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1.  The genetic profile of bone repair 
Bone repair following a fracture is a complex, well orchestrated, physiological process in response to injury. Even though the exact number of the genes and expressed proteins involved in fracture healing remains unknown, the molecular complexity of the repair process has been demonstrated, and it involves numerous genes and molecules, such as extracellular matrix genes, growth and differentiation factors, matrix metalloproteinases, angiogenic factors and others. Discrepancies in fracture healing responses and final outcome seen in the clinical practice may be attributed among other factors to biological variations between patients and different genetic “profiles”, resulting in “altered” signalling pathways that regulate the bone repair process. Preliminary human studies support a “genetic” component in the pathophysiology of impaired bone repair seen in atrophic non-unions by correlating genetic variations of specific molecules regulating fracture healing with non-union. However, the role of the genetic “profile” of each individual in fracture healing and final outcome, and its possible interaction with other exogenous factors remains a topic of extensive research.
PMCID: PMC3710004  PMID: 23858305
genetic profile; genetic variation; bone repair; fracture healing
2.  Assessment of Lateral Compression type 1 pelvic ring injuries by intraoperative manipulation: which fracture pattern is unstable? 
International Orthopaedics  2012;36(12):2553-2558.
We performed a prospective study to document, by intra-operative manipulation under anaesthesia (MUA) of the pelvic ring, the stability of lateral compression type 1 injuries that were managed in a Level-I Trauma Centre. The documentation of the short-term outcome of the management of these injuries was our secondary aim.
A total of 63 patients were included in the study. Thirty-five patients (group A) were treated surgically whereas 28 (group B) were managed nonoperatively. Intraoperative rotational instability, evident by more than two centimetres of translation during the manipulation manoeuvre, was combined with a complete sacral fracture in all cases.
A statistically significant difference was present between the length of hospital stay, the time to independent pain-free mobilisation, post-manipulation pain levels and opioid requirements between the two groups, with group A demonstrating significantly decreased values in all these four variables (p < 0.05). There was also a significant difference between the pre- and 72-hour post-manipulation visual analogue scale and analgesic requirements of the group A patients, whereas the patients in group B did not demonstrate such a difference.
LC-1 injuries with a complete posterior sacral injury are inheritably rotationally unstable and patients presenting with these fracture patterns definitely gain benefit from surgical stabilisation.
PMCID: PMC3508039  PMID: 23096135
3.  Nonunion of fibula: a systematic review 
International Orthopaedics  2012;36(9):1757-1765.
The purpose of this systematic review was to analyse the available evidence regarding nonunions of the fibula. We focussed on the incidence, risk factors, evaluation, and treatment modalities for fibular nonunions as evident in the current literature and propose a treatment algorithm.
This was an Institutional Review Board (IRB) exempt study performed at a level one trauma centre. We systematically reviewed the published evidence on fibular nonunion or delayed union from 1950 to February, 2011.
Twelve articles were included in this systematic review. In summary, nonunion of the fibula is becoming increasingly more common in association with intramedullary nailing of concomitant tibial shaft fractures. A treatment algorithm for nonunion of the fibula has been proposed.
The suspicion for nonunion of the fibula should be heightened in lower leg fractures if the patient is symptomatic, and the progression of healing is not as expected. Ideally, prospective, multicentre studies would be performed to provide more rigorous data on the incidence, risk factors, and optimum treatment.
PMCID: PMC3427429  PMID: 22643795
4.  Reconstruction of iliac crest with bovine cancellous allograft after bone graft harvest for symphysis pubis arthrodesis 
International Orthopaedics  2012;36(8):1701-1707.
The aim of this study was to evaluate the safety and efficiency, as well as the incorporation characteristics of a specific type of xenograft used for iliac crest defects post-harvesting tri-cortical iliac crest bone graft.
Sixteen patients diagnosed with chronic anterior pelvic pain were operated for pubic symphysis fusion. The tri-cortical graft harvested from the iliac crest was inserted into the pubic symphysis and compressed with a reconstruction plate. The defect in the iliac crest was filled with a block of cancellous bovine substitute (Tutobone®). The length of iliac crest defect, time to fusion of pubic symphysis, time to incorporation of the graft and complications were recorded. The postoperative pain and patients’ satisfaction were evaluated.
