Osteogenesis Imperfecta (OI) is a heritable bone disorder characterized by bone fragility and often caused by mutations in the Type I collagen-encoding genes COL1A1 and COL1A2. The pathophysiology of OI, particularly at the cellular level, is still not well understood. This contributes to the lack of a cure for this disorder as well as an effective preventive or management options of its complications. In the bone environment, mesenchymal stem cells (MSCs) and osteoblasts (Ob) exert their function, at least partially, through the secretion of extracellular vesicles (EV). EV is a heterogeneous group of nanosized membrane-enclosed vesicles that carry/transfer a cargo of proteins, lipid and nucleic acids from the secreting cell to its target cells. Our objective is to characterize EVs secreted by human control (HC)- and OI-MSCs and their derived Obs, with focus on their protein content. We hypothesize that there will be differences in the protein content of EVs secreted by OI-Obs compared to HC-Ob, which may indicate a deviation from healthy Ob behavior and, thus, a role in OI pathophysiology. MSCs were harvested from the adipose tissue of four COL1A1-OI and two HC patients. They were proliferated in an EV-depleted media, then induced to differentiate to extracellular matrix (ECM)-producing osteoblasts, which then gets mineralized. EVs secreted by MSCs (MSC-EV) and Obs (Ob-EV) were then purified and concentrated. Using liquid chromatography- tandem mass spectrometry, proteomic analysis of the EV groups was done. A total of 384 unique proteins were identified in all EVs, 373 were found in Vesiclepedia indicating a good enrichment of our samples with EV proteins. 67 proteins of the total 384 were exclusively or significantly upregulated (p-value < 0 .05) in OI-Ob-EV and 28 proteins in the HC-Ob-EVs, relative to each other. These two groups of differentially expressed proteins were compared by Gene Ontology (GO) analysis of their cellular compartment, molecular functions and biological processes. We observed that there were differences in the cellular origin of EV-proteins, which may indicate heterogeneity of the isolated EVs. Molecular function and biological process analyses of the HC-Ob-EV proteins showed, as expected, predominantly calcium-related activities such as extracellular matrix (ECM) mineralization. OI-Ob-EV proteins were still predominantly exhibiting ECM organization and formation functions. Annexins A1,2,4,5 and 6 were differentially and significantly upregulated by the HC-Ob-EVs. Fibronectin (FN), Fibulin-1 and −2, and Laminins (α4 & γ1), which are amongst the early non-collagenous proteins to form the ECM, were differentially and significantly upregulated in the OI-Ob-EVs. We concluded that the persistent expression of Fibronectin (FN), Fibulin-1 and −2, and Laminins in OI-Ob-EVs might indicate the presence of an immature ECM that the OI-Obs are trying to organize. ECM mineralization is largely dependent on the presence of an organized mature ECM, and this being compromised in OI bone environment, may be a contributor to the bone fragility seen in these patients. Annexins, which are calcium-binders that are vital for ECM mineralization, were significantly downregulated in the OI-Ob-EVs and this may be a further contributor to ECM mineralization impairment and bone fragility

Background. 70% of Breast Cancer patients develop metastatic bone deposits, predominantly spinal metasases. Adult Mesenchymal Stem Cells (MSCs) are multiprogenitor stem cells found within the bone marow which have the ability to self renew and differentiate into multiple cell types. MSCs home specifically to tumour sites, highlighting their potential as delivery vehicles for therapeutic agents. However studies show they may also increase tumour metastatic potential. Aims. The aim of this study was to investigate interactions between MSCs and breast cancer cells to further elucidate their role in the tumour microenvironment and hence understand factors involved in stimulating the formation of bone metastases. Methods. MSCs harvested from the iliac crest of healthy volunteers were grown for collection of conditioned medium (CM), containing all factors secreted by the cells. Breast cancer cell lines (T47D, SK-BR-3, MDA-MB-231) were then cultured in MSC CM +/− antibodies to TGFβ, VEGF, MCP-1 and CCL5 for 72hrs. Cell proliferation was assessed using an Apoglow(r) assay and RNA harvested for analysis of changes in Epithelial Mesenchymal Transition specific gene expression : N-Cadherin, E-Cadherin, Vimentin, Twist, Snail. Results. A significant down regulation of breast cancer cell proliferation in the presence of MSC secreted factors was observed (p<0.05). There was a dramatic increase in expression of EMT specific genes in both cell lines following exposure to MSC-secreted factors. Inclusion of antibodies to TGF, VEGF, MCP-1 and CCL5 inhibited the effect seen, suggesting these paracrine factors played a role in the elevated expression levels. Conclusion. MSCs clearly have a distinct paracrine effect on breast cancer epithelial cells, mediated at least in part through secretion of growth factors and chemokines. These factors play an important role in the metastatic cascade and may represent potential therapeutic targets to inhibit MSC-breast cancer interactions, helping to prevent the formation of bone metastases in cancer

