The ability to edit DNA at the nucleotide level using clustered regularly interspaced short palindromic repeats (CRISPR) systems is a relatively new investigative tool that is revolutionizing the analysis of many aspects of human health and disease, including orthopaedic disease. CRISPR, adapted for mammalian cell genome editing from a bacterial defence system, has been shown to be a flexible, programmable, scalable, and easy-to-use gene editing tool. Recent improvements increase the functionality of CRISPR through the engineering of specific elements of CRISPR systems, the discovery of new, naturally occurring CRISPR molecules, and modifications that take CRISPR beyond gene editing to the regulation of gene transcription and the manipulation of RNA. Here, the basics of CRISPR genome editing will be reviewed, including a description of how it has transformed some aspects of molecular musculoskeletal research, and will conclude by speculating what the future holds for the use of CRISPR-related treatments and therapies in clinical orthopaedic practice. Cite this article: Bone Joint Res 2020;9(7):351–359

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Vertebrates have adapted to life on Earth and its constant gravitational field, which exerts load on the body and influences the structure and function of tissues. While the effects of microgravity on muscle and bone homeostasis are well described, with sarcopenia and osteoporosis observed in astronauts returning from space, the effects of shorter exposures to increased gravitational fields are less well characterized. We aimed to test how hypergravity affects early cartilage and skeletal development in a zebrafish model.

Aims. This study aimed to explore the role of small colony variants (SCVs) of Staphylococcus aureus in intraosseous invasion and colonization in patients with periprosthetic joint infection (PJI). Methods. A PJI diagnosis was made according to the MusculoSkeletal Infection Society (MSIS) for PJI. Bone and tissue samples were collected intraoperatively and the intracellular invasion and intraosseous colonization were detected. Transcriptomics of PJI samples were analyzed and verified by polymerase chain reaction (PCR). Results. SCVs can be isolated from samples collected from chronic PJIs intraoperatively. Transmission electron microscopy (TEM) and immunofluorescence (IF) showed that there was more S. aureus in bone samples collected from chronic PJIs, but much less in bone samples from acute PJIs, providing a potential mechanism of PJI. Immunofluorescence results showed that SCVs of S. aureus were more likely to invade osteoblasts in vitro. Furthermore, TEM and IF also demonstrated that SCVs of S. aureus were more likely to invade and colonize in vivo. Cluster analysis and principal component analysis (PCA) showed that there were substantial differences in gene expression profiles between chronic and acute PJI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these differentially expressed genes were enriched to chemokine-related signal pathways. PCR also verified these results. Conclusion. Our study has shown that the S. aureus SCVs have a greater ability to invade and colonize in bone, resulting in S. aureus remaining in bone tissues long-term, thus explaining the pathogenesis of chronic PJI. Cite this article: Bone Joint Res 2022;11(12):843–853

Aims. To fully quantify the effect of posterior tibial slope (PTS) angles on joint kinematics and contact mechanics of intact and anterior cruciate ligament-deficient (ACLD) knees during the gait cycle. Methods. In this controlled laboratory study, we developed an original multiscale subject-specific finite element musculoskeletal framework model and integrated it with the tibiofemoral and patellofemoral joints with high-fidelity joint motion representations, to investigate the effects of 2.5° increases in PTS angles on joint dynamics and contact mechanics during the gait cycle. Results. The ACL tensile force in the intact knee was significantly affected with increasing PTS angle. Considerable differences were observed in kinematics and initial posterior femoral translation between the intact and ACLD joints as the PTS angles increased by more than 2.5° (beyond 11.4°). Additionally, a higher contact stress was detected in the peripheral posterior horn areas of the menisci with increasing PTS angle during the gait cycle. The maximum tensile force on the horn of the medial meniscus increased from 73.9 N to 172.4 N in the ACLD joint with increasing PTS angles. Conclusion. Knee joint instability and larger loading on the medial meniscus were found on the ACLD knee even at a 2.5° increase in PTS angle (larger than 11.4°). Our biomechanical findings support recent clinical evidence of a high risk of failure of ACL reconstruction with steeper PTS and the necessity of ACL reconstruction, which would prevent meniscus tear and thus the development or progression of osteoarthritis. Cite this article: Bone Joint Res 2022;11(10):739–750