The median age of patients was 36.5 years (range 27–75). Fusion was obtained in 15 patients (94 %). The median time to fusion was four months (range three to seven). The length of the iliac crest bone defect ranged from 40 to 70 mm. Integration of the bovine substitute was achieved in 15 patients (94 %) over a median period of three months (range two to six). The postoperative median pain score was 2 (range 1–5). Twelve patients (75 %) reported good satisfaction. No major complications or allergic reactions were observed.
The xenograft used in this study provided a safe and effective method of reconstruction of iliac crest donor site defects. It has satisfactory incorporation, high biocompatibility and no signs of inflammatory reactions. This new technique is simple and easily reproducible in routine clinical practice.
PMCID: PMC3535019  PMID: 22729663
6.  Release of growth factors and the effect of age, sex, and severity of injury after long bone fracture 
Acta Orthopaedica  2013;84(1):65-70.
Background and purpose
The systemic response after fracture is regulated by a complex mechanism involving numerous growth factors. In this study, we analyzed the kinetics of key growth factors following lower-limb long bone fracture.
Materials and methods
Human serum was isolated from 15 patients suffering from lower-limb long bone fracture (tibia/femur) requiring surgical fixation. The levels of platelet-derived growth factor (PDGF-BB), vascular edothelial growth factor (VEGF), insulin growth factor-I (IGF-I), and transforming growth factor β1 (TGF-β1) were assayed by colorimetric ELISA at different time points during the first week after fracture. 10 healthy volunteers made up the control group of the study. Serum levels of the growth factors measured were compared to age, sex, and injury severity score.
We found that there was a decline in the levels of PDGF-BB, IGF-I and TGF-β1 during the first 3 days after fracture. However, VEGF levels remained unchanged. The levels of all the growth factors studied then increased, with the highest concentrations noted at day 7 after surgery. No correlation was found between circulating levels of growth factors and age, injury severity score (ISS), blood loss, or fluid administration.
There are systemic mitogenic and osteogenic signals after fracture. Important growth factors are released into the peripheral circulation, but early after surgery it appears that serum levels of key growth factors fall. By 7 days postoperatively, the levels had increased considerably. Our findings should be considered in cases where autologous serum is used for ex vivo expansion of mesenchymal stem cells. There should be further evaluation of the use of these molecules as biomarkers of bone union.
PMCID: PMC3584605  PMID: 23343371
7.  Management of Infection After Intramedullary Nailing of Long Bone Fractures: Treatment Protocols and Outcomes 
Implant related sepsis is a relatively unusual complication of intra-medullary nail fixation of long bone fractures. Depending on the extent of infection, timing of diagnosis and progress of fracture union, different treatment strategies have been developed. The aim of this review article is to collect and analyze the existing evidence about the incidence and management of infection following IM nailing of long bone fractures and to recommend treatment algorithms that could be valuable in everyday clinical practice. After searching the P u b M e d /Medline databases, 1270 articles were found related to the topic during the last 20 years. The final review included 28 articles that fulfilled the inclusion criteria.
Only a few prospective studies exist to report on the management of infection following IM nailing of long-bone fractures. In general, stage I (early) infections only require antibiotic administration with/without debridement. Stage II (delayed) infections can be successfully treated with debridement, IM reaming, antibiotic nails, and administration of antibiotics. Infected non-unions are best treated with exchange nailing, antibiotic administration and when infection has been eradicated with graft implantation if it is needed. Debridement, exchange nailing and systemic administration of antibiotics is the best indication for stage III (late) infections, while stage III infected non-unions can successfully be treated with nail removal and Ilizarov frame, especially when large bone defects exist.
PMCID: PMC3731810  PMID: 23919097
Intramedullary nailing; infection; long bone fractures; reaming; review.
8.  “Internal fixation of proximal humeral fractures using the Polarus intramedullary nail: our institutional experience and review of the literature” 
The purpose of this study is to evaluate the functional outcome, union and complication rates after surgical treatment of unstable or displaced proximal humeral fractures using the Polarus intramedullary nail, by reviewing our institutional experience and the relevant current literature.
