Matthew D. Gardiner

Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo

OBJECTIVE Mechanical joint loading is critical for the development of osteoarthritis (OA). Although once regarded as a disease of cartilage attrition, OA is now known to be controlled by the expression and activity of key proteases, such as ADAMTS-5, that drive matrix degradation. This study was undertaken to investigate the link between protease expression and mechanical joint loading in vivo. METHODS We performed a microarray analysis of genes expressed in the whole joint following surgical induction of murine OA (by cutting the medial meniscotibial ligament). Gene expression changes were validated by reverse transcriptase-polymerase chain reaction in whole joints and microdissected tissues of the joint, including the articular cartilage, meniscus, and epiphysis. Following surgery, mouse joints were immobilized, either by prolonged anesthesia or by sciatic neurectomy. RESULTS Many genes were regulated in the whole joint within 6 hours of surgical induction of OA in the mouse. These included Arg1, Ccl2, Il6, Tsg6, Mmp3, Il1b, Adamts5, Adamts4, and Adamts1. All of these were significantly regulated in the articular cartilage. When joints were immobilized by prolonged anesthesia, regulation of the vast majority of genes was abrogated. When joints were immobilized by sciatic neurectomy, regulation of selected genes was abrogated, and OA was prevented up to 12 weeks postsurgery. CONCLUSION These findings indicate that gene expression in the mouse joint following the induction of OA is rapid and highly mechanosensitive. Regulated genes include the known pathogenic protease ADAMTS-5. Targeting the mechanosensing mechanisms of joint tissue may offer new strategies for disease modification.

Strategies to ensure success of microvascular free tissue transfer.

Free tissue transfer has revolutionised tissue reconstruction. Surgical technique is just one of many perioperative factors that determine the eventual outcome of the procedure. Many of these factors can be modified to ensure success. A search of the MEDLINE database using search terms related to perioperative management of free tissue transfer was performed. Further articles were identified by performing related-article searches in MEDLINE. The various perioperative factors that have been demonstrated to affect clinical outcome are discussed along with the current evidence for their optimisation. We present an algorithm for the management of patients undergoing free tissue transfer.

Transcriptional analysis of micro-dissected articular cartilage in post-traumatic murine osteoarthritis.

Summary Objective Identify gene changes in articular cartilage of the medial tibial plateau (MTP) at 2, 4 and 8 weeks after destabilisation of the medial meniscus (DMM) in mice. Compare our data with previously published datasets to ascertain dysregulated pathways and genes in osteoarthritis (OA). Design RNA was extracted from the ipsilateral and contralateral MTP cartilage, amplified, labelled and hybridized on Illumina WGv2 microarrays. Results were confirmed by real-time polymerase chain reaction (PCR) for selected genes. Results Transcriptional analysis and network reconstruction revealed changes in extracellular matrix and cytoskeletal genes induced by DMM. TGFβ signalling pathway and complement and coagulation cascade genes were regulated at 2 weeks. Fibronectin (Fn1) is a hub in a reconstructed network at 2 weeks. Regulated genes decrease over time. By 8 weeks fibromodulin (Fmod) and tenascin N (Tnn) are the only dysregulated genes present in the DMM operated knees. Comparison with human and rodent published gene sets identified genes overlapping between our array and eight other studies. Conclusions Cartilage contributes a minute percentage to the RNA extracted from the whole joint (<0.2%), yet is sensitive to changes in gene expression post-DMM. The post-DMM transcriptional reprogramming wanes over time dissipating by 8 weeks. Common pathways between published gene sets include focal adhesion, regulation of actin cytoskeleton and TGFβ. Common genes include Jagged 1 (Jag1), Tetraspanin 2 (Tspan2), neuroblastoma, suppression of tumourigenicity 1 (Nbl1) and N-myc downstream regulated gene 2 (Ndrg2). The concomitant genes and pathways we identify may warrant further investigation as biomarkers or modulators of OA.