NICE technology appraisal guidance 157 suggests that the oral anticoagulation medication Dabigatran etexilate (Pradaxa®, Boehringer Ingelheim) can be used for the primary prevention of venous thromboembolic events (VTE's) in adult patients who have undergone elective total hip (THR) or knee replacement (TKR) surgery. The NICE guidance and the Pradaxa® Summary of Product characteristics (SPC) report that 13.8% of patients receiving recommended doses of Dabigatran experience adverse bleeding events. In the manufacturer's pivotal clinical trials, wound secretion accounted for 4.9% of patients treated with Dabigatran as compared to 3.0% treated with Enoxaparin. The aim of this audit was to assess the impact of Dabigatran on wound complications at a UK district general hospital and to quantify the effect on the postoperative discharge home support services provided by the award-winning South Warwickshire Accelerated Transfer Team (SWATT). We report our experience of Dabigatran use at Warwick Hospital from March 2009 to March 2010. Of the 788 lower limb arthroplasties performed, 681 patients (81.0%) were accepted for SWATT follow-up. Fifty-five (8.6%) of patients accepted by SWATT showed increased wound secretion for greater than 5 days. This included 12.7% of THR and 5.5% of TKR patients. Increased wound secretion resulted in 226 extra home visits by SWATT, at an extra cost of £23,104 (7.5% increase in SWATT budget). Twenty-six of the 55 patients had positive microbial growth when wound secretions were swabbed. Five patients were admitted for management of wound infections. Incidentally, there were 2 reported cases of DVT and PE. These were not in the increased wound secretion patients. In summary, Dabigatran at Warwick Hospital was associated with a higher than predicted incidence of surgical site morbidity, increased resource output and increased postoperative discharge costs. As a consequence, Dabigatran use has been reduced and other oral anticoagulants are being trialled

Total joint replacement (TJR) is by far the most effective therapy for end-stage OA patients. Most of patients achieve joint pain reduction and function improvement following to TJR, however up to 22% of them either do not improve or deteriorate after surgery. The aim of this study was to identify genetic variants to be associated with poor outcome of TJR in primary OA patients by a genome-wide association approach (GWAS). Study participants were primary OA patients from the Newfoundland Osteoarthritis Study (NFOAS) that comprised total knee or hip replacement and recruited before 2016 in St. John's, NL. DNA samples were extracted from patients' blood. Study participants completed their pre-operation and 3.99±1.38 years post-surgery outcome assessment using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). DNA samples were genotyped using the genome-wide Illumina HumanOmni2.58 genotyping microarray containing 2.4 million SNPs. Pre-association quality control filtering was conducted for the raw genotyping data using PLINK 1.7 program, and genotype imputation was performed using the IMPUTE2 algorithm with multiple population reference data from 1000 Genome Project. The imputed data with ∼3.1 million variants was used to test the association with non-responders to TJR using the additive genetic model. Eighty three primary OA patients (44 responders and 39 non-responders) were included in the analysis. Association analysis detected three chromosomal regions on chr5, 7, and 8 to be significantly associated with non-responding to pain. The top SNPs at these loci are intergenic variants that include SNP (rs17118094, p=4.4×10-5) on chr5. This SNP is adjacent to SGCD gene that plays an important role in muscular strength and maintenance. Another associated SNP (rs71572810, p=4.7×10-5) is nearby IMMP2L gene on chr7. This gene is reported to be associated with behavioral abnormalities. Finally, SNP (rs6992938, p=5.8×10-5) on chr8 is located downstream of TRPA1 gene that is known to have a central role in the pain response to endogenous inflammatory mediators. Three loci were also found to be significantly associated with non-responding to function. The lead variant in the locus on chr1 is an intergenic SNP (rs9729377, p=1.7×10-5) falling between CTBS and MCOLN2 genes. CTBS gene is associated with TNF-α, a cytokine that stimulate the inflammation acute phase reaction, and MCOLN2 gene plays a role in the chemokine secretion and macrophage migration in the innate immune response. Other top SNPs in loci on chr2 and 10 harbor CCDC93, INSIG2, and KLF6 genes that are associated with heel bone mineral density, hypercholesterolemia, obesity and BMI. To our knowledge, this project is the first study that investigated the association between genetic factors and TJR non-responders. Our results demonstrated that genes related to muscle strength, behavioral trait, pain response, and inflammation play a significant role in poor outcome of TJR, warranting further investigation

Noting a decreasing number of transfemoral amputations following infection of Total Knee Arthroplasty (TKA) I studied a case of a patient which suffered an amputation following infection of TKA by MRSA. With assistance of all hospitals and the NHS it was able to classify all costs of this poor case. This study exposes a drama of a person which received a Total Knee Arthroplasty in the right knee at 66.0 years. 2 weeks after the implantation of TKA she presented a wound secretion, the microbiology shows: MRSA, Pseudomonas aeroguinos and Streptococcus. 4 surgical revisions followed without removing the TKA. 35 month later, with 68.9 years it was indispensable to remove the TKA in a 6th operation, implanting a spacer with Vancomycine. 1 month later removing of the spacer and implanting a second cemented TKA in the 7th surgery. With 70.2 years the removal of the second TKA was necessary because of infection with Pseudomonas aeroguinosa and Morganelli morganii. Now implantation of another spacer with Vancomycine. 1 month later with 70.3 years removal of the spacer molding an arthrodesis of the knee using an intramedullary femur to tibia rod. After that 4 revision surgeries with changing the intramedullary rod some wound revisions followed, ending in the 23rd operation with a transfemoral amputation with 71.1 years – 5 years after primary TKA. 3 month after transfemoral amputation the patient presented high temperature and a secretion of the scarf of the TT-stump; microbiology: MRSA. 2 more surgeries are necessary to stop the infection. This patient suffered over all 25 surgical procedures in 5.5 years. The hospitalization for acute infection of TKA led to 431 days in different hospitals in 33 months. Statement of charges from the hospitals € 74.046,92 in the last three years before amputation. Payments by the health insurance € 155.424,00 for all procedures. We will demonstrate the different costs of hospital procedures and distribution for the insurance for all performances

