Non-technical skills of Norwegian medical students at different training sites: a comparative, observational cohort study.

PURPOSE: Mastering non-technical skills (NTS) is a fundamental part of the training of new physicians to perform effectively and safely in the medical practice environment. Ideally, they learn these skills during medical school. Decentralized medical education is being implemented increasingly worldwide. Two of the three training sites studied, Bodø (a regional hospital) and Finnmark (a rural local hospital), implemented decentralized medical education. The third training site was the main campus in Tromsø, located at an urban university hospital. The training in Finnmark emphasised training in non-technical skills using simulation to a larger extent than the two other university campuses. This study aimed to compare the NTS performance of medical students in their last year of education at three different training sites of the same university. METHODS: This blinded cohort study included students from the three training sites who participated in identical multi-professional simulations over a six-year period. Eight raters evaluated the video recordings of eight students from each training site using the Norwegian Medical Students Non-Technical Skills (NorMS-NTS) tool. The NorMS-NTS tool, which comprises four categories and 13 elements, assesses the NTS of Norwegian medical students and assigns an overall global score. Pairwise significant differences in the NTS performance levels between the training sites studied were assessed using Tukey's test. RESULTS: The overall NTS performance levels of the medical students from Finnmark (mean 4.5) were significantly higher than those of the students from Tromsø (mean 3.8) and Bodø (mean 3.5). Similarly, the NTS performance levels at category-level of the students in Finnmark were significantly higher than those of the students from Bodø and Tromsø. Except for one category, no significant differences were observed between the students from Bodø and Tromsø in terms of the overall or category-level NTS performance. CONCLUSION: The NTS performance levels of the medical students from Finnmark, which implements rural, decentralized medical education, were significantly higher than those of the students from Tromsø and Bodø.

Novel In Vitro Platform for Studying the Cell Response to Healthy and Diseased Tendon Matrices.

Current in vitro models poorly represent the healthy or diseased tendon microenvironment, limiting the translation of the findings to clinics. The present work aims to establish a physiologically relevant in vitro tendon platform that mimics biophysical aspects of a healthy and tendinopathic tendon matrix using a decellularized bovine tendon and to characterize tendon cells cultured using this platform. Bovine tendons were subjected to various decellularization techniques, with the efficacy of decellularization determined histologically. The biomechanical and architectural properties of the decellularized tendons were characterized using an atomic force microscope. Tendinopathy-mimicking matrices were prepared by treating the decellularized tendons with collagenase for 3 h or collagenase-chondroitinase (CC) for 1 h. The tendon tissue collected from healthy and tendinopathic patients was characterized using an atomic force microscope and compared to that of decellularized matrices. Healthy human tendon-derived cells (hTDCs) from the hamstring tendon were cultured on the decellularized matrices for 24 or 48 h, with cell morphology characterized using f-actin staining and gene expression characterized using real-time PCR. Tendon matrices prepared by freeze-thawing and 48 h nuclease treatment were fully decellularized, and the aligned structure and tendon stiffness (1.46 MPa) were maintained. Collagenase treatment prepared matrices with a disorganized architecture and reduced stiffness (0.75 MPa), mimicking chronic tendinopathy. Treatment with CC prepared matrices with a disorganized architecture without altering stiffness, mimicking early tendinopathy (1.52 MPa). hTDCs on a healthy tendon matrix were elongated, and the scleraxis (SCX) expression was maintained. On tendinopathic matrices, hTDCs had altered morphological characteristics and lower SCX expression. The expression of genes related to actin polymerization, matrix degradation and remodeling, and immune cell invasion were higher in hTDCs on tendinopathic matrices. Overall, the present study developed a physiological in vitro system to mimic healthy tendons and early and late tendinopathy, and it can be used to better understand tendon cell characteristics in healthy and diseased states.

Collecting evidence of validity for an assessment tool for Norwegian medical students' non-technical skills (NorMS-NTS): usability and reliability when used by novice raters.

