, vBMD was on average -4.7% (cortical) to -25.4% (total) lower, trabecular microarchitecture was on average -19.8% (number) to 102% (inhomogeneity) inferior, cortices were thinner (-21.1%) and more porous (18.2%) (all p < 0.05). Adding parameters of vBMD and microarchitecture in multivariate models did not offer additional discriminative capacity of fracture status compared with using T-score at FN. In old postmenopausal women with already excessive loss of bone mass, measuring bone microarchitecture may provide limited added value to improve identification of risk of femoral neck fracture.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037450PMC
http://dx.doi.org/10.1038/srep34185DOI Listing
September 2016

Bone formation and degradation behavior of nanocrystalline hydroxyapatite with or without collagen-type 1 in osteoporotic bone defects - an experimental study in osteoporotic goats.

Injury 2016 Jun;47 Suppl 2:S58-65

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China.

The intention of the current work is to assess new bone formation and degradation behavior of nanocrystalline hydroxyapatite with (HA/col-1) or without collagen-type I (HA) in osteoporotic metaphyseal bone defects in goats. After ovariectomy and special low-calcium diet for three months, 3 drill hole defects in the vertebrae of L3, L4, L5, 4 drill hole defects in the right and left iliac crest and 1 drill hole defect at the distal femur were created in three Chinese mountain goats with a total of 24 defects. The defects were either filled with one of the biomaterials or left empty (empty defect control group). After 42 days, the animals were euthanized and the samples were assessed for new bone formation using high-resolution peripheral quantitative computed tomography (HR-pQCT) and histomorphometry with 2 regions of interest. Detail histology, enzymehistochemistry and immunohistochemistry as well as connexin-43 in situ hybridization and transmission electron microscopy were carried out for evaluation of degradation behavior of the materials and cellular responses of the surrounding tissue in respect to the implants. HR-pQCT showed the highest BV/TV ratio (p = 0.008) and smallest trabecular spacing (p = 0.005) for HA compared to the other groups in the region of interest at the interface with 1mm distance to the initially created defect. The HA/col-1 yielded the highest connectivity density (Conn.D) (p = 0.034) and the highest number of trabeculae (Tb.N) (p = 0.002) compared to the HA and the control group. Histomorphometric analysis for the core region of the initially created defect revealed a statistically higher new bone formation in the HA (p = 0.001) and HA/col-1 group (p = 0.001) compared to the empty defect group including all defect sites. This result was confirmed for site specific analysis with significant higher new bone formation for the HA group for vertebral defects compared to the empty defect group (p = 0.029). For the interface region, no statistically significant differences were found between the three groups (p = 0.08). Histology revealed a good biocompatibility without inflammatory reaction for the HA- and HA/col-1 implants with a higher fragmentation of the HA-implant compared to the HA/col-1 biomaterial and formation of new bone in the region between the biomaterial fragments by osteoblasts. Fragmentation was shown by transmission electron microscopy to be caused by multinuclear osteoclast-like cells with degradation of the implant via intracellular incorporation of degraded implant material particles. In conclusion, both nanoparticulate HA with and without collagen type-1 showed better new bone formation compared to untreated drill hole defects in metaphyseal regions of this osteoporotic Chinese mountain goat model with good biocompatibility.
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http://dx.doi.org/10.1016/S0020-1383(16)47010-5DOI Listing
June 2016

Housing design and testing of a surgical robot developed for orthopaedic surgery.

J Orthop Translat 2016 Apr 11;5:72-80. Epub 2016 Mar 11.

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, China.

Background/objective: Surgical technology has advanced rapidly with the introduction of robot technology. Apart from mechanical and electronic elements, housing design is an essential component that must be thoughtfully considered, bearing in mind the general requirements for medical devices used in operating theatres. The aim of this study was to design a modern and safe housing for a surgical robotic system for orthopaedic applications in Hong Kong that would meet the general requirements for obtaining local regulatory body approval.

Methods: Based on the general requirements for Class II Medical Devices, industrial product designers worked in close collaboration with a robot research team formed by engineers and orthopaedic surgeons to design a modern and safe housing for the HybriDot Surgical Robotic System that performs computer-assisted surgery.

Results: The design received local regulatory body approval for its application in operating theatres and was approved for orthopaedic surgery in Hong Kong after fulfilling the general requirements for safety, accuracy, movability and operability.

Conclusion: This project demonstrated a good model of multidisciplinary R&D of surgical robotics led by orthopaedic surgeons, in collaboration with mechanical and electronic engineers and industrial designers.
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http://dx.doi.org/10.1016/j.jot.2016.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987043PMC
April 2016

Ultrasound and fragility fracture: is there a role?

Injury 2016 Jan;47 Suppl 1:S39-42

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong.