Twenty-seven patients were treated operatively for proximal humeral fracture using the Polarus nail. Fractures were classified according to Neer’s classification. A number of parameters including patient demographics, mechanism of injury, operative time, time to union and complications were recorded. Functional outcome was evaluated using the Constant Shoulder Score. A comparison among functional outcomes in patients >60 years in relation to the younger ones was performed. Moreover, a review of the literature was carried out to evaluate the overall union and complication rates.
Two patients lost to follow-up were excluded from the analysis. For the twenty-five patients (mean age: 61 years), the mean follow-up was 36 months. There were 7 complications (28%), including one fixation failure, four protruded screws, one superficial infection and one case of impingement. The union rate was 96% (mean time to union: 4.2 months). The mean Constant score was 74.5 (range: 48–89). Patients under the age of 60 had a better functional outcome compared to patients >60 years of age (p<0.05). From the literature review and from a total of 215 patients treated with a Polarus nail, the mean union rate was 95.8%, the overall reported complication rate, including both minor and major complications, ranged widely from 9.3% up to 70%.
The Polarus nail was found to be an effective implant for stabilisation of proximal humeral fractures. Functional outcome is for the vast majority of the cases excellent or good, but in elderly patients a lower Constant score can be expected.
PMCID: PMC3554551  PMID: 23253302
Proximal humeral fractures; Polarus nail; Union; Complications; Functional outcome
9.  The role of stem cells in fracture healing and nonunion 
International Orthopaedics  2011;35(11):1587-1597.
Nonunion and large bone defects present a therapeutic challenge to the surgeon and are often associated with significant morbidity. These defects are expensive to both the health care system and society. However, several surgical procedures have been developed to maximise patient satisfaction and minimise health-care-associated and socioeconomic costs. Integrating recent evidence into the diamond concept leads to one simple conclusion that not only provides us with answers to the “open questions” but also simplifies our entire understanding of bone healing. It has been shown that a combination of neo-osteogenesis and neovascularisation will restore tissue deficits, and that the optimal approach includes a biomaterial scaffold, cell biology techniques, a growth factor and optimisation of the mechanical environment. Further prospective, controlled, randomised clinical studies will determine the effectiveness and economic benefits of treatment with mesenchymal stem cells, not in comparison to other conventional surgical approaches but in direct conjunction with them.
PMCID: PMC3193959  PMID: 21863226
10.  Angiographic embolisation of pelvic ring injuries. Treatment algorithm and review of the literature 
International Orthopaedics  2011;35(9):1381-1390.
The purpose of this study was to evaluate the relation between pelvic fracture patterns and the angiographic findings, and to assess the effectiveness of the embolisation.
This retrospective study, included patients with pelvic fractures and angiographic evaluation. Demographics, Injury Severity Score (ISS), associated injuries, embolisation time, blood units needed, method of treatment and complications were recorded and analysed. Fractures were classified according to the Burgess system.
Between 1998 and 2008, 34 patients with pelvic fractures underwent angiographic investigation. Twenty six were males. The mean age was 41 years. Twenty-seven were motor vehicle accidents and seven were falls. There were 11 anterior posterior (APC) fractures, 12 lateral compression (LC), eight vertical shear (VS) patterns and three with combined mechanical injuries. The median ISS was 33.1 (range 5–66). From the 34 who underwent angiography, 29 had positive vascular extravasations. From them, 21 had embolisation alone, two had vascular repair and embolisation, five required vascular repair alone and one patient died while being prepared for embolisation. Five cases were re-embolised. The findings suggested that AP fractures have a higher tendency to bleeding compared with LC fractures. Both had a higher chance of blood loss compared to VS and complex fracture patterns. We reported 57 additional injuries and 65 fractures. The complications were: one non lethal pulmonary embolism, one renal failure, one liver failure, one systemic infection, two deep infections and two psychological disorientations. Seven patients died in hospital.
Control of pelvic fracture bleeding is based on the multidisciplinary approach mainly related to hospital facilities and medical personnel’s awareness. The morphology of the fracture did not have a predictive value of the vascular lesion and the respective bleeding.