Adolescent idiopathic scoliosis (AIS) is a poorly understood progressive curvature of the spine. The 3-dimmensionnal spinal deformation brings abnormal biomechanical stresses on the load-bearing organs. We have recently reported for the first time the presence of facet joint cartilage degeneration comparable to age-related osteoarthritis in scoliotic adolescents. To better understand the degenerative mechanisms and explore new therapeutic possibilities, we focused on Toll-like receptors (TLRs) which are germline-encoded pattern recognition receptors that recognize pathogens and endogenous proteins such as fragmented extracellular matrix components (alarmins) present in intervertebral discs (IVD) and articular cartilage. Once activated, they regulate the production pro-inflammatory cytokines, proteases and neurotrophins which can lead to matrix catabolism, inflammation and potentially pain. These mechanisms have however not been studied in the context of AIS or facet joints. Facet joints of AIS patients undergoing corrective surgery and of cadaveric donors (non-scoliotic) were collected from consenting patients or organ donors with ethical approval. Cartilage biopsies and chondrocytes were isolated using 3mm biopsy punches and collagenase type 2 digestion respectively. qPCR was used to assess gene expression of the degenerative factors (MMP3, MMP13, IL-1ß, IL-6, IL-8) The biopsies were cut into two equal halves, one was treated for 4 days with a TLR2 agonist (Pam2CSK4, Invivogen) in serum-free chondrocyte media while the other one was cultured in media alone. MMP3, MMP13, IL-6 and IL-8 ELISAs and DMMB assays were performed on the biopsy cultured media. The ex vivo cartilage was then fixed, cryosectionned and also stained with SafraninO-Fast Green dyes. Baseline gene expression levels of TLR1,−2,−4,−6 were all upregulated in scoliotic chondodryctes compared to non-scoliotic. Pearson correlation analysis revealed that all TLR1,−2,−4,−6 gene expression correlated strongly and significantly with degenerative markers (MMP3, MMP13, IL-6, IL-8) in scoliotic chondrocytes but not in non-scoliotic. (Figure 1) When monolayer facet joint chondrocytes were activated with Pam2CSk4, there was a significant upregulation in previously described degenerative markers, TLR2 and NGF, a potent neurotrophin. These findings were strengthened by protein secretion analysis of select markers such as MMP-3, −13, IL-6 and IL-8 which were all upregulated after TLR2 activation. The scoliotic biopsies which were treated with Pam2CSK4 had a significant loss of proteoglycan content as shown by histology, was reflected in the proteoglycan content found in the media by DMMB. TLR gene expression levels were upregulated and correlated with proteases and pro-inflammatory cytokines in degenerating scoliotic cartilage, suggesting they promote cartilage degradation, especially considering the lack of correlations in non-scoliotic healthy cartilage. Furthermore, when TLRs are activated by Pam2CSK4 it triggers the release of the same proteases and pro-inflammatory cytokines in our ex vivo experiment. All this exacerbates the loss of proteoglycan in the cartilage ex vivo model after four days of insult with a TLR2 specific agonist. These results suggest that TLRs are an important pathway partaking in the cartilage degeneration of scoliotic facet joints and potentially all cartilage beyond our scope. Future studies aim at blocking TLRs to alleviate proteolysis and inflammation. For any figures or tables, please contact the authors directly