BACKGROUND: The NorMS-NTS tool is an assessment tool for assessing Norwegian medical students' non-technical skills (NTS). The NorMS-NTS was designed to provide student feedback, training evaluations, and skill-level comparisons among students at different study sites. Rather than requiring extensive rater training, the tool should capably suit the needs of busy doctors as near-peer educators. The aim of this study was to examine the usability and preliminary assess validity of the NorMS-NTS tool when used by novice raters. METHODS: This study focused on the usability of the assessment tool and its internal structure. Three raters used the NorMS-NTS tool to individually rate the team leader, a medical student, in 20 video-recorded multi-professional simulation-based team trainings. Based on these ratings, we examined the tools' internal structure by calculating the intraclass correlation coefficient (ICC) (version 3.1) interrater reliability, internal consistency, and observability. After the rating process was completed, the raters answered a questionnaire about the tool's usability. RESULTS: The ICC agreement and the sum of the overall global scores for all raters were fair: ICC (3,1) = 0.53. The correlation coefficients for the pooled raters were in the range of 0.77-0.91. Cronbach's alpha for elements, categories and global score were mostly above 0.90. The observability was high (95%-100%). All the raters found the tool easy to use, none of the elements were redundant, and the written instructions were helpful. The raters also found the tool easier to use once they had acclimated to it. All the raters stated that they could use the tool for both training and teaching. CONCLUSIONS: The observed ICC agreement was 0.08 below the suggested ICC level for formative assessment (above 0.60). However, we know that the suggestion is based on the average ICC, which is always higher than a single-measure ICC. There are currently no suggested levels for single-measure ICC, but other validated NTS tools have single-measure ICC in the same range. We consider NorMS-NTS as a usable tool for formative assessment of Norwegian medical students' non-technical skills during multi-professional team training by raters who are new to the tool. It is necessary to further examine validity and the consequences of the tool to fully validate it for formative assessments.

Combined Growth Factor Hydrogel Enhances Rotator Cuff Enthesis Healing in Rat But Not Sheep Model.

We hypothesized that a combined growth factor hydrogel would improve chronic rotator cuff tear healing in a rat and sheep model. Insulin-like growth factor 1, transforming growth factor ß1, and parathyroid hormone were combined into a tyraminated poly-vinyl-alcohol (PVA-Tyr) hydrogel and applied directly at the enthesis. In total, 30 Sprague-Dawley rats and 16 Romney ewes underwent unilateral rotator cuff tenotomy and then delayed repairs were performed after 3-4 weeks. The animals were divided into a control group (repair alone) and treatment group. The rotator cuffs were harvested at 12 weeks after surgery for biomechanical and histological analyses of the repair site. In the rat model, the stress at failure and Young's modulus were higher in the treatment group in comparison with the control group (73% improvement, p = 0.010 and 56% improvement, p = 0.028, respectively). Histologically, the repaired entheses in the treatment group demonstrated improved healing with higher semi-quantitative scores (10.1 vs. 6.55 of 15, p = 0.032). In the large animal model, there was no observable treatment effect. This PVA-Tyr bound growth factor system holds promise for improving rotator cuff healing. However, our approach was not scalable from a small to a large animal model. Further tailoring of this growth factor delivery system is still required. Level of Evidence: Basic Science Study; Biomechanics and Histology; Animal Model Impact Statement Previous studies using single-growth factor treatment to improve enthesis healing after rotator cuff repair have reported promising, but inconsistent results. A novel approach is to combine multiple growth factors using controlled-release hydrogels that mimic the normal healing process. In this study, we report that a combined growth factor hydrogel can improve the histological quality and strength of rotator cuff repair in a rat chronic tear model. This novel hydrogel growth factor treatment has the potential to be used in human clinical applications to improve healing after rotator cuff repair.

Crew Autonomy During Simulated Medical Event Management on Long Duration Space Exploration Missions.