Osteoporotic fracture is known to have impaired healing capacity and therefore takes longer time to heal, as compared with younger one. The mechanism of impaired osteoporotic fracture healing is multifactorial, where lower responsiveness to mechanical loading is generally believed to be one factor, yet not absolutely confirmed. In recent years, low intensity pulsed ultrasound (LIPUS) is demonstrated to have good efficacy in treating normal fracture healing, as proven by many randomized controlled trials, as well as in vitro and animal evidences. The effects of LIPUS on osteoporotic fracture healing was also validated in an animal study, which revealed that osteoporotic fractured bone of SD rats showed radiologically and biomechanically comparable responses to LIPUS as age-matched normal fracture healing, in terms of callus width, bridging rate, bone volume fraction, and stiffness etc. Gene expression profiling also confirmed that osteoporotic fractured bone responded to LIPUS very well by upregulating Col1 and BMP2 (osteogenesis) at early phase, VEGF (angiogenesis) at middle phase and RANKL (remodeling) at late phase. These confirm that osteoporotic bones respond well to LIPUS as good as normal bone. These findings may be associated with estrogen receptors (ERs), as estrogen depletion is sensed and relayed by ERs and ERs also function as mechano-sensors. A previous study observed a delayed ERs expression pattern in fracture callus of OVX rats, as compared with SHAM rats, which correlated well with the expression pattern of BMP-2 (callus formation-related gene). Hence, the responses of osteoporotic fractured bone to LIPUS may be related to the local ERs expression at fracture callus that needs further experiments to validate.
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http://dx.doi.org/10.1016/S0020-1383(16)30010-9DOI Listing
January 2016

Effect of Low-Magnitude, High-Frequency Vibration Treatment on Retardation of Sarcopenia: Senescence-Accelerated Mouse-P8 Model.

Rejuvenation Res 2016 Aug 19;19(4):293-302. Epub 2016 Feb 19.

1 Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong , Hong Kong SAR, China .

Sarcopenia-related falls and fall-related injuries in community-dwelling elderly people garnered more and more interest in recent years. Low-magnitude high-frequency vibration (LMHFV) was proven beneficial to musculoskeletal system and recommended for sarcopenia treatment. This study aimed to evaluate the effects of LMHFV on the sarcopenic animals and explore the mechanism of the stimulatory effects. Senescence-accelerated mouse P8 (SAMP8) mice at month 6 were randomized into control (Ctrl) and vibration (Vib) groups and the mice in the Vib group were given LMHFV (0.3 g, 20 min/day, 5 days/week) treatment. At months 0, 1, 2, 3, and 4 post-treatment, muscle mass, structure, and function were assessed. The potential proliferation capacity of the muscle was also evaluated by investigating satellite cells (SCs) pool and serum myostatin expression. At late stage, the mice in the Vib group showed higher muscle strength (month 4, p = 0.028). Generally, contractibility was significantly improved by LMHFV (contraction time [CT], p = 0.000; half-relaxation time [RT50], p = 0.000). Enlarged cross-sectional area of fiber type IIA was observed in the Vib group when compared with Ctrl group (p = 0.000). No significant difference of muscle mass was observed. The promotive effect of LMHFV on myoregeneration was reflected by suppressed SC pool reduction (month 3, p = 0.000; month 4, p = 0.000) and low myostatin expression (p = 0.052). LMHFV significantly improved the structural and functional outcomes of the skeletal muscle, hence retarding the progress of sarcopenia in SAMP8. It would be a good recommendation for prevention of the diseases related to skeletal muscle atrophy.
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http://dx.doi.org/10.1089/rej.2015.1759DOI Listing
August 2016

Muscle mass, structural and functional investigations of senescence-accelerated mouse P8 (SAMP8).

Exp Anim 2015 17;64(4):425-33. Epub 2015 Jul 17.

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, P.R. China.

Sarcopenia is an age-related systemic syndrome with progressive deterioration in skeletal muscle functions and loss in mass. Although the senescence-accelerated mouse P8 (SAMP8) was reported valid for muscular ageing research, there was no report on the details such as sarcopenia onset time. Therefore, this study was to investigate the change of muscle mass, structure and functions during the development of sarcopenia. Besides the average life span, muscle mass, structural and functional measurements were also studied. Male SAMP8 animals were examined at month 6, 7, 8, 9, and 10, in which the right gastrocnemius was isolated and tested for ex vivo contractile properties and fatigability while the contralateral one was harvested for muscle fiber cross-sectional area (FCSA) and typing assessments. Results showed that the peak of muscle mass appeared at month 7 and the onset of contractility decline was observed from month 8. Compared with month 8, most of the functional parameters at month 10 decreased significantly. Structurally, muscle fiber type IIA made up the largest proportion of the gastrocnemius, and the fiber size was found to peak at month 8. Based on the altered muscle mass, structural and functional outcomes, it was concluded that the onset of sarcopenia in SAMP8 animals was at month 8. SAMP8 animals at month 8 should be at pre-sarcopenia stage while month 10 at sarcopenia stage. It is confirmed that SAMP8 mouse can be used in sarcopenia research with established time line in this study.
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http://dx.doi.org/10.1538/expanim.15-0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637380PMC
June 2016

A Comparative Study on the Biomechanical and Histological Properties of Bone-to-Bone, Bone-to-Tendon, and Tendon-to-Tendon Healing: An Achilles Tendon-Calcaneus Model in Goats.