PMCID: PMC3167455  PMID: 21584644
11.  Proximal tibial fractures: early experience using polyaxial locking-plate technology 
International Orthopaedics  2010;35(8):1215-1221.
Between 2004 and 2009, 60 patients with proximal tibial fractures were included in this prospective study. All fractures were treated with the polyaxial locked-plate fixation system (DePuy, Warsaw, IN, USA). Clinical and radiographic data, including fracture pattern, changes in alignment, local and systemic complications, hardware failure and fracture union were analysed. The mean follow-up was 14 (12–36) months. According to the Orthopaedic Trauma Association (OTA) classification, there were five 41-A, 28 41-B and 27 41-C fractures. Fractures were treated percutaneously in 30% of cases. Double-plating was used in 11 cases. All but three fractures progressed to union at a mean of 3.2 (2.5–5) months. There was no evidence of varus collapse as a result of polyaxial screw failure. No plate fractured, and no screw cut out was noted. There was one case of lateral joint collapse (>10°) in a patient with open bicondylar plateau fracture. The mean Knee Society Score at the time of final follow-up was 91 points, and the mean functional score was 89 points. The polyaxial locking-plate system provided stable fixation of extra-articular and intra-articular proximal tibial fractures and good functional outcomes with a low complication rate.
PMCID: PMC3167437  PMID: 21107983
12.  The role of barrier membranes for guided bone regeneration and restoration of large bone defects: current experimental and clinical evidence 
BMC Medicine  2012;10:81.
Treatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Although there are several methods for bone reconstruction, they all have specific indications and limitations. The concept of using barrier membranes for restoration of bone defects has been developed in an effort to simplify their treatment by offering a sinlge-staged procedure. Research on this field of bone regeneration is ongoing, with evidence being mainly attained from preclinical studies. The purpose of this review is to summarize the current experimental and clinical evidence on the use of barrier membranes for restoration of bone defects in maxillofacial and orthopedic surgery. Although there are a few promising preliminary human studies, before clinical applications can be recommended, future research should aim to establish the 'ideal' barrier membrane and delineate the need for additional bone grafting materials aiming to 'mimic' or even accelerate the normal process of bone formation. Reproducible results and long-term observations with barrier membranes in animal studies, and particularly in large animal models, are required as well as well-designed clinical studies to evaluate their safety, efficacy and cost-effectiveness.
PMCID: PMC3423057  PMID: 22834465
bone regeneration; bone defect; barrier membranes; non-resorbable membranes; bioresorbable/absorbable membranes
13.  Reamer-irrigator-aspirator indications and clinical results: a systematic review 
International Orthopaedics  2011;35(7):951-956.
The ‘reamer-irrigator-aspirator’ (RIA) is an innovation developed to reduce fat embolism (FE) and thermal necrosis (TN) that can occur during reaming/nailing of long-bone fractures. Since its inception its indications have expanded to include the treatment of long-bone osteomyelitis and as a harvester of bone graft/mesenchymal stem cells (MSCs).
This study involved a systematic review, via Pubmed® and Google Scholar®, of English language sources (nine non-clinical studies, seven clinical studies and seven case reports) using the keywords: ‘reamer’, ‘irrigator’, ‘aspirator’ (1st May 2010). Sources were reviewed with reference to the RIAs efficacy in (1) preventing FE/TN, (2) treating long-bone osteomyelitis, (3) harvesting bone graft/MSCs, and (4) operating safely. Experimental data supports the use of the RIA in preventing FE and TN, however, there is a paucity of clinical data.
The RIA is a reliable method in achieving high volumes of bone graft/MSCs, and high union rates are reported when using RIA bone-fragments to treat non-unions. Evidence suggests possible effectiveness in treating long-bone osteomyelitis. The RIA appears relatively safe, with a low rate of morbidity provided a meticulous technique is used. When complications occur they respond well to conventional techniques. The RIA demands further investigation especially with respect to the optimal application of MSCs for bone repair strategies.
PMCID: PMC3167404  PMID: 21243358
14.  Spinal metastasis in thyroid cancer 
Head & Neck Oncology  2012;4:39.