The clinical case refers to a male patient, 34 years old, admitted at the Emergency Department after a fall of 2 meters. Of that trauma, resulted an exposed Monteggia fracture type III – Gustillo & Anderson IIA – on his left arm. With this work, the authors intend to describe the evolution of the patient's clinical condition, as well as the surgical procedures he was submitted to. The authors used the patient's records from Hospital's archives, namely from the Emergency Department, Operating Room, Infirmary and Consultation, and also the diagnostic exams performed throughout the patient's clinical evolution. The clinical case began in December 2011, when the patient suffered a fall of 2 meters in his workplace. From the evaluation in the Emergency Department, it was concluded that the patient presented, at the left forearm, an exposed Monteggia type III fracture – Gustillo & Anderson IIA – combined with a comminuted fracture of the radial head. At the admission day, the wound site was thoroughly rinsed, the fracture was reduced and immobilized with an above-the-elbow cast, and antibiotics were initiated. Six days after admission, the patient was submitted to open reduction with internal fixation with plate and screws of the fracture of the ulna and radial head arthroplasty. The postoperative period was uneventful. Two months after the surgical procedure, inflammatory signals appeared with purulent secretion in the ulnar suture. Accordingly, the patient was submitted to fistulectomy, rinsing of the surgical site and a cycle of antibiotics with Vancomycin, directed to the S. aureus isolated from the purulent secretion. The clinical evolution was unfavorable, leading to the appearance of a metaphyseal pseudarthrosis or the ulna and dislocation of the radial head prosthesis. The previously implanted material was therefore removed, 4 months after the traumatic event; at the same time an external fixation device was applied and the first part of a Masquelet Technique was conducted. The second part of the aforementioned procedure was carried out in December 2012. The patient was discharged from the consultation after a 2 years follow-up, with a range of motion of the left elbow acceptable for his daily living activities. In spite of the multiple surgical rinsing procedures and directed antibiotics, the development of a metaphyseal pseudarthrosis of the ulna was inevitable. This clinical case illustrates how the Masquelet Technique presents itself as a good solution for the cases of non-union of fractures in the context of infection

Osteochondral (OC) defects of the knee are associated with pain and significant limitation of activity. Studies have demonstrated the therapeutic efficacy of mesenchymal stem cell (MSC) therapies in treating osteochondral defects. There is increasing evidence that the efficacy of MSC therapies may be a result of the paracrine secretion, particularly exosomes. Here, we examine the effects of MSC exosomes in combination with Hyaluronic Acid (HA) as an injectable therapy on functional osteochondral regeneration in a rabbit osteochondral defect model. Exosomes were purified from human MSC conditioned medium by size fractionation. A circular osteochondral defect of 4.5 mm diameter and 2.5 mm depth was surgically created in the trochlear grooves of 16 rabbit knees. Thereafter, eight knees received three weekly injections of 200 µg of exosomes in one ml of 3% HA, and the remaining eight knees received three weekly injections of one ml of 3% HA only. The rabbits were sacrificed at six weeks. Analyses were performed by macroscopic and histological assessments, and functional competence was analysed via Young Modulus calculation at five different points (central, superior, inferior, medial and lateral) of the repaired osteochondral defect site. MSC exosomes displayed a modal size of 100 nm and expressed exosome markers (CD81, TSG101 and ALIX). When compared to HA alone, MSC exosomes in combination with HA showed significantly better repair histologically and biomechanically. The Young Modulus was higher in 4 out of the 5 points. In the central region, the Young Modulus of MSC exosome and HA combination therapy was significantly higher: 5.42 MPa [SD=1.19, 95% CI: 3.93–6.90] when compared to HA alone: 2.87 MPa [SD=2.10, 95% CI: 0.26–5.49], p < 0 .05. The overall mean peripheral region was also significantly higher in the MSC exosome and HA combination therapy group: 5.87 MPa [SD=1.19, 95% CI: 4.40–7.35] when compared to HA alone: 2.70 MPa [SD=1.62, 95% CI: 0.79–4.71], p < 0 .05. The inferior region showed a significantly higher Young Modulus in the combination therapy: 7.34 MPa [SD=2.14, 95% CI: 4.68–10] compared to HA alone: 2.92 MPa [SD=0.98, 95% CI: 0.21–5.63], p < 0.05. The superior region showed a significantly higher Young Modulus in the combination therapy: 7.31 MPa [SD=3.29, 95% CI: 3.22–11.39] compared to HA alone: 3.59 MPa [SD=2.55, 95% CI: 0.42–6.76], p < 0.05. The lateral region showed a significantly higher Young Modulus in the combination therapy: 8.05 MPa [SD=2.06, 95% CI: 5.49–10.61] compared to HA alone: 3.56 MPa [SD=2.01, 95% CI: 1.06–6.06], p < 0.05. The medial region showed a higher Young Modulus in the combination therapy: 6.68 MPa [SD=1.48, 95% CI: 4.85–8.51] compared to HA alone: 3.45 MPa [SD=3.01, 95% CI: −0.29–7.19], but was not statistically significant. No adverse tissue reaction was observed in all the immunocompetent animals treated with MSC exosomes. Three weekly injections of MSC exosomes in combination with HA therapy results in a more functional osteochondral regeneration as compared to HA alone

NICE technology appraisal guidance 157 suggests that the oral anticoagulation medication Dabigatran etexilate can be used for the primary prevention of venous thromboembolic events (VTE's) in adult patients who have undergone elective total hip or knee replacement surgery. The NICE guidance reports that 13.8% of patients receiving recommended doses of Dabigatran experienced adverse bleeding events. In the pivotal hip and knee VTE trial, wound secretion only accounted for 4.9% of patients treated with Dabigatran (cf 3.0% of patients treated with Enoxaparin). We report our wound secretion experience after Dabigatran use at Warwick Hospital from March 2009 to March 2010. Of the 788 lower-limb arthroplasties performed, 55 patients (6.9%) had oozing wounds after discharge (Mean=8 days, Range=1-39 days). This resulted in 226 extra home-visits by discharge nurses, 26 positive microbiology cultures and 5 confirmed wound infections needing antibiotic treatment and/or surgical intervention. Incidentally, there were also 2 known cases each of deep vein thrombosis and pulmonary embolus in this cohort. The number of complications was markedly increased from previous years when LMWH was the VTE prophylaxis used. This data suggests that the use of Dabigatran in Warwick Hospital may significantly increase surgical site morbidity and resource output after lower limb arthroplasty