Am J Sports Med 2015 Jun 30;43(6):1413-21. Epub 2015 Mar 30.

Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China Translational Medicine Research and Development Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China

Background: Surgical repair around the bone-tendon insertion (BTI) may involve bone-to-bone (BB), bone-to-tendon (BT), or tendon-to-tendon (TT) reattachment with varying healing outcome.

Hypothesis: The repair of Achilles tendon-calcaneus (ATC) by reattachment of homogeneous tissue (BB or TT) would heal faster, with respect to tensile properties at the healing complex, than those of reattachment of heterogeneous tissues (BT) over time.

Study Design: Controlled laboratory study.

Methods: Forty-seven adolescent male Chinese goats were divided into BB, BT, and TT groups. Osteotomy of the calcaneus, reattachment of Achilles tendon to the calcaneus after removal of the insertion, and tenotomy of the Achilles tendon were performed to simulate BB, BT, and TT repair, respectively. The ATC healing complexes were harvested at 6, 12, or 24 weeks postoperatively. Mechanical and morphological properties of the healing ATC complexes were assessed by tensile testing and qualitative histology, respectively. The contralateral intact ATC complex was used as the control.

Results: Failure load of BT was 33.4% lower than that of TT (P = .0243) at week 12. Ultimate strength of BT was 50.2% and 45.3% lower than that of TT at weeks 12 (P = .0002) and 24 (P = .0001), respectively. Tissue morphological characteristics of the BB and TT groups showed faster remodeling. The BT group showed limited regeneration of fibrocartilage zone and excessive formation of fibrous tissue at the healing interface.

Conclusion: BTI repair between homogeneous tissues (BB and TT healing) showed better healing quality with respect to mechanical and histological assessments than did healing between heterogeneous tissues (BT healing).

Clinical Relevance: Anatomic reconstruction of ATC complex injury may be a primary concern when selecting the proper surgical approach. However, it is recommended to select fracture fixation (BB) or tendon repair (TT) instead of bone-tendon reattachment (BT) if possible to ensure better outcome at the healing interface.
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http://dx.doi.org/10.1177/0363546515576904DOI Listing
June 2015

Low intensity pulsed ultrasound enhanced mesenchymal stem cell recruitment through stromal derived factor-1 signaling in fracture healing.

PLoS One 2014 2;9(9):e106722. Epub 2014 Sep 2.

Department of Orthopaedics and Traumatology, Clinical Sciences Building, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Translational Medicine Research & Development Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.

Low intensity pulsed ultrasound (LIPUS) has been proven effective in promoting fracture healing but the underlying mechanisms are not fully depicted. We examined the effect of LIPUS on the recruitment of mesenchymal stem cells (MSCs) and the pivotal role of stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) pathway in response to LIPUS stimulation, which are essential factors in bone fracture healing. For in vitro study, isolated rat MSCs were divided into control or LIPUS group. LIPUS treatment was given 20 minutes/day at 37 °C for 3 days. Control group received sham LIPUS treatment. After treatment, intracellular CXCR4 mRNA, SDF-1 mRNA and secreted SDF-1 protein levels were quantified, and MSCs migration was evaluated with or without blocking SDF-1/CXCR4 pathway by AMD3100. For in vivo study, fractured 8-week-old young rats received intracardiac administration of MSCs were assigned to LIPUS treatment, LIPUS+AMD3100 treatment or vehicle control group. The migration of transplanted MSC to the fracture site was investigated by ex vivo fluorescent imaging. SDF-1 protein levels at fracture site and in serum were examined. Fracture healing parameters, including callus morphology, micro-architecture of the callus and biomechanical properties of the healing bone were investigated. The in vitro results showed that LIPUS upregulated SDF-1 and CXCR4 expressions in MSCs, and elevated SDF-1 protein level in the conditioned medium. MSCs migration was promoted by LIPUS and partially inhibited by AMD3100. In vivo study demonstrated that LIPUS promoted MSCs migration to the fracture site, which was associated with an increase of local and serum SDF-1 level, the changes in callus formation, and the improvement of callus microarchitecture and mechanical properties; whereas the blockade of SDF-1/CXCR4 signaling attenuated the LIPUS effects on the fractured bones. These results suggested SDF-1 mediated MSCs migration might be one of the crucial mechanisms through which LIPUS exerted influence on fracture healing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106722PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4152330PMC
November 2015

Low-magnitude high-frequency vibration enhances gene expression related to callus formation, mineralization and remodeling during osteoporotic fracture healing in rats.