Aims. High-energy injuries can result in multiple complications, the most prevalent being infection. Vancomycin powder has been used with increasing frequency in orthopaedic trauma given its success in reducing infection following spine surgery. Additionally, large, traumatic injuries require wound coverage and management by dressings such as negative pressure wound therapy (NPWT). NPWT has been shown to decrease the ability of antibiotic cement beads to reduce infection, but its effect on antibiotic powder is not known. The goal of this study was to determine if NPWT reduces the efficacy of topically applied antibiotic powder. Methods. Complex musculoskeletal wounds were created in goats and inoculated with a strain of Staphylococcus aureus modified to emit light. Six hours after contaminating the wounds, imaging, irrigation, and debridement and treatment application were performed. Animals received either vancomycin powder with a wound pouch dressing or vancomycin powder with NPWT. Results. There were no differences in eradication of bacteria when vancomycin powder was used in combination with NPWT (4.5% of baseline) compared to vancomycin powder with a wound pouch dressing (1.7% of baseline) (p = 0.986), even though approximately 50% of the vancomycin was recovered in the NPWT exudate canister. Conclusion. The antimicrobial efficacy of the vancomycin powder was not diminished by the application of NPWT. These topical and locally applied therapies are potentially effective tools that can provide quick, simple treatments to prevent infection while providing coverage. By reducing the occurrence of infection, the recovery is shortened, leading to an overall improvement in quality of life. Cite this article: Bone Joint Res 2021;10(2):149–155

MicroRNAs (miRNAs) are a class of small non-coding RNAs that have emerged as potential predictive, prognostic, and therapeutic biomarkers, relevant to many pathophysiological conditions including limb immobilization, osteoarthritis, sarcopenia, and cachexia. Impaired musculoskeletal homeostasis leads to distinct muscle atrophies. Understanding miRNA involvement in the molecular mechanisms underpinning conditions such as muscle wasting may be critical to developing new strategies to improve patient management. MicroRNAs are powerful post-transcriptional regulators of gene expression in muscle and, importantly, are also detectable in the circulation. MicroRNAs are established modulators of muscle satellite stem cell activation, proliferation, and differentiation, however, there have been limited human studies that investigate miRNAs in muscle wasting. This narrative review summarizes the current knowledge as to the role of miRNAs in the skeletal muscle differentiation and atrophy, synthesizing the findings of published data. Cite this article: Bone Joint Res 2020;9(11):798–807

Aims. Preoperative diagnosis is important for revision surgery after prosthetic joint infection (PJI). The purpose of our study was to determine whether reverse transcription-quantitative polymerase chain reaction (RT-qPCR), which is used to detect bacterial ribosomal RNA (rRNA) preoperatively, can reveal PJI in low volumes of aspirated fluid. Methods. We acquired joint fluid samples (JFSs) by preoperative aspiration from patients who were suspected of having a PJI and failed arthroplasty; patients with preoperative JFS volumes less than 5 ml were enrolled. RNA-based polymerase chain reaction (PCR) and bacterial culture were performed, and diagnostic efficiency was compared between the two methods.According to established Musculoskeletal Infection Society (MSIS) criteria, 21 of the 33 included patients were diagnosed with PJI. Results. RNA-based PCR exhibited 57.1% sensitivity, 91.7% specificity, 69.7% accuracy, 92.3% positive predictive value, and 55.0% negative predictive value. The corresponding values for culture were 28.6%, 83.3%, 48.5%, 75.0%, and 40.0%, respectively. A significantly higher sensitivity was thus obtained with the PCR method versus the culture method. Conclusion. In situations in which only a small JFS volume can be acquired, RNA-based PCR analysis increases the utility of preoperative puncture for patients who require revision surgery due to suspected PJI. Cite this article:Bone Joint Res. 2020;9(5):219–224

Aims. This study aimed to explore whether serum combined with synovial interleukin-6 (IL-6) measurement can improve the accuracy of prosthetic joint infection (PJI) diagnosis, and to establish the cut-off values of IL-6 in serum and synovial fluid in detecting chronic PJI. Methods. Patients scheduled to have a revision surgery for indications of chronic infection of knee and hip arthroplasties or aseptic loosening of an implant were prospectively screened before being enrolled into this study. The Musculoskeletal Infection Society (MSIS) definition of PJI was used for the classification of cases as aseptic or infected. Serum CRP, ESR, IL-6, and percentage of polymorphonuclear neutrophils (PMN%) and IL-6 in synovial fluid were analyzed. Statistical tests were performed to compare these biomarkers in the two groups, and receiver operating characteristic (ROC) curves and area under the curve (AUC) were analyzed for each biomarker. Results. A total of 93 patients were enrolled. There was no difference in demographic data between both groups. Synovial fluid IL-6, with a threshold of 1,855.36 pg/ml, demonstrated a mean sensitivity of 94.59% (95% confidence interval (CI) 81.8% to 99.3%) and a mean specificity of 92.86% (95% CI 82.7 to 98.0) for detecting chronic PJI. Then 6.7 pg/ml was determined to be the optimal threshold value of serum IL-6 for the diagnosis of chronic PJI, with a mean sensitivity of 97.30% (95% CI 85.8% to 99.9%) and a mean specificity of 76.79% (95% CI 63.6% to 87.0%). The combination of synovial IL-6 and serum IL-6 led to improved accuracy of 96.77% in diagnosing chronic PJI. Conclusion. The present study identified that a combination of IL-6 in serum and synovial IL-6 has the potential for further improvement of the diagnosis of PJI. Cite this article: Bone Joint Res 2020;9(9):587–592