OBJECTIVE: Our primary aim was to investigate crew performance during medical emergencies with and without ground-support from a flight surgeon located at mission control. BACKGROUND: There are gaps in knowledge regarding the potential for unanticipated in-flight medical events to affect crew health and capacity, and potentially compromise mission success. Additionally, ground support may be impaired or periodically absent during long duration missions. METHOD: We reviewed video recordings of 16 three-person flight crews each managing four unique medical events in a fully immersive spacecraft simulator. Crews were randomized to two conditions: with and without telemedical flight surgeon (FS) support. We assessed differences in technical performance, behavioral skills, and cognitive load between groups. RESULTS: Crews with FS support performed better clinically, were rated higher on technical skills, and completed more clinical tasks from the medical checklists than crews without FS support. Crews with FS support also had better behavioral/non-technical skills (information exchange) and reported significantly lower cognitive demand during the medical event scenarios on the NASA-TLX scale, particularly in mental demand and temporal demand. There was no significant difference between groups in time to treat or in objective measures of cognitive demand derived from heart rate variability and electroencephalography. CONCLUSION: Medical checklists are necessary but not sufficient to support high levels of autonomous crew performance in the absence of real-time flight surgeon support. APPLICATION: Potential applications of this research include developing ground-based and in-flight training countermeasures; informing policy regarding autonomous spaceflight, and design of autonomous clinical decision support systems.

The development of a tool to assess medical students' non-technical skills - The Norwegian medical students' non-technical skills (NorMS-NTS).

PURPOSE: New physicians need to master non-technical skills (NTS), as high levels of NTS have been shown to increase patient safety. It has also been shown that NTS can be improved through training. This study aimed to establish the necessary NTS for Norwegian medical students to create a tool for formative and summative assessments. METHODS: Focus group interviews were conducted with colleagues and patients of newly graduated physicians. Interviews were then analyzed using card sort methods, and the identified NTS were used to establish a framework. Focus groups commented on a prototype of an NTS assessment tool. Finally, we conducted a search of existing tools and literature. The final tool was developed based on the combined inputs. RESULTS: We created Norwegian medical students' non-technical skills (NorMS-NTS) assessment tool containing four main categories; together comprising 13 elements and a rating scale for the NTS of the person observed. CONCLUSIONS: The NorMS-NTS represents a purpose-made tool for assessing newly graduated physicians' NTS. It is similar to existing assessment tools but based on domain-specific user perspectives obtained through focus group interviews and feedback, integrated with results from a literature search, and with consideration of existing NTS tools.

Ethnicity, sex, and socioeconomic disparities in the treatment of traumatic rotator cuff injuries in Aotearoa/New Zealand.

HYPOTHESIS AND BACKGROUND: Traumatic rotator cuff injuries can be a leading cause of prolonged shoulder pain and disability and contribute to significant morbidity and health care costs. Previous studies have shown evidence of sociodemographic disparities with these injuries. The purpose of this nationwide study was to better understand these disparities based on ethnicity, sex, and socioeconomic status, in order to inform future health care strategies. METHODS: Accident Compensation Corporation (ACC) is a no-fault comprehensive compensation scheme encompassing all of Aotearoa/New Zealand (population in 2018, 4.7 million). Using the ACC database, traumatic rotator cuff injuries were identified between January 2010 and December 2018. Injuries were categorized by sex, ethnicity, age, and socioeconomic deprivation index of the claimant. RESULTS: During the 9-year study period, there were 351,554 claims accepted for traumatic rotator cuff injury, which totaled more than NZ$960 million. The greatest proportion of costs was spent on vocational support (49.8%), then surgery (26.3%), rehabilitation (13.1%), radiology (8.1%), general practitioner (1.6%), and "Other" (1.1%). Asian, Maori (indigenous New Zealanders), and Pacific peoples were under-represented in the age-standardized proportion of total claims and had lower rates of surgery than Europeans. Maori had higher proportion of costs spent on vocational support and lower proportions spent on radiology, rehabilitation, and surgery than Europeans. Males had higher number and costs of claims and were more likely to have surgery than females. There were considerably fewer claims from areas of high socioeconomic deprivation. DISCUSSION AND CONCLUSION: This large nationwide study demonstrates the important and growing economic burden of rotator cuff injuries. Indirect costs, such as vocational supports, are a major contributor to the cost, suggesting improving treatment and rehabilitation protocols would have the greatest economic impact. This study has also identified sociodemographic disparities that need to be addressed in order to achieve equity in health outcomes.

Cytotoxicity of tranexamic acid to tendon and bone in vitro: Is there a safe dosage?