J Orthop Res 2014 Dec 17;32(12):1572-9. Epub 2014 Aug 17.

Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China.

Low magnitude high frequency vibration (LMHFV) has been shown to improve anabolic and osteogenic responses in osteoporotic intact bones and during osteoporotic fracture healing; however, the molecular response of LMHFV during osteoporotic fracture healing has not been investigated. It was hypothesized that LMHFV could enhance osteoporotic fracture healing by regulating the expression of genes related to chondrogenesis (Col-2), osteogenesis (Col-1) and remodeling (receptor activator for nuclear factor- κ B ligand (RANKL) and osteoproteger (OPG)). In this study, the effects of LMHFV on both osteoporotic and normal bone fracture healing were assessed by endpoint gene expressions, weekly radiographs, and histomorphometry at weeks 2, 4 and 8 post-treatment. LMHFV enhanced osteoporotic fracture healing by up-regulating the expression of chondrogenesis-, osteogenesis- and remodeling-related genes (Col-2 at week 4 (p=0.008), Col-1 at week 2 and 8 (p<0.001 and p=0.008) and RANKL/OPG at week 8 (p=0.045)). Osteoporotic bone had a higher response to LMHFV than normal bone and showed significantly better results as reflected by increased expression of Col-2 and Col-1 at week 2 (p<0.001 for all), larger callus width at week 2 (p=0.001), callus area at week 1 and 5(p<0.05 for all) and greater relative area of osseous tissue (p=0.002) at week 8. This study helps to understand how LMHFV regulates gene expression of callus formation, mineralization and remodeling during osteoporotic fracture healing.
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http://dx.doi.org/10.1002/jor.22715DOI Listing
December 2014

Callus formation is related to the expression ratios of estrogen receptors-alpha and -beta in ovariectomy-induced osteoporotic fracture healing.

Arch Orthop Trauma Surg 2014 Oct 2;134(10):1405-16. Epub 2014 Aug 2.

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Introduction: This study characterizes ovariectomized (OVX)-induced osteoporotic fracture healing with focus on estrogen receptors (ERs). Callus formation plays a critical role in fracture healing, and ERs are well-known mechanosensors in osteogenic pathways. It was hypothesized that callus formation was related to and partially determined by the difference in expression patterns of ERs in both normal and OVX-induced osteoporotic fractures.

Methods: Closed femoral fracture in SHAM and ovariectomized rats were used in this study. Weekly callus width (CW) and area (CA), endpoint mechanical properties, gene expressions of Col-1, BMP-2, ER-α, ER-β and ER-α:ER-β ratios (ER-ratios), and correlations were assessed at 2, 4 and 8 weeks post-fracture.

Results: CW and CA results confirmed that OVX-induced osteoporotic fracture was delayed at 2-4 weeks with impaired endpoint mechanical properties. Gene expressions of ER-α and ER-β were higher in the SHAM group at week 2 (p < 0.05) and later lowered at week 8; whereas the OVX group showed an opposing trend. Moderate correlation existed between ER-α and BMP-2 (0.545, p = 0.003), and ER-ratio and BMP-2 (0.601, p = 0.001), and BMP-2 to CW and CA (r = 0.709, p = 0.000 and r = 0.588, p = 0.001, respectively). ER-α and ER-β proteins expressions were confirmed by immunohistochemistry at the fracture callus in reparative progenitor cells, osteoblasts- and osteoclasts-like cells.

Conclusion: We conclude that the delayed healing rate and impaired callus quality in OVX-induced osteoporotic fracture is related to the delayed expression of ERs. A high ER-α:ER-β ratio favors callus formation.
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http://dx.doi.org/10.1007/s00402-014-2070-0DOI Listing
October 2014

Trial to re-evaluate ultrasound in the treatment of tibial fractures (TRUST): a multicenter randomized pilot study.

Trials 2014 Jun 4;15:206. Epub 2014 Jun 4.

Department of Anesthesia, McMaster University, HSC-2U1, 1200 Main St, West, Hamilton, ON L8S 4 K1, Canada.

Background: The role of low-intensity pulsed ultrasound (LIPUS) in the management of fractures remains controversial. The purpose of this study was to assess the feasibility of a definitive trial to determine the effect of LIPUS on functional and clinical outcomes in tibial fractures managed operatively.