Objectives. The aim of this study was to investigate the biomechanical effect of the anterolateral ligament (ALL), anterior cruciate ligament (ACL), or both ALL and ACL on kinematics under dynamic loading conditions using dynamic simulation subject-specific knee models. Methods. Five subject-specific musculoskeletal models were validated with computationally predicted muscle activation, electromyography data, and previous experimental data to analyze effects of the ALL and ACL on knee kinematics under gait and squat loading conditions. Results. Anterior translation (AT) significantly increased with deficiency of the ACL, ALL, or both structures under gait cycle loading. Internal rotation (IR) significantly increased with deficiency of both the ACL and ALL under gait and squat loading conditions. However, the deficiency of ALL was not significant in the increase of AT, but it was significant in the increase of IR under the squat loading condition. Conclusion. The results of this study confirm that the ALL is an important lateral knee structure for knee joint stability. The ALL is a secondary stabilizer relative to the ACL under simulated gait and squat loading conditions. Cite this article: Bone Joint Res 2019;8:509–517

Aims. In orthopaedic and trauma surgery, implant-associated infections are increasingly treated with local application of antibiotics, which allows a high local drug concentration to be reached without eliciting systematic adverse effects. While ceftriaxone is a widely used antibiotic agent that has been shown to be effective against musculoskeletal infections, high local concentrations may harm the surrounding tissue. This study investigates the acute and subacute cytotoxicity of increasing ceftriaxone concentrations as well as their influence on the osteogenic differentiation of human bone progenitor cells. Methods. Human preosteoblasts were cultured in presence of different concentrations of ceftriaxone for up to 28 days and potential cytotoxic effects, cell death, metabolic activity, cell proliferation, and osteogenic differentiation were studied. Results. Ceftriaxone showed a cytotoxic effect on human bone progenitor cells at 24 h and 48 h at concentrations above 15,000 mg/l. With a longer incubation time of ten days, subtoxic effects could be observed at concentrations above 500 mg/l. Gene and protein expression of collagen, as well as mineralization levels of human bone progenitor cells, showed a continuous decrease with increasing ceftriaxone concentrations by days 14 and 28, respectively. Notably, mineralization was negatively affected already at concentrations above 250 mg/l. Conclusion. This study demonstrates a concentration-dependent influence of ceftriaxone on the viability and mineralization potential of primary human bone progenitor cells. While local application of ceftriaxone is highly established in orthopaedic and trauma surgery, a therapeutic threshold of 250 mg/l or lower should diminish the risk of reduced osseointegration of prosthetic implants. Cite this article: Bone Joint Res 2021;10(3):218–225

Objectives. The aim of this study was to review the current evidence and future application for the role of diagnostic and therapeutic ultrasound in fracture management. Methods. A review of relevant literature was undertaken, including articles indexed in PubMed with keywords “ultrasound” or “sonography” combined with “diagnosis”, “fracture healing”, “impaired fracture healing”, “nonunion”, “microbiology”, and “fracture-related infection”. Results. The use of ultrasound in musculoskeletal medicine has expanded rapidly over the last two decades, but the diagnostic use in fracture management is not routinely practised. Early studies have shown the potential of ultrasound as a valid alternative to radiographs to diagnose common paediatric fractures, to detect occult injuries in adults, and for rapid detection of long bone fractures in the resuscitation setting. Ultrasound has also been shown to be advantageous in the early identification of impaired fracture healing; with the advent of 3D image processing, there is potential for wider adoption. Detection of implant-related infection can be improved by ultrasound mediated sonication of microbiology samples. The use of therapeutic ultrasound to promote union in the management of acute fractures is currently a controversial topic. However, there is strong in vitro evidence that ultrasound can stimulate a biological effect with potential clinical benefit in established nonunions, which supports the need for further investigation. Conclusion. Modern ultrasound image processing has the potential to replace traditional imaging modalities in several areas of trauma practice, particularly in the early prediction of impaired fracture healing. Further understanding of the therapeutic application of ultrasound is required to understand and identify the use in promoting fracture healing. Cite this article: J. A. Nicholson, S. T. J. Tsang, T. J. MacGillivray, F. Perks, A. H. R. W. Simpson. What is the role of ultrasound in fracture management? Diagnosis and therapeutic potential for fractures, delayed unions, and fracture-related infection. Bone Joint Res 2019;8:304–312. DOI: 10.1302/2046-3758.87.BJR-2018-0215.R2