Thyroid carcinoma generally responds well to treatment and spinal metastasis is an uncommon feature. Many studies have looked at the management of spinal metastasis and proposed treatments, plans and algorithms. These range from well-established methods to potentially novel alternatives including bisphosphonates and vascular endothelial growth factor (VEGF) therapy, amongst others.
The purposes of this systematic review of the literature are twofold. Firstly we sought to analyse the proposed management options in the literature. Then, secondly, we endeavoured to make recommendations that might improve the prognosis of patients with spinal metastasis from thyroid carcinomas.
We conducted an extensive electronic literature review regarding the management of spinal metastasis of thyroid cancer.
We found that there is a tangible lack of studies specifically analysing the management of spinal metastasis in thyroid cancer. Our results show that there are palliative and curative options in the management of spinal metastasis, in the forms of radioiodine ablation, surgery, selective embolisation, bisphosphonates and more recently the VEGF receptor targets.
The management of spinal metastasis from thyroid cancer should be multi-disciplinary. There is an absence; it seems, of a definitive protocol for treatment. Research shows increased survival with 131I avidity and complete bone metastasis resection. Early detection and treatment therefore are crucial. Studies suggest in those patients below the age of 45 years that treatment should be aggressive, and aim for cure. In those patients in whom curative treatment is not an option, palliative treatments are available.
PMCID: PMC3466148  PMID: 22730910
15.  Analysis of the compatibility of dental implant systems in fibula free flap reconstruction 
Head & Neck Oncology  2012;4:37.
As a result of major ablative surgery, head and neck oncology patients can be left with significant defects in the orofacial region. The resultant defect raises the need for advanced reconstruction techniques. The reconstruction in this region is aimed at restoring function and facial contour. The use of vascularised free flaps has revolutionised the reconstruction in the head and neck. Advances in reconstruction techniques have resulted in continuous improvement of oral rehabilitation. For example, endosteal implants are being used to restore the masticatory function by the way of prosthetic replacement of the dentition. Implant rehabilitation usually leads to improved facial appearance, function, restoration of speech and mastication. Suitable dental implant placement’s site requires satisfactory width, height and quality of bone. Reconstruction of hard tissue defects therefore will need to be tailored to meet the needs for implant placement.
The aim of this feasibility study was to assess the compatibility of five standard commercially available dental implant systems (Biomet 3i, Nobel Biocare, Astra tech, Straumann and Ankylos) for placement into vascularised fibula graft during the reconstruction of oromandibular region.
Radiographs (2D) of the lower extremities from 142 patients in the archives of the Department of Radiology in University College London Hospitals (UCLH) were analysed in this study. These radiographs were from 61 females and 81 males. Additionally, 60 unsexed dry fibular bones, 30 right sided, acquired from the collection of the Department of Anatomy, University College London (UCL) were also measured to account for the 3D factor.
In the right fibula (dry bone), 90% of the samples measured had a width of 13.1 mm. While in the left fibula (dry bone), 90% of the samples measured had a width of 13.3 mm. Fibulas measured on radiographs had a width of 14.3 mm in 90% of the samples. The length ranges of the dental implants used in this study were: 7-13 mm (Biomet 3i), 10-13 mm (Nobel biocare), 8-13 mm (Astra Tech), 8-12 mm (Straumann ) and 8-11 mm (Ankylos).
This study reached a conclusion that the width of fibula is sufficient for placement of most frequently used dental implants for oral rehabilitation after mandibular reconstructive procedures.
PMCID: PMC3448503  PMID: 22721258
16.  The management of nonunion and delayed union of patella fractures: a systematic review of the literature 
International Orthopaedics  2010;35(6):791-795.
Nonunion and delayed union of patella fractures are rare conditions that are fraught with challenges. There exists limited evidence in the literature to guide the clinician in the management of these complications. Therefore, the purpose of this study was to perform a systematic review of the available evidence on the management of nonunion and delayed union of patella fractures. A total of five publications which met our criteria were identified and formed the basis of this study. The decision making in the treatment of this condition is based on the functional demands of the patient, the factors that led to the development of the nonunion, the potential impact of the biomechanical effects of a total patellectomy, and the presence of an intact extensor mechanism of the knee for a later reconstructive procedure. Patients with low functional demands may be managed with nonoperative methods; however, those who perform heavy physical work or participate in sports usually require open reduction and internal fixation. Tension band wiring is the treatment of choice for patients suitable for a reconstructive procedure. Partial or total patellectomy is also an option for small distal fragments or an inability to satisfactorily perform internal fixation.