Methods: We conducted a multicenter, concealed, blinded randomized trial of 51 skeletally mature adults with operatively managed tibial fractures who were treated with either LIPUS or a sham device. All participating centers were located in Canada and site investigators were orthopedic surgeons specializing in trauma surgery. The goals of our pilot study were to determine recruitment rates in individual centers, investigators' ability to adhere to study protocol and data collection procedures, our ability to achieve close to 100% follow-up rates, and the degree to which patients were compliant with treatment. Patients were followed for one year and a committee (blinded to allocation) adjudicated all outcomes. The committee adjudicators were experienced (10 or more years in practice) orthopedic surgeons with formal research training, specializing in trauma surgery.

Results: Our overall rate of recruitment was approximately 0.8 patients per center per month and site investigators successfully adhered to the study protocol and procedures. Our rate of follow-up at one year was 84%. Patient compliance, measured by an internal timer in the study devices, revealed that 39 (76%) of the patients were fully compliant and 12 (24%) demonstrated a greater than 50% compliance. Based on patient feedback regarding excessive questionnaire burden, we conducted an analysis using data from another tibial fracture trial that revealed the Short Musculoskeletal Function Assessment (SMFA) dysfunction index offered no important advantages over the SF-36 Physical Component Summary (PCS) score. No device-related adverse events were reported.

Conclusions: Our pilot study identified key issues that might have rendered a definitive trial unfeasible. By modifying our protocol to address these challenges we have enhanced the feasibility of a definitive trial to explore the effect of LIPUS on tibial fracture healing.

Trial Registration: The TRUST definitive trial was registered at ClinicalTrials.gov on 21 April 2008 (identifier: NCT00667849).
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http://dx.doi.org/10.1186/1745-6215-15-206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060850PMC
June 2014

Osteocytes exposed to far field of therapeutic ultrasound promotes osteogenic cellular activities in pre-osteoblasts through soluble factors.

Ultrasonics 2014 Jul 11;54(5):1358-65. Epub 2014 Feb 11.

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China.

Low intensity pulsed ultrasound (LIPUS) was reported to accelerate the rate of fracture healing. When LIPUS is applied to fractures transcutaneously, bone tissues at different depths are exposed to different ultrasound fields. Measurement of LIPUS shows pressure variations in near field (nearby transducer); uniform profile was found beyond it (far field). Moreover, we have reported that the therapeutic effect of LIPUS is dependent on the axial distance of ultrasound beam in rat fracture model. However, the mechanisms of how different axial distances of LIPUS influence the mechanotransduction of bone cells are not understood. To understand the cellular mechanisms underlying far field LIPUS on enhanced fracture healing in rat model, the present study investigated the effect of ultrasound axial distances on (1) osteocyte, the mechanosensor, and (2) mechanotransduction between osteocyte and pre-osteoblast (bone-forming cell) through paracrine signaling. We hypothesized that far field LIPUS could enhance the osteogenic activities of osteoblasts via paracrine factors secreted from osteocytes. The objective of this study was to investigate the effect of axial distances of LIPUS on osteocytes and osteocyte-osteoblast mechanotransduction. In this study, LIPUS (plane; 2.2 cm in diameter, 1.5MHz sine wave, ISATA=30 mW/cm(2)) was applied to osteocytes (mechanosensor) at three axial distances: 0mm (near field), 60mm (mid-near field) and 130 mm (far field). The conditioned medium of osteocytes (OCM) collected from these three groups were used to culture pre-osteoblasts (effector cell). In this study, (1) the direct effect of ultrasound fields on the mechanosensitivity of osteocytes; and (2) the osteogenic effect of different OCM treatments on pre-osteoblasts were assessed. The immunostaining results indicated the ultrasound beam at far field resulted in more β-catenin nuclear translocation in osteocytes than all other groups. This indicated that osteocytes could detect the acoustic differences of LIPUS at various axial distances. Furthermore, we found that the soluble factors secreted by far field LIPUS exposed osteocytes could further promote pre-osteoblasts cell migration, maturation (transition of cell proliferation into osteogenic differentiation), and matrix calcification. In summary, our results of this present study indicated that axial distance beyond near field could transmit ultrasound energy to osteocyte more efficiently. The LIPUS exposed osteocytes conveyed mechanical signals to pre-osteoblasts and regulated their osteogenic cellular activities via paracrine factors secretion. The soluble factors secreted by far field exposed osteocytes led to promotion in migration and maturation in pre-osteoblasts. This finding demonstrated the positive effects of far field LIPUS on stimulating osteocytes and promoting mechanotransduction between osteocytes and osteoblasts.
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http://dx.doi.org/10.1016/j.ultras.2014.02.003DOI Listing
July 2014

Extracorporeal shockwave enhanced regeneration of fibrocartilage in a delayed tendon-bone insertion repair model.

J Orthop Res 2014 Apr 23;32(4):507-14. Epub 2013 Dec 23.

Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Fibrous tissue is often formed in delayed healing of tendon bone insertion (TBI) instead of fibrocartilage. Extracorporeal shockwave (ESW) provides mechanical cues and upregulates expression of fibrocartilage-related makers and cytokines. We hypothesized that ESW would accelerate fibrocartilage regeneration at the healing interface in a delayed TBI healing model. Partial patellectomy with shielding at the TBI interface was performed on 32 female New Zealand White Rabbits for establishing this delayed TBI healing model. The rabbits were separated into the control and ESW group for evaluations at postoperative week 8 and 12. Shielding was removed at week 4 and a single ESW treatment was applied at week 6. Fibrocartilage regeneration was evaluated histomorphologically and immunohistochemically. Vickers hardness of the TBI matrix was measured by micro-indentation. ESW group showed higher fibrocartilage area, thickness, and proteoglycan deposition than the control in week 8 and 12. ESW increased expression of SOX9 and collagen II significantly in week 8 and 12, respectively. ESW group showed a gradual transition of hardness from bone to fibrocartilage to tendon, and had a higher Vickers hardness than the control group at week 12. In conclusion, ESW enhanced fibrocartilage regeneration at the healing interface in a delayed TBI healing model.
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http://dx.doi.org/10.1002/jor.22566DOI Listing
April 2014

Investigation of rat bone fracture healing using pulsed 1.5 MHz, 30 mW/cm(2) burst ultrasound--axial distance dependency.

Ultrasonics 2014 Mar 1;54(3):850-9. Epub 2013 Nov 1.

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People's Republic of China.

This study investigated the effect of LIPUS on fracture healing when fractures were exposed to ultrasound at three axial distances: z=0 mm, 60 mm, and 130 mm. We applied LIPUS to rat fracture at these three axial distances mimicking the exposure condition of human fractures at different depths under the soft tissue. Measurement of LIPUS shows pressure variations in near field (nearby transducer); uniform profile was found beyond it (far field). We asked whether different positions of the fracture within the ultrasound field cause inconsistent biological effect during the healing process. Closed femoral fractured Sprague-Dawley rats were randomized into control, near-field (0mm), mid-near field (60 mm) or far-field (130 mm) groups. Daily LIPUS treatment (plane, but apodized source, see details in the text; 2.2 cm in diameter; 1.5 MHz sine waves repeating at 1 kHz PRF; spatial average temporal average intensity, ISATA=30 mW/cm(2)) was given to fracture site at the three axial distances. Weekly radiographs and endpoint microCT, histomorphometry, and mechanical tests were performed. The results showed that the 130 mm group had the highest tissue mineral density; and significantly higher mechanical properties than control at week 4. The 60 mm and 0 mm groups had significantly higher (i.e. p<0.05) woven bone percentage than control group in radiological, microCT and histomorphometry measurements. In general, LIPUS at far field augmented callus mineralization and mechanical properties; while near field and mid-near field enhanced woven bone formation. Our results indicated the therapeutic effect of LIPUS is dependent on the axial distance of the ultrasound beam. Therefore, the depth of fracture under the soft tissue affects the biological effect of LIPUS. Clinicians have to be aware of the fracture depth when LIPUS is applied transcutaneously.
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http://dx.doi.org/10.1016/j.ultras.2013.10.013DOI Listing
March 2014

Pathomorphological changes of bone marrow adipocytes in process of steroid-associated osteonecrosis.

Int J Clin Exp Pathol 2013 15;6(6):1046-50. Epub 2013 May 15.

Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.

Objective: The role of extravascular fat deposition in pathogenesis of steroid-associated osteonecrosis (ON) still remains unclear. This study aimed to explore the pathomorphological changes of bone marrow adipocytes over time in a rabbit ON model.

Methods: Thirty-two adult rabbits were divided into control group (n=16) and steroid group (n=16). Rabbits in the steroid group were injected with venous lipopolysaccharide once and intramuscular methylprednisolone trice to induce ON. Rabbits in the control group were treated with normal saline of equal volume. 2 weeks (early stage; n=8) and 4 weeks (late stage; n=8) after the last steroid injection, animals were sacrificed, and bilateral femora were harvested. The density, diameter and area of bone marrow adipocytes were determined by histomorphometry, and ON was evaluated histopathologically.

Results: The adipocyte density in steroid group increased by 67.1% and 54.4% at week 2 and week 4, respectively, when compared with control group, but there was no significant difference between week 2 and week 4. The adipocyte diameter in the steroid group at week 4 was significantly larger than that in the control group, but the adipocyte diameter in the steroid group at week 2 was slightly smaller than that in the control group. The adipocyte area in the steroid group increased by 44% and 83.4% at week 2 and week 4, respectively, when compared with the control group, and the adipocyte area in the steroid group at week 4 was markedly larger than that at week 2. In the control group, there were a largest number of adipocytes with 40-50 μm in diameter. When compared with the control group, most of increased adipocytes in the steroid group at week 2 were 30-40 μm in diameter, and those at week 4 were 50-60 μm in diameter. In the steroid group, histopathological examination showed ON was found in 25% (2/8) of rabbits at week 2 and 87.5% (7/8) of rabbits at week 4.