INTRODUCTION: Tranexamic acid (TXA) has been shown to be effective at reducing peri-operative blood loss and haemarthrosis in arthroplasty and arthroscopic soft tissue reconstructions. Intra-articular application, as an injection or peri-articular wash, is becoming increasingly common. Recent studies have shown TXA has the potential to be cytotoxic to cartilage, but its effects on human tendon and bone remain poorly understood. The aim of this study was to investigate whether TXA has any detrimental effects on tendon-derived cells and osteoblast-like cells and determine whether there is a safe dosage for clinical application. MATERIALS AND METHODS: Primary tendon-derived cells and osteoblast-like cells were harvested from hamstring tendons and trabecular bone explants, respectively, and analysed in vitro with a range of TXA concentrations (0 to 100 mg/ml) at time points: 3 and 24 h. The in vitro toxic effect of TXA was investigated using viability assays (alamarBlue), functional assays (collagen deposition), fluorescent microscopy and live/apoptosis/necrosis staining for cell death mechanisms in 2D monolayer and 3D collagen gel cell culture. RESULTS: There was a significant (P < 0.05) decrease in tendon-derived cell and osteoblast-like cell numbers following treatment with TXA ≥ 50 mg/ml after 3 h and ≥ 20 mg/ml after 24 h. In tendon-derived cells, increasing concentrations > 35 mg/ml resulted in significantly (P < 0.05) reduced collagen deposition. Fluorescence imaging confirmed atypical cellular morphologies with increasing TXA concentrations and reduced cell numbers. The mechanism of cell death was demonstrated to be occurring through apoptosis. CONCLUSIONS: Topical TXA treatment demonstrated dose- and time-dependent cytotoxicity to tendon-derived cells and osteoblast-like cells with concentrations 20 mg/ml and above in isolated 2D and 3D in vitro culture. On the basis of these findings, concentrations of less than 20 mg/ml are expected to be safe. Orthopaedic surgeons should show caution when considering topical TXA treatments, particularly in soft tissue and un-cemented arthroplasty procedures.

Changes in Physiological Tendon Substrate Stiffness Have Moderate Effects on Tendon-Derived Cell Growth and Immune Cell Activation.

Tendinopathy is characterised by pathological changes in tendon matrix composition, architecture, and stiffness, alterations in tendon resident cell characteristics, and fibrosis, with inflammation also emerging as an important factor in tendinopathy progression. The sequence of pathological changes in tendinopathy and the cellular effects of the deteriorating matrix are largely unknown. This study investigated the effects of substrate stiffness on tendon-derived cells (TDCs) and THP-1 macrophages using PDMS substrates representing physiological tendon stiffness (1.88 MPa), a stiff gel (3.17 MPa) and a soft gel (0.61 MPa). Human TDCs were cultured on the different gel substrates and on tissue culture plastic. Cell growth was determined by alamarBlue™ assay, cell morphology was analysed in f-actin labelled cells, and phenotypic markers were analysed by real-time PCR. We found that in comparison to TDCs growing on gels with physiological stiffness, cell growth increased on soft gels at 48 h (23%, p = 0.003). Cell morphology was similar on all three gels. SCX expression was slightly reduced on the soft gels (1.4-fold lower, p = 0.026) and COL1A1 expression increased on the stiff gels (2.2-fold, p = 0.041). Culturing THP-1 macrophages on soft gels induced increased expression of IL1B (2-fold, p = 0.018), and IL8 expression was inhibited on the stiffer gels (1.9-fold, p = 0.012). We also found that culturing TDCs on plastic increased cell growth, altered cell morphology, and inhibited the expression of SCX, SOX9, MMP3, and COL3. We conclude that TDCs and macrophages respond to changes in matrix stiffness. The magnitude of responses measured in TDCs were minor on the range of substrate stiffness tested by the gels. Changes in THP-1 macrophages suggested a more inflammatory phenotype on substrates with non-physiological stiffness. Although cell response to subtle variations in matrix stiffness was moderate, it is possible that these alterations may contribute to the onset and progression of tendinopathy.

A high-fat diet has negative effects on tendon resident cells in an in vivo rat model.