Objectives. The aim of this study was to review the impact of smoking tobacco on the musculoskeletal system, and on bone fractures in particular. Methods. English-language publications of human and animal studies categorizing subjects into smokers and nonsmokers were sourced from MEDLINE, The Cochrane Library, and SCOPUS. This review specifically focused on the risk, surgical treatment, and prevention of fracture complications in smokers. Results. Smokers have an increased risk of fracture and experience more complications with delayed bone healing, even if they have already stopped smoking, because some adverse effects persist for a prolonged period. Some risks can be reduced during and after surgery by local and general prevention, and smoking cessation is an important factor in lessening this risk. However, if a patient wants to stop smoking at the time of a fracture, the cessation strategies in reducing tobacco use are not easy to implement. The patient should also be warned that using e-cigarettes or other tobaccos does not appear to reduce adverse effects on health. Conclusion. The evidence reviewed in this study shows that smoking has a negative effect in terms of the risk and treatment of fractures. Cite this article: J. Hernigou, F. Schuind. Tobacco and bone fractures: A review of the facts and issues that every orthopaedic surgeon should know. Bone Joint Res 2019;8:255–265. DOI: 10.1302/2046-3758.86.BJR-2018-0344.R1

Aims

Open lower limb fracture is a life-changing injury affecting 11.5 per 100,000 adults each year, and causes significant morbidity and resource demand on trauma infrastructures. This study aims to identify what, and how, outcomes have been reported for people following open lower limb fracture over ten years.

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Open lower limb fracture is life-changing, resulting in substantial morbidity and resource demand, while inconsistent outcome-reporting hampers systematic review and meta-analysis. A core outcome set establishes consensus among key stakeholders for the recommendation of a minimum set of outcomes. This study aims to define a core outcome set for adult open lower limb fracture.

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This cross-sectional study aimed to investigate the in vivo ankle kinetic alterations in patients with concomitant chronic ankle instability (CAI) and osteochondral lesion of the talus (OLT), which may offer opportunities for clinician intervention in treatment and rehabilitation.

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This study aimed to analyze kinematics and kinetics of the tibiofemoral joint in healthy subjects with valgus, neutral, and varus limb alignment throughout multiple gait activities using dynamic videofluoroscopy.

Objectives. Unicompartmental knee arthroplasty (UKA) is one surgical option for treating symptomatic medial osteoarthritis. Clinical studies have shown the functional benefits of UKA; however, the optimal alignment of the tibial component is still debated. The purpose of this study was to evaluate the effects of tibial coronal and sagittal plane alignment in UKA on knee kinematics and cruciate ligament tension, using a musculoskeletal computer simulation. Methods. The tibial component was first aligned perpendicular to the mechanical axis of the tibia, with a 7° posterior slope (basic model). Subsequently, coronal and sagittal plane alignments were changed in a simulation programme. Kinematics and cruciate ligament tensions were simulated during weight-bearing deep knee bend and gait motions. Translation was defined as the distance between the most medial and the most lateral femoral positions throughout the cycle. Results. The femur was positioned more medially relative to the tibia, with increasing varus alignment of the tibial component. Medial/lateral (ML) translation was smallest in the 2° varus model. A greater posterior slope posteriorized the medial condyle and increased anterior cruciate ligament (ACL) tension. ML translation was increased in the > 7° posterior slope model and the 0° model. Conclusion. The current study suggests that the preferred tibial component alignment is between neutral and 2° varus in the coronal plane, and between 3° and 7° posterior slope in the sagittal plane. Varus > 4° or valgus alignment and excessive posterior slope caused excessive ML translation, which could be related to feelings of instability and could potentially have negative effects on clinical outcomes and implant durability. Cite this article: K. Sekiguchi, S. Nakamura, S. Kuriyama, K. Nishitani, H. Ito, Y. Tanaka, M. Watanabe, S. Matsuda. Bone Joint Res 2019;8:126–135. DOI: 10.1302/2046-3758.83.BJR-2018-0208.R2

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Bacteriophages infect, replicate inside bacteria, and are released from the host through lysis. Here, we evaluate the effects of repetitive doses of the Staphylococcus aureus phage 191219 and gentamicin against haematogenous and early-stage biofilm implant-related infections in Galleria mellonella.