The iBRA (implant breast reconstruction evaluation) study: protocol for a prospective multi-centre cohort study to inform the feasibility, design and conduct of a pragmatic randomised clinical trial comparing new techniques of implant-based breast reconstruction

BackgroundImplant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure in the UK. The introduction of techniques to augment the subpectoral pocket has revolutionised the procedure, but there is a lack of high-quality outcome data to describe the safety or effectiveness of these techniques. Randomised controlled trials (RCTs) are the best way of comparing treatments, but surgical RCTs are challenging. The iBRA (implant breast reconstruction evaluation) study aims to determine the feasibility, design and conduct of a pragmatic RCT to examine the effectiveness of approaches to IBBR.Methods/designThe iBRA study is a trainee-led research collaborative project with four phases:Phase 1 – a national practice questionnaire (NPQ) to survey current practicePhase 2 – a multi-centre prospective cohort study of patients undergoing IBBR to evaluate the clinical and patient-reported outcomesPhase 3– an IBBR-RCT acceptability survey and qualitative work to explore patients’ and surgeons’ views of proposed trial designs and candidate outcomes.Phase 4 – phases 1 to 3 will inform the design and conduct of the future RCTAll centres offering IBBR will be encouraged to participate by the breast and plastic surgical professional associations (Association of Breast Surgery and British Association of Plastic Reconstructive and Aesthetic Surgeons).Data collected will inform the feasibility of undertaking an RCT by defining current practice and exploring issues surrounding recruitment, selection of comparator arms, choice of primary outcome, sample size, selection criteria, trial conduct, methods of data collection and feasibility of using the trainee collaborative model to recruit patients and collect data.DiscussionThe preliminary work undertaken within the iBRA study will determine the feasibility, design and conduct of a definitive RCT in IBBR. It will work with the trainee collaborative to build capacity by creating an infrastructure of research-active breast and plastic surgeons which will facilitate future high-quality research that will ultimately improve outcomes for all women seeking reconstructive surgery.Trial registrationISRCTN37664281

3D bioprinting for reconstructive surgery: Principles, applications and challenges

Despite the increasing laboratory research in the growing field of 3D bioprinting, there are few reports of successful translation into surgical practice. This review outlines the principles of 3D bioprinting including software and hardware processes, biocompatible technological platforms and suitable bioinks. The advantages of 3D bioprinting over traditional tissue engineering techniques in assembling cells, biomaterials and biomolecules in a spatially controlled manner to reproduce native tissue macro-, micro- and nanoarchitectures are discussed, together with an overview of current progress in bioprinting tissue types relevant for plastic and reconstructive surgery. If successful, this platform technology has the potential to biomanufacture autologous tissue for reconstruction, obviating the need for donor sites or immunosuppression. The biological, technological and regulatory challenges are highlighted, with strategies to overcome these challenges by using an integrated approach from the fields of engineering, biomaterial science, cell biology and reconstructive microsurgery.

The TeaM (Therapeutic Mammaplasty) study: Protocol for a prospective multi-centre cohort study to evaluate the practice and outcomes of therapeutic mammaplasty

Highlights • Multicentre prospective study involving breast and plastic surgical units across the UK.• Will produce valuable data regarding the practice and outcomes of therapeutic mammaplasty.• Will inform decision-making and lead to future definitive study.• Will strengthen the collaborative network to facilitate the delivery of future projects.• Will increase awareness of the techniques among trainees such that participation is educational.

Meta-analysis of antibiotics for simple hand injuries requiring surgery.

Simple hand trauma is very common, accounting for 1·8 million emergency department visits annually in the USA alone. Antibiotics are used widely as postinjury prophylaxis, but their efficacy is unclear. This meta‐analysis assessed the effect of antibiotic prophylaxis versus placebo or no treatment on wound infection rates in hand injuries managed surgically.

Randomized feasibility trial of replacing or discarding the nail plate after nail-bed repair in children.

Nail‐bed injuries are the most common hand injury in children. Surgical dogma is to replace the nail plate after repairing the nail bed. Recent evidence suggests this might increase infection rates and returns to clinic. The aim of this feasibility trial was to inform the design and conduct of a definitive trial comparing replacing or discarding the nail plate after nail‐bed repair.

Surgical training and clinical trial involvement—the trainees’ view

As surgical trainees across multiple disciplines, it is our collective aim for all surgical patients to have the opportunity to participate in at least one clinical trial during their hospital episode.1 We recognise that most patients wish to have this option,2 and we want our training to facilitate this. Because patients have the right to be involved in improving surgical …

Strategies to secure surgical research funding: fellowships and grants.

Summary Innovation and advances in surgery are entirely dependent on research. Fellowships and grants are the principal means by which surgical research projects are funded. However, these are scarce and highly competitive. This article offers guidance through the application process for the aspiring academic surgeon. Approaching the application in a timely and structured manner, seeking advice from current and previous award-holders and members of review panels, and obtaining preliminary data are key ingredients to success.