PMCID: PMC3103972  PMID: 20680273
17.  Surgical treatment of coccygodynia: an analytic review of the literature 
European Spine Journal  2010;20(5):698-705.
Coccygodynia is a pathological condition associated with pain–discomfort all around the bottom end of the spine. The aetiology and the intensity of the symptoms may defer significantly. The effectiveness of the surgical treatment remains obscure. Our purpose, through this systematic review is to evaluate the results of surgical treatment of coccygectomy. Literature retrieval was performed by the use of the PubMed searching engine utilising the terms ‘coccygodynia–coccygectomy’ in the English language from January 1980 to January 2010. Case reports and tumour related case series were excluded as well as articles published in other languages. In total 24 manuscripts were analyzed. Only 2 of them were prospective studies whereas 22 were retrospective case series; five were classified as Level III studies and the remaining as Level IV studies. In total, 671 patients with coccygodynia underwent coccygectomy following failed conservative management. The sex ratio, male/female was 1:4.4. The most popular aetiology for coccygodynia was direct trauma in 270 patients. 504 of the patients reported an excellent/good outcome following the procedure. There were 9 deep and 47 superficial infections. Other complications included two haematomas, six delayed wound healings and nine wound dehiscence. The overall complication rate was 11%. Patients with history of spinal or rectal disorders, as well as idiopathic or with compensation issues, had less predictable outcome than those with history of trauma or childbirth. Coccygectomy can provide pain relief to as high as 85% of the cases. The most common reported complication was wound infection.
PMCID: PMC3082682  PMID: 21046173
Coccygodynia; Coccygectomy; Coccyx surgical treatment
18.  Effects of Antithrombotic Drugs Fondaparinux and Tinzaparin on In Vitro Proliferation and Osteogenic and Chondrogenic Differentiation of Bone-Derived Mesenchymal Stem Cells 
Journal of Orthopaedic Research  2011;29(9):1327-1335.
An unexpected side effect of some classes of anticoagulants has been osteoporosis which may be, at least in part, related to deranged mesenchymal stem cell (MSC) function. The aim of the present study was to compare the effect of fondaparinux (FDP), a novel antithrombotic with a traditional widely used low molecular weight heparin, tinzaparin (TZP) on MSC proliferation and differentiation. MSCs were isolated from trabecular bone of 14 trauma patients by a collagenase-based digestion procedure and expanded in standard conditions until passage 3. Proliferation and differentiation of MSCs to chondrocytes and osteoblasts was assessed with or without the addition of FDP and TZP using standard in vitro assays and a broad range of drug concentrations. Flow cytometry was used for MSC phenotyping. In the age studied group (17–74 years old) the MSC frequency in collagenase-released fractions was 641/106 cells (range 110–2,158) and their growth characteristics were ∼4 days/population doubling. Cultures had a standard MSC phenotype (CD73+, CD105+, CD146+, CD106+, and CD166+). Cell proliferation was assessed by both colony-forming unit-fibroblast (CFU-F) and colorimetric tetrazolium salt XTT assays. In both assays, MSC proliferation was inhibited by the addition of TZP, particularly at high concentrations. In contrast, FDP had no effect on MSC proliferation. Osteogenic differentiation and chondrogenic differentiation were not affected by the addition of either TZP or FDP. Whilst MSC proliferation, but not differentiation, is negatively affected by TZP, there was no evidence for adverse effects of FDP in this in vitro model system which argues well for its use in the orthopedic setting. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1327–1335, 2011
PMCID: PMC3193377  PMID: 21432897
low molecular heparins; bone healing; MSC; chemical thromboprophylaxis
19.  High abundance of CD271+ multipotential stromal cells (MSCs) in intramedullary cavities of long bones 
Bone  2012;50(2):510-517.