BACKGROUND: Tendinopathy is a major complication of diet-induced obesity. However, the effects of a high-fat diet (HFD) on tendon have not been well characterised. We aimed to determine: [1] the impact of a HFD on tendon properties and gene expression; and [2] whether dietary transition to a control diet (CD) could restore normal tendon health. METHODS: Sprague-Dawley rats were randomised into three groups from weaning and fed either a: CD, HFD or HFD for 12 weeks and then CD thereafter (HF-CD). Biomechanical, histological and structural evaluation of the Achilles tendon was performed at 17 and 27 weeks of age. Tail tenocytes were isolated with growth rate and collagen production determined. Tenocytes and activated THP-1 cells were exposed to conditioned media (CM) of visceral adipose tissue explants, and gene expression was analysed. RESULTS: There were no differences in the biomechanical, histological or structural tendon properties between groups. However, tenocyte growth and collagen production were increased in the HFD group at 27 weeks. There was lower SOX-9 expression in the HFD and HF-CD groups at 17 weeks and higher expression of collagen-Iα1 and matrix metalloproteinase-13 in the HFD group at 27 weeks. THP-1 cells exposed to adipose tissue CM from animals fed a HFD or HF-CD had lower expression of Il-10 and higher expression of Il-1ß. CONCLUSIONS: In this rodent model, a HFD negatively altered tendon cell characteristics. Dietary intervention restored some gene expression changes; however, adipose tissue secretions from the HF-CD group promoted an increased inflammatory state in macrophages. These changes may predispose tendon to injury and adverse events later in life.

Novel Growth Factor Combination for Improving Rotator Cuff Repair: A Rat In Vivo Study.

BACKGROUND: The lack of healing at the repaired tendon-bone interface is an important cause of failure after rotator cuff repair. While augmentation with growth factors (GFs) has demonstrated promise, the ideal combination must target all 3 tissue types at the tendon-bone interface. HYPOTHESIS: The GF combination of transforming growth factor beta 1, Insulin-like growth factor 1, and parathyroid hormone will promote tenocyte proliferation and differentiation and improve the biomechanical and histological quality of the repaired tendon-bone interface. STUDY DESIGN: Controlled laboratory study. METHODS: In vitro, human tenocytes were cultured in the presence of the GF combination for 72 hours, and cell growth assays and the expression of genes specific to tendon, cartilage, and bone were analyzed. In vivo, adult rats (N = 46) underwent detachment and repair of the left supraspinatus tendon. A PVA-tyramine gel was used to deliver the GF combination to the tendon-bone interface. Histological, biomechanical, and RNA microarray analysis was performed at 6 and 12 weeks after surgery. Immunohistochemistry for type II and X collagen was performed at 12 weeks. RESULTS: When treated with the GF combination in vitro, human tenocytes proliferated 1.5 times more than control (P = .04). The expression of scleraxis increased 65-fold (P = .013). The expression of Sox-9 (P = .011), type I collagen (P = .021), fibromodulin (P = .0075), and biglycan (P = .010) was also significantly increased, while the expression of PPARγ was decreased (P = .007). At 6 and 12 weeks postoperatively, the quality of healing on histology was significantly higher in the GF group, with the formation of a more mature tendon-bone interface, as confirmed by immunohistochemistry for type II and X collagen. The GF group achieved a load at failure and Young modulus >1.5 times higher at both time points. Microarrays at 6 weeks demonstrated upregulation of genes involved in leukocyte aggregation (S100A8, S100A9) and tissue mineralization (Bglap, serglycin, Fam20c). CONCLUSION: The GF combination promoted protendon and cartilage responses in human tenocytes in vitro; it also improved the histological appearance and mechanical properties of the repair in vivo. Microarrays of the tendon-bone interface identified inflammatory and mineralization pathways affected by the GF combination, providing novel therapeutic targets for further research. CLINICAL RELEVANCE: The use of this GF combination is translatable to patients and may improve healing after rotator cuff repair.

Age-related differences in hamstring tendon used as autograft in reconstructive anterior cruciate ligament surgery.