Aim. Posttraumatic pelvic-osteomyelitis is one of the most serious complications after pelvic-fractures. The necessary extensive surgical debridement as part of interdisciplinary treatment is complicated by the possible persistence of pelvic instability. The aim of this study was to determine the outcome and outline the course of treatment after early posttraumatic pelvic bone infections due to type-C pelvic ring injuries. Method. In a retrospective cohort study (2005–2015) all patients with pelvic-osteomyelitis within six weeks of surgical stabilization of a type-C pelvic-fracture were assessed. Microbiological results, risk factors, course of treatment and functional long-term outcome using the Orlando-Pelvic-Score were analyzed. Results. A total of 18 patients (age 43.7 years; Body-Mass-Index 27.9 kg/m2; ASA-physical-status 1.8; Injury-Severity-Score 38) developed a pelvic-osteomyelitis within an average of 27 days after internal surgical stabilization of a type-C pelvic injury (AO-type C1: 10, C2: 4, C3: 4). Os pubis was affected in 7 and Os ilium in 11 cases. In addition to the pelvic-fracture, major vascular injuries occurred in 8, nerve injuries in 9, and intestinal and/or bladder ruptures in 11 cases. In 14 cases a mass transfusion was necessary. In addition to clinical signs of inflammation, (10 × redness, 12 × wound secretion, 6 × fistula) elevated levels of c-reactive-protein (7.7 mg/dl) and white-blood-cells (10.5/nl) were found. Bacterial cultures harvested during the initial surgical revision demonstrated mixed cultures in 17/18 cases, with an average of 3 different organisms isolated per case (61% intestinal bacteria). During the scheduled repetitive debridement a reduction of the initial mixed cultures into a single organism was observed. Overall 6.8 surgical interventions, including implant removal, were necessary until osteomyelitis was eradicated. In no cases was re-osteosynthesis performed. In 6/18 cases recurrence of infection occurred after an average of 5 months, followed by an additional repetitive debridement. An average 3-year-follow-up after the initial osteomyelitis-diagnosis demonstrated eradication of infection in 17/18 cases combined with an Orlando-Pelvic-Score of 21.9 points (best possible function: 40 points). Despite significant pelvic malalignment the ability to walk was achieved in all patients, with one exception due to a spinal cord injury. Conclusions. Despite no new surgical stabilization of the initial unstable pelvic injury, the early removal of implants combined with extensive debridement and antibiotic therapy led to sufficient long-term outcomes in patients with early posttraumatic pelvic-osteomyelitis. In particular, due to the severity of the initial injury and the complex interdisciplinary approach, early diagnosis of the osteomyelitis is essential

Aim. The current treatment concepts of acute and chronic osteomyelitis are associated with unsolved challenges and problems, underlining the need for ongoing medical research. The invention and prevalence of an absorbable, gentamicin-loaded ceramic bone graft, that is well injectable for orthopedic trauma and bone infections, enlarges the treatment scope regarding the rise of posttraumatic deep bony infections. This substance can be used either for infection, dead-space, or reconstruction management. The bone cement, eluting antibiotics continuously to the surrounding tissue, outperforms the intravenous antibiotic therapy and enhances the local concentration levels efficiently. This study aims to evaluate the power and practicability of bone cement in several locations of bony infections. Method. The occurrence of posttraumatic infections with acute or chronic osteomyelitis increases in trauma surgery along with progression of high impact injuries and consecutively high incidence of e.g. open fractures. We present a case-series of 33 patients (18w/15m; 56,8±19,4 years) with posttraumatic osteomyelitis at different anatomic sites, who were treated in our level I trauma center. All of these patients received antibiotic eluting bone cement (Cerement® G) for infection and reconstruction management. Results. With admission to our trauma-center all patients with obvious or suspected osteomyelitis undergo an interdisciplinary pre-work up, including thorough clinical examination and different measures of diagnostic imaging, ultimately leading to the definition of an individual treatment plan. We diagnosed 33 bone infections anatomically allocated to the proximal and distal femur (12x), the pelvis (2x), distal tibia (3x), tibial diaphysis (10x), the ankle joint (4x) and calcaneus (2x). According to Cierny-Mader we diagnosed grade I (6), II (7), III (13) and IV (7). These 33 patients were treated (1) with surgical debridement, (2) with Cerament G, (3) bone stabilisation (including nail osteosynthesis, arthrodesis nails, plates, or external ring fixation), (4) optionally VAC-conditioning, and (5) optionally soft tissue closure with local or free flaps. The overall number of surgery was 2.9±2.26. We observed very good clinical, functional and radiological results by using bone cement augmented with gentamicin. The overall recurrence rate of infection is low (12%, 4/33). “White fluid” secretion was observed in six cases. Conclusions. Current concepts for treatment of osteomyelitis include radical surgical debridement and additional antibiotic therapy. It could be demonstrated that the usage of an antibiotic biocement with osteoconductive characteristics enlarges the success rate in septic bone surgery. The treatment concepts, however, remain complex, time consuming, require a high patient compliance, and are highly individually

Aims

Chronic osteomyelitis (COM) of the lower limb in adults can be surgically managed by either limb reconstruction or amputation. This scoping review aims to map the outcomes used in studies surgically managing COM in order to aid future development of a core outcome set.