Aspiration of iliac crest bone marrow (ICBM) remains the most frequent technique used in harvesting multipotential stromal cells (MSCs) for bone regeneration. Although this tissue type is easily accessed by a surgeon, it has a low frequency of MSCs, which is significant given the high cell numbers required for bone regeneration strategies. Lipoaspirates possess higher MSC frequencies, albeit cells with a differentiation profile less suited to orthopaedic interventions. Intra-medullary cavities of long bones have previously been shown to harbour MSCs in animals, however evaluation of their frequency, differentiation capacity and phenotype in humans had not previously been performed.
Long bone fatty bone marrow (LBFBM) was collected prior to harvesting bone graft. Basic cellular compositions of donor-matched LBFBM and ICBM aspirates, including the numbers of CD34+ hematopoietic stem cells and CD31+ endothelial cells, were similar. MSCs were enumerated using colony-forming-unit-fibroblast assays and flow cytometry for the presence of a resident LBFBM CD45−/low CD271+ MSC population and revealed a trend for higher MSC numbers (average 5 fold, n = 6) per millilitre of LBFBM compared to donor-matched ICBM. Functional characteristics of resident MSCs, including their growth rates, differentiation potentials and surface phenotypes (CD73+CD105+CD90+) before and after culture-amplification, were similar. Enhanced numbers of MSCs could be recovered following brief enzymatic treatment of solid fragments of LBFBM.
Our findings therefore reveal that the intramedullary cavity of the human femur is a depot of MSCs, which, although closely associated with fat, have a differentiation profile equivalent to ICBM. This anatomical site is frequently accessed by the orthopaedic/trauma surgeon and aspiration of the intramedullary cavity represents a ‘low-tech’ method of harvesting potentially large numbers of MSCs for regenerative therapies and research.
This article is part of a Special Issue entitled: Interactions Between Bone, Adipose Tissue and Metabolism.
PMCID: PMC3268250  PMID: 21807134
Multipotential stromal cells; Mesenchymal stem cells; Long bone; Bone marrow; Intramedullary cavity; Bone regeneration
20.  Do Nonsteroidal Anti-Inflammatory Drugs Affect Bone Healing? A Critical Analysis 
The Scientific World Journal  2012;2012:606404.
Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the available in vitro animal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal and in vitro studies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients.
PMCID: PMC3259713  PMID: 22272177
21.  The role of reduction and internal fixation of Lisfranc fracture–dislocations: a systematic review of the literature 
International Orthopaedics  2010;34(8):1083-1091.
A systematic review of the literature was performed in order to evaluate the role of reduction and internal fixation in the management of Lisfranc joint fracture–dislocations. Articles were extracted from the Pubmed database and the retrieved reports were included in the study only if pre-specified eligibility criteria were fulfilled. Eleven articles were eligible for the final analysis, reporting data for the management of 257 patients. Injuries of the first three metatarsal rays were treated by closed reduction and internal fixation with screws in 16.3% of the patients, open reduction and internal fixation with screws in 66.5% and open reduction and internal fixation with Kirschner wires (K-wires) in 17.1% of the patients. The preferred method for the stabilisation of the fourth and fifth metatarsal rays was K-wires. Screw-related complications were common and were reported in 16.1% of the cases. The mean American Orthopaedic Foot and Ankle Society midfoot score was 78.1 points. Post-traumatic radiographic arthritis was reported in 49.6% of the patients, but only in 7.8% of them it was severe enough to warrant an arthrodesis. We conclude that open reduction and internal fixation of the first three metatarsal rays with screws is a reliable method for the management of Lisfranc injuries. This can be complemented by K-wires application in the fourth and fifth metatarsal rays if needed.
PMCID: PMC2989076  PMID: 20683593
22.  Trauma networks: present and future challenges 
BMC Medicine  2011;9:121.