Conclusion: In the process of ON, extravascular fat deposition is characterized by increased small adipocytes at the early stage and hypertrophy of adipocytes at the late stage.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657356PMC
December 2013

Structural, densitometric and biomechanical evaluations of Chinese patients with long-term bisphosphonate treatment.

Chin Med J (Engl) 2013 Jan;126(1):27-33

Department of Orthopaedics and Traumatology and Bone Quality and Health Center, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Background: The association of long-term bisphosphonate treatment for osteoporosis and related safety problems such as atypical fractures were not clearly defined. This study was to evaluate the structural, densitometric and biomechanical properties of the prolonged bisphosphonate-loaded bones.

Methods: Bone mineral density (BMD) at hip and femoral midshaft, bone cross-sectional area, moment of inertia of both femurs, bone formation and resorption biochemical markers were compared between 28 elderly with at least 4 years of bisphosphonate treatment from 2002 through 2006 and age-matched group of 37 elderly.

Results: The total hip BMD and t-score were found not different between two groups. However, bisphosphonate treated patients were found to have significantly lower bone mineral content in the femoral shaft (P < 0.05); morphological study showed lower cross-sectional area in subtrochanteric and mid-diaphyseal region and thus significantly lower moment of inertia (P < 0.01). High resolution-peripheral quantitative computed tomography showed significantly decreased trabecular density, bone volume ratio, trabecular number but increased trabecular spacing in tibia and distal radius. Finite element analysis further confirmed significantly lower stiffness and failure load in tibia. Biochemical studies also showed lower bone resorption and severely suppressed bone formation activity (P < 0.001).

Conclusions: The unchanged total hip BMD between two groups confirmed the beneficial effects of bisphosphonate on trabecular bone, thus preventing osteoporotic fractures at large in previous studies. However, the inferior structural, densitometric and biomechanical properties at cortical bones, especially femur midshaft, need a special attention to look into the association between long-term bisphosphonate intake and the occurrence of stress fractures. When patients taking bisphosphonate complain of proximal thigh pain or discomfort, plain X-ray film can be the first line screening. All patients prescribed with bisphosphonate should be informed of such a complication though we must stress its rarity.
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January 2013

Extracorporeal shockwave therapy for treatment of delayed tendon-bone insertion healing in a rabbit model: a dose-response study.

Am J Sports Med 2012 Dec 17;40(12):2862-71. Epub 2012 Oct 17.

Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.

Background: Tendon-bone insertion (TBI) consists of both hard and soft tissues. TBI injury with delayed repair is not uncommon. High-dose extracorporeal shockwave (ESW) is effective for treating nonunion fracture, whereas low-dose ESW is used for tendinopathy therapy. The dosing effect of ESW on delayed TBI healing is lacking.

Hypothesis: Low-dose ESW might have a healing enhancement effect comparable to that of high-dose ESW in treating delayed TBI healing.

Study Design: Controlled laboratory study.

Methods: Partial patellectomy was adopted to create a delayed TBI healing model by shielding the healing interface between tendon and bone. Ninety-six female New Zealand White rabbits with unilateral delayed TBI healing at the knee joint were divided into 3 groups: controls, low-dose ESW (LD-ESW; 0.06 mJ/mm(2), 4 Hz, 1500 impulses), and high-dose ESW (HD-ESW; 0.43 mJ/mm(2), 4 Hz, 1500 impulses). The TBI shielding was removed at week 4 after partial patellectomy, followed by treatment with control or ESW at week 6. The rabbits were euthanized at week 8 and week 12 for radiological, microarchitectural, histological, and mechanical assessments of healing tissues.

Results: Radiologically, both the LD-ESW group and the HD-ESW group showed larger new bone area than the controls at week 8 and week 12. Microarchitectural measurements showed that the LD-ESW and HD-ESW groups had larger new bone volume than the controls at week 12. Histological assessments confirmed osteogenesis enhancement. Both the LD-ESW and HD-ESW groups showed significantly higher failure load at the TBI healing complex than the control group at week 12. No significant difference was detected between the 2 ESW treatment groups at week 8 or week 12.

Conclusion: Extracorporeal shockwave, a unique noninvasive physical modality, had similar effects between the low and high dose for treating delayed TBI healing.

Clinical Relevance: Low-dose ESW for TBI delayed healing might be more desirable and have better compliance in clinical applications.
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http://dx.doi.org/10.1177/0363546512461596DOI Listing
December 2012

Applications of exogenous mesenchymal stem cells and low intensity pulsed ultrasound enhance fracture healing in rat model.