Aims

This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms.

Aim. The current treatment concepts of acute and chronic osteitis are associated with unsolved challenges and problems, underlining the need for ongoing medical research. The invention and prevalence of an absorbable, gentamicin-loaded ceramic bone graft, that is well injectable for orthopedic trauma and bone infections, enlarges the treatment scope regarding the rise of posttraumatic deep bone infections. This substance can be used either for infection, dead-space, or reconstruction management. The bone cement, eluting antibiotics continuously to the surrounding tissue, outperforms the intravenous antibiotic therapy and enhances the local concentration levels efficiently. This study aims to evaluate the power and practicability of bone cement in several locations of bone infections. Method. The occurrence of posttraumatic infections with acute or chronic osteitis increases in trauma surgery along with progression of high impact injuries and consecutively high incidence of e.g. open fractures. We present a case-series of 10 patients with posttraumatic osteitis at different anatomic sites, who were treated in our level I trauma center. All of these patients received antibiotic eluting bone cement* for infection and reconstruction management. Results. With admission to our trauma-center all patients with obvious or suspected osteitis undergo an inter-disciplinary pre-work up, including thorough clinical examination and different measures of diagnostic imaging, ultimately leading to the definition of an individual treatment plan. We diagnosed 10 bone infections anatomically allocated to the proximal (2x) and distal femur (3x), distal tibia (3x), tibial diaphysis (1x) and the ankle joint (1x). These ten patients were treated (1) with surgical debridement, (2) with an antibiotic eluting bone cement*, (3) bone stabilisation (including nail osteosynthesis, arthrodesis nails, plates, or external ring fixation), (4) optionally VAC-conditioning, and (5) optionally soft tissue closure with local or free flaps. We observed very good clinical, functional and radiological results by using bone cement augmented with gentamicin. The overall treatment failure rate is low, throughout, all patients showed no signs of acute recurrence of infection. Pain and immobility decreased continuously with time. “White fluid” secretion was observed in one case. Conclusion. Current concepts for treatment of osteitis include radical surgical debridement and additional antibiotic therapy. It could be demonstrated that the usage of an antibiotic biocement with osteoconductive characteristics enlarges the success rate in septic bone surgery. The treatment concepts, however, remain complex, time consuming, require a high patient compliance, and are highly individually. *Cerement® G

The appearance of a tumor as a result of chronic osteomyelitis is a relatively rare complication and of late-onset, with a low frequence in the modern world. For the majority of patients, the interval between the onset of primitive osteomyelitis and malignant degeneration is of several decades. We present our cases and the protocol of treatment used. From January 1977 to December 2014 we treated 36 patients (33M, 3F) suffering from squamous cell tumor out of a series of 247 tibial and 74 calcaneal osteomyelitis. 26 patients had chronic osteomyelitis of tibia, 10 of the calcaneus. Based on the functional needs of patients after resection of the tumor, in 18 we applied the Ilizarov apparatus, in 14 we opted for a two steps surgery, with the help of plastic surgeon; four required amputation. 29 patients healed. After 2-years of follow up 3 patients underwent to an amputation in the proximal third of the leg, 4 had a local recurrence. All patients were assessed by SF32 and the QoL test. Squamous cell tumor is the most common malignant tumor in chronic osteomyelitis. For the diagnosis of malignant transformation from a chronic ulcer there is a thorough process. Serial biposies must be performed, especially with the emergence of new clinical signs (increased pain, a bad smell, and changes in secretion by the wound). The definitive treatment is often amputation proximal to the tumor or wide local excision in combination with adjuvant chemotherapy and radiotherapy in selected patients. Early detection can sometimes allow limb salvage. However, the most effective treatment is prevention with the definitive treatment of osteomyelitis, including appropriate debridement, wide excision of the affected area, and early reconstruction