In England, trauma is the leading cause of death across all age groups, with over 16,000 deaths per year. Major trauma implies the presence of multiple, serious injuries that could result in death or serious disability. Successive reports have documented the fact that the current ad hoc unstructured management of this patient group is associated with considerable avoidable death and disability. The reform of trauma care in England, especially of the severely injured patient, has already begun. Strong clinical leadership is embraced as the way forward. The present article summarises the steps that have been made over the last decade that led to the recent decision to move towards a long anticipated restructure of the National Health Service (NHS) trauma services with the introduction of Regional Trauma Networks (RTNs). While, for the first time, a genuine political will and support exists, the changes required to maintain the momentum for the implementation of the RTNs needs to be marshalled against arguments, myths and perceptions from the past. Such an approach may reverse the disinterest attitude of many, and will gradually evolve into a cultural shift of the public, clinicians and policymakers in the fullness of time.
PMCID: PMC3229440  PMID: 22078223
23.  Challenges and barriers to improving care of the musculoskeletal patient of the future - a debate article and global perspective 
With greater technological developments in the care of musculoskeletal patients, we are entering an era of rapid change in our understanding of the pathophysiology of traumatic injury; assessment and treatment of polytrauma and related disorders; and treatment outcomes. In developed countries, it is very likely that we will have algorithms for the approach to many musculoskeletal disorders as we strive for the best approach with which to evaluate treatment success. This debate article is founded on predictions of future health care needs that are solely based on the subjective inputs and opinions of the world's leading orthopedic surgeons.
Hence, it functions more as a forum-based rather than a scientific-based presentation. This exposé was designed to stimulate debate about the emerging patients' needs in the future predicted by leading orthopedic surgeons that provide some hint as to the right direction for orthopedic care and outlines the important topics in this area.
The authors aim to provide a general overview of orthopedic care in a typical developed country setting. However, the regional diversity of the United States and every other industrialized nation should be considered as a cofactor that may vary to some extent from our vision of improved orthopedic and trauma care of the musculoskeletal patient on an interregional level.
In this forum, we will define the current and future barriers in developed countries related to musculoskeletal trauma, total joint arthroplasty, patient safety and injuries related to military conflicts, all problems that will only increase as populations age, become more mobile, and deal with political crisis.
It is very likely that the future will bring a more biological approach to fracture care with less invasive surgical procedures, flexible implants, and more rapid rehabilitation methods. This international consortium challenges the trauma and implants community to develop outcome registries that are managed through health care offices and to prepare effectively for the many future challenges that lie in store for those who treat musculoskeletal conditions.
PMCID: PMC3196685  PMID: 21943304
Global perspective; Future trends and needs; Algorithms of patient care; Quality assurance in Patient care; Registries
24.  Intramedullary Nailing as a ‘Second Hit’ Phenomenon in Experimental Research: Lessons Learned and Future Directions 
The ‘second hit’ phenomenon is based on the fundamental concept that sequential insults, which are individually innocuous, can lead to overwhelming physiologic reactions. This response can be expressed in several organic systems and can be examined by measurement of several parameters.
The purpose of this study was to evaluate the incidence of systemic effects of intramedullary nailing and the role of concurrent head and thoracic injuries as they have been recorded in vivo. We also wanted to determine what would be the optimal animal model for future research and what variables should be investigated.
We reviewed the available literature of animal studies that used surgery, and particularly nailing, as a second hit. The reviewed studies were retrieved through an electronic search of the MEDLINE database. We analyzed the methods of creating the first and second hits (nailing), the characteristics of the animal models, the variables examined, and the pathophysiologic responses, which appeared after the second hit.
Second hit reamed intramedullary nailing was found to provoke consumption of coagulation factors, whereas the effect of unreamed nailing on coagulation factors appears inconsistent. Hemodynamic factors were affected only transiently by the second hit, whereas the pulmonary function was affected only when the first hit included lung injury.
Thoracic and head injuries predispose to an aggravated second hit. Primate animal models are considered to be closer to clinical reality and should be preferred for future studies. Future studies should include measurements of proinflammatory and antiinflammatory markers.
PMCID: PMC2919890  PMID: 20012236
25.  Bone regeneration: current concepts and future directions 
BMC Medicine  2011;9:66.
Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis. Currently, there is a plethora of different strategies to augment the impaired or 'insufficient' bone-regeneration process, including the 'gold standard' autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved 'local' strategies in terms of tissue engineering and gene therapy, or even 'systemic' enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis.
PMCID: PMC3123714  PMID: 21627784

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