Ultrasound Med Biol 2013 Jan 11;39(1):117-25. Epub 2012 Oct 11.

Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

The present study aimed to investigate the effects of combined treatment of exogenous mesenchymal stem cells (MSCs) and low intensity pulsed ultrasound (LIPUS) on fracture healing by comparing LIPUS-MSC, MSC and control (CTL) groups. Radiography and quantitative callus width/area demonstrated that the MSC-LIPUS group had the best healing, MSC group the second and CTL group the poorest with significant differences among each at different time points. Micro-CT data supported that MSC-LIPUS had the highest bone volume/tissue volume. Histomorphometry showed a significantly faster remodeling in late phase in MSC-LIPUS and MSC groups. These indicated that the combined treatment of MSCs and LIPUS was beneficial to fracture healing. Regenerative power and homing ability of MSCs were shown by promotion in fracture healing and locally found green fluorescent protein (GFP)-labeled MSCs at fracture calluses. This evidence reflects that co-treatment of MSCs and LIPUS may be developed as an intervention for delayed union or nonunion.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2012.08.015DOI Listing
January 2013

Stimulated angiogenesis for fracture healing augmented by low-magnitude, high-frequency vibration in a rat model-evaluation of pulsed-wave doppler, 3-D power Doppler ultrasonography and micro-CT microangiography.

Ultrasound Med Biol 2012 Dec 11;38(12):2120-9. Epub 2012 Oct 11.

Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.

This study aimed to investigate the mechanism of low-magnitude high-frequency vibration (LMHFV) treatment on angiogenesis and blood flow for enhancement of fracture healing. Nine-month-old ovariectomized (OVX) and sham-operated (Sham) rats received closed fractures creation at the femora and were randomized into LMHFV treatment (Sham-V, OVX-V) or control (Sham-C, OVX-C) groups. Pulsed-wave Doppler indicated an increase in blood flow velocity of the femoral artery at weeks 2 (OVX pair: p = 0.030) and 4 (OVX pair: p = 0.012; Sham pair: p = 0.020) post-treatment. Significantly enhanced vascular volume (VV) at the fracture site in the vibration groups was demonstrated by 3-D high-frequency power Doppler at week 2 (Sham pair: p = 0.021) and micro-computed tomography (microCT) microangiography at weeks 2 (OVX pair: p = 0.009) and 4 (OVX pair: p = 0.034), which echoed the osteogenesis findings by radiographic and microCT analysis. VV in the OVX groups was inferior to the Sham groups. However, OVX-V showed higher percentages of angiogenic enhancement than Sham-V. Despite impaired neo-angiogenesis in osteoporotic fractures, LMHFV could increase blood flow and angiogenesis in both normal and osteoporotic fractures, thus enhancing fracture healing.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2012.07.025DOI Listing
December 2012

Exogenous phytoestrogenic molecule icaritin incorporated into a porous scaffold for enhancing bone defect repair.

J Orthop Res 2013 Jan 13;31(1):164-72. Epub 2012 Jul 13.

Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China.

This study was designed to develop a bioactive scaffold to enhance bone defect repair in steroid-associated osteonecrosis (SAON). Icaritin, a metabolite of the herb Epimedium, has been identified as an angiogenic and osteogenic phytomolecule. Icaritin was homogenized into poly lactic-co-glycolic acid/tricalcium phosphate (PLGA/TCP) to form an icaritin-releasing porous composite scaffold (PLGA/TCP/icaritin) by fine-spinning technology. In vitro, high performance liquid chromatography was used to determine the release of icaritin during degradation of PLGA/TCP/icaritin. The osteogenic effects of PLGA/TCP/icaritin were evaluated using rat bone marrow mesenchymal stem cells (BMSCs). In vivo, the osteogenic effect of PLGA/TCP/icaritin was determined within a bone tunnel after core decompression in SAON rabbits and angiography within scaffolds was examined in rabbit muscle pouch model. In vitro study confirmed the sustainable release of icaritin from PLGA/TCP/icaritin with the bioactive scaffold promoting the proliferation and osteoblastic differentiation of rat BMSCs. In vivo study showed that PLGA/TCP/icaritin significantly promoted new bone formation within the bone defect after core decompression in SAON rabbits and enhanced neovascularization in the rabbit muscle pouch experiment. In conclusion, PLGA/TCP/icaritin is an innovative local delivery system that demonstrates sustainable release of osteogenic phytomolecule icaritin enhancing bone repair in an SAON rabbit model. The supplement of scaffold materials with bioactive phytomolecule(s) might improve treatment efficiency in challenging orthopedic conditions.
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http://dx.doi.org/10.1002/jor.22188DOI Listing
January 2013