Osteomyelitis is an infectious process in bone occasionally leading to bone destruction. Traditionally a two-stage operation is performed using PMMA + antibiotic beads or a spacer. In the second operation the void filler is removed and the defect is filled with autologous bone. Bioactive glass (BAG) S53P4 is an antibacterial biodegradable bone substitute. This feature is based on an increase in pH and the osmotic pressure around the BAG, a phenomenon which has been shown to kill both planktonic bacteria and bacteria in biofilm in-vitro. We analyzed retrospectively our early results of osteomyelitis patients treated with BAG from the patient's clinical history. The diagnosis was stated in addition to bacterial samples by MRI, CT and plain radiographs or by a combination of these. Between 2007–2013 we applied BAG as a void-filler in 20 cases (15 male and 5 female) of osteomyelitis in the lower (19) or the upper (1) limb in one-stage procedure. The patients had been suffering from symptoms of osteomyelitis a mean 3,5 months (0,25–24,00) and had a history of mean 3,5 (1–11) earlier operations. Osteomyelitis was estimated to be healed when the enclosed systemic antibiotic treatment and clinical controls were carried out and the patient didn't have symptoms of a persisting disease. The average postoperative follow up was 7,8 (3,0–59,0) months. Fifteen (75%) of the patients healed. One patient run out of controls, but was symptom free during his last visit. In four cases we had to remove the bioactive glass because of continuous secretion. In three cases the debridement was incomplete and one had a poor soft tissue cover and a candida infection. Adjuvant systemic antibiotic treatment was prescribed postoperatively 7,3 (4–19) weeks. Bioactive glass is an effective void filling material in the treatment of osteomyelitis. Proper debridement and a soft tissue cover should be performed. Main reason for that the five patients did not heal is, that this procedure is new and we were looking for the right indications and techniques

Bone metastases are common and severe complications of cancers. It is estimated to occur in 65–75% of breast and prostate cancer patients and cause 80% of breast cancer-related deaths. Metastasised cancer cells have devastating impacts on bone due to their ability to alter bone remodeling by interacting with osteoblasts and osteoclasts. Exercise, often used as an intervention for cancer patients, regulates bone remodeling via osteocytes. Therefore, we hypothesise that bone mechanical loading may regulate bone metastases via osteocytes. This provides novel insights into the impact of exercises on bone metastases. It will assist in designing cancer intervention programs that lowers the risk for bone metastases. Investigating the mechanisms for the observed effects may also identify potential drug targets. MLO-Y4 osteocyte-like cells (gift of Dr. Bonewald, University of Missouri-Kansas City) on glass slides were placed in flow chambers and subjected to oscillatory fluid flow (1Pa; 1Hz; 2 hours). Media were extracted (conditioned media; CM) post-flow. RAW264.7 osteoclast precursors were conditioned in MLO-Y4 CM for 7 days. Migration of MDA-MB-231 breast cancer cells and PC3 prostate cancer cells towards CM was assayed using Transwell. Viability, apoptosis, and proliferation of the cancer cells in the CM were measured with Fixable Viability Dye eFluor 450, APOPercentage, and BrDu, respectively. P-values were calculated using Student's t-test. Significantly more MDA-MB-231 and PC3 cells migrated towards the CM from MLO-Y4 cells with exposure to flow in comparison to CM from MLO-Y4 cells not exposed to flow. The preferential migration is abolished with anti-VEGF antibodies. MDA-MB-231 cells apoptosis rate was slightly lower in CM from MLO-Y4 cells exposed to flow, while proliferation rate was slightly higher. The current data showed no difference in cancer cells viability and adhesion to collagen between any two groups. On the other hand, it was observed that less MDA-MB-231 cells migrated towards CM from RAW264.7 cells conditioned in CM from MLO-Y4 cells stimulated with flow in comparison to those conditioned in CM from MLO-Y4 cells not stimulated with flow. TRAP staining results confirmed that there were less differentiated osteoclasts when RAW264.7 cells were cultured in CM from MLO-Y4 cells exposed to flow. Overall, this study suggests that when only osteocytes and cancer cells are involved, osteocytes subjected to mechanical loading can promote metastases due to the increased secretion of VEGF. However, with the incorporation of osteoclasts, mechanical loading on osteocytes seems to reduce MDA-MB-231 cell migration. This is likely because osteocytes reduce osteoclastogenesis in response to mechanical stimulation, and osteoclasts have been shown to support cancer cells. Animal studies will also be conducted to verify the pro- or anti-metastatic effect of mechanical loading that is observed in the in vitro part of this study

After a few years from its introduction, the limits of the THA became evident, mainly due to high rates of mobilization for polyethylene wear and to the release of metal ions from MOM and MOP couplings. Ceramic bearings were thus introduced in surgery to obtain lower levels of friction and wear. These issues have now been well recognized by several studies, which show that ceramic-on-ceramic joint has the lowest wear rate among various articulations and that ceramic particles induce less macrophage reaction and decrease cytokine secretion, allowing to have little periprosthetic osteolysis. After the first results in the late 70′s and early 80′s, the mechanical reliability was improved due to the manufacturers' efforts to reduce the ceramic fragility evolving average grain microstructure and lowering the degree of impurity. Betterment and standardization of production have led to 3. rd. generation alumina, Biolox Forte in 1994, that achieved a lower incidence of fracture. The purpose of our study has been to assess long-term follow-up results of alumina-on-alumina 3. rd. generation ceramic total hip cementless arthroplasty performed at our institution from January 1995 to December 2000. We prospectively followed more than 200 patients operated of THA for primary or secondary hip osteoarthritis analyzing clinical and radiographs features. In this period, the total hip replacement were performed by a single surgeon, who is the senior author (A.T.) in our Institution. All patients were clinically examined to confirm the diagnosis and all of them were checked with a standard plain radiographs in two projections and, when necessary, the radiographic examination was completed by CT scans. The same prosthesis was used in all patients, a 3. rd. generation alumina COC articulation, composed of a hemispherical titanium alloy cup and a 28-mm alumina ceramic femoral head. The modular ceramic head was fixed to a 12/14 taper cone. Proximally plasma-spray hydroxyapatite coated Ti alloy stems completes the implant features. Modular necks were used in retro or anteversion and varus or valgus offset, allowing changes in neck-shaft angle and giving a perfect intraoperative stability. Clinical assessment was performed using the Merle-D'Aubigne and Postel hip score. Each patient was assessed before surgery, after 30 days, afterwards at 4 months and annually after surgery. The mode of femoral component fixation was radiographically classified as bone ingrowth fixation, stable fibrous fixation or unstable fixation, according to the criteria Engh-Bobyn. Osteolysis was evaluated on the femoral side at each Gruen zone. Osteolysis on the acetabular side was evaluated by DeLee and Chanley zone. Our study has concluded that cementless modular hip arthroplasty with 3. rd. generation ceramic-on-ceramic bearing, with a 13 to 18 years follow-up, shows an excellent survivorship, in particular for the very low volume release of microparticles during friction, which consequently reduction of cytokine release, thus diminishing the risk of periprosthetic osteolysis and loosening of implant components

Introduction:. 20 cases of bone defect have been treated by the induced membrane technique avoiding allograft, microsurgery and amputation. Material and Methods:. 9 cases of long bone defect (humerus and forearm) and 11 cases of bone defect at the hand have been included in this multicentre prospective study (3 centers). The aetiology in 11 cases was trauma, 7 cases were septic nonunions and 2 cases followed tumors. In the hand the bone loss was at least one phalanx, and for long bones the mean defect was 5 cm (3–11). All cases were treated by the induced membrane technique which consists in stable fixation, flap if necessary and in filling the void created by the bone defect by a cement spacer (PMMA). This technique needs a second stage procedure at the 2. nd. month where the cement is removed and the void is filled by cancellous bone. The key point of this induced membrane technique is to respect the foreign body membrane which appeared around the cement spacer and which creates a biologic chamber for the second procedure. Bone union was evaluated prospectively in each case by a surgeon not involved in the treatment, by X-ray and CT scan. Failure was defined as a nonunion at 1 year, or an uncontrolled sepsis at 1 month. Results:. 3 cases failed to achieve bone union, 2 in the hand and 1 in a long bone. No septic complications occurred and all septic cases healed. In 14 cases bone union was achieved with a delay of 5 months (1, 5–12). 2 biopsies allowed us to prove that osteoid tissue was created by the technique. At hand level all fingers have included. At shoulder and elbow level, function reached 75% of motion of the contralateral side. Discussion:. Masquelet first reported 35 cases of large bone defect of tibia nonunion treated by the induced membrane technique which allow filling a bone defect with cancellous bone alone. The cement spacer induces a foreign body membrane (neo periosteum) which constitute a biological chamber. Animal models showed the properties of the membrane: secretion of growths factors (VEGF, TGFbéta1, BMP2) and osteoinductive activitie of the cells. Conclusion:. This technique is useful in emergency or in septic condition where a bone defect cannot be solved by shortening. The technique avoids the use of microsurgery and the limit is the quantity of available cancellous bone

Over 80% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Although thought to involve a complex cascade of cell-cell interactions, the factors controlling the development of bone metastases are still poorly understood. Osteoblasts may have an important role in mediating homing and proliferation of breast cancer cells to the bony environment. This study aimed to examine the potential role osteoblasts have in the migration of circulating tumour cells to bone and the factors involved in this attraction. Culture of osteoblasts and MDA-MB-231 breast cancer cells was performed. Breast cancer cell migration in response to osteoblasts was measured using Transwell Migration Inserts. Potential mediators of cell migration were detected using ChemiArray & ELISA assays. A luminometer based Vialight assay was used to measure breast cancer cell proliferation in response to factors secreted by osteoblasts. There was a 3-4 fold increase of MDA-MB-231 migration in response to osteoblasts. ChemiArray analysis of osteoblast-conditioned medium revealed a range of secreted chemokines including IL-6 & 8, TIMP 1 & 2 and MCP-1. Initially, MCP-1 was quantified at 282 pg/ml, but rose to over 9000 pg/ml when osteoprogenitor cells were differentiated into mature osteoblasts. Inclusion of a monoclonal antibody to MCP-1 in osteoblast-conditioned medium resulted in a significant decrease in breast cancer cell migration to osteoblasts. There was no significant change in proliferation of MDA-MB 231 cells when exposed to osteoblast-conditioned medium. Osteoblasts are capable of inducing breast cancer cell migration mediated at least in part by chemokine secretion. MCP-1 produced by the osteoblasts was shown to play a central role in mediating homing of the breast cancer cells. Increased understanding of the pathways involved in the development of bone metastases may provide new targets for therapeutic intervention