PURPOSE: The hamstring tendon is the most commonly used autograft material in reconstructive surgeries of anterior cruciate ligament (ACL) tears. Younger patients have worse surgical outcomes, with a higher risk of re-rupture. We hypothesized that age-related changes in hamstring tendon properties affect the tendon's propensity to rupture when used as an autograft in ACL reconstructions. The purpose of this study was to compare hamstring tendon samples obtained from people aged 20 years or younger to samples obtained from older people. METHODS: Superfluous hamstring tendon material was collected from 13 young donors (aged 16-20 years) and 17 older donors undergoing ACL reconstructive surgery. Sections of the tendon samples were used for biomechanical testing, structural analysis of collagen fibrils by electron microscopy, and global analysis of gene expression by microarrays. RESULTS: We found that tendon samples from the older group had lower Young's modulus than the younger group (P = 0.015), whereas the stress to failure was similar in the two groups. We found no difference in the average diameter of collagen fibrils between the two groups. Microarray analysis identified 162 differentially expressed genes (fold change ≥ 1.5, P < 0.05), with overrepresentation of several biological processes, including regulation of adhesion, migration, inflammation, and differentiation (fold enrichment > 2.0, false discovery rate P < 0.05). CONCLUSION: The hamstring tendon from younger people has higher stiffness than tendon from older people, and the profile of gene expression in tendon varies with age. These differences may negatively affect the performance of the hamstring tendon in ACL reconstructions in younger people.

Modelling gluteus medius tendon degeneration and repair in a large animal model.

INTRODUCTION: Gluteus medius tendon tears often occur in the context of chronic tendinopathy and remain a difficult clinical problem. Surgical repair is challenging as it is often delayed and performed in degenerative tendons. No animal model currently exists to mimic the delayed repair of tendinopathic gluteus medius tears. The aims of this study were to develop a chronic model of gluteus medius tendinopathy and tear and then compare this model to an acute gluteus medius tear and repair. MATERIALS AND METHODS: Six gluteus medius muscles were dissected and examined in mature sheep to confirm anatomical similarity to the human counterpart. Ten separate adult sheep underwent tendon detachment, followed by relook and histological sampling at 6 and 16 weeks to assess the extent of tendon degeneration. Six adult sheep underwent tendon repair at 6 weeks and were later assessed for healing of the tendon and compared to a further four adult sheep who underwent an acute tendon detachment and repair procedure. RESULTS: The sheep gluteus medius muscle consisted of three compartments, the anterior, middle and posterior. All compartments inserted via the common tendon on the superolateral aspect of the greater trochanter. At both 6 and 16 weeks, there was significant tendinopathic changes on histology compared to controls as assessed by modified Movin's score (p = 0.018, p = 0.047) but no difference between the 6- and 16-week groups (p = 0.25). There were significant differences between delayed and acute repair in both histological appearance (p = 0.025) and biomechanical properties (p = 0.019), with acute repair superior in both. CONCLUSIONS: Tendon detachment for 6 weeks is sufficient to produce histological changes similar to chronic tendinopathy and repair of this degenerative tendon results in significantly poorer healing when compared to an acute repair model. Animal models for gluteus medius tears should use a delayed repair model to improve clinical validity.

Obesity Impairs Enthesis Healing After Rotator Cuff Repair in a Rat Model.

BACKGROUND: Being overweight or obese is associated with poor outcomes and an increased risk of failure after rotator cuff (RC) surgery. However, the effect of obesity on enthesis healing has not been well characterized. HYPOTHESES: Diet-induced obesity (DIO) would result in inferior enthesis healing in a rat model of RC repair, and a dietary intervention in the perioperative period would improve enthesis healing. STUDY DESIGN: Controlled laboratory study. METHODS: Male Sprague-Dawley rats were divided into 3 weight-matched groups (n = 26 per group): control diet (CD), high-fat diet (HFD), or HFD until surgery and then CD thereafter (HF-CD). After 12 weeks, the left supraspinatus tendon was detached, followed by immediate repair. Animals were sacrificed, and RCs were harvested at 2 and 12 weeks after surgery for biomechanical and histological evaluations. Metabolic end points were assessed using dual-energy X-ray absorptiometry and plasma analyses. RESULTS: DIO was established in the HFD and HF-CD groups before surgery and subsequently reversed in the HF-CD group after surgery. At 12 weeks after surgery, the body fat percentage (P = .0021) and plasma leptin concentration (P = .0025) were higher in the HFD group compared with the CD group. Histologically, the appearance of the repaired entheses was poorer in both the HFD and HF-CD groups compared with the CD group at 12 weeks after surgery, with semiquantitative scores of 6.20 (P = .0078), 4.98 (P = .0003), and 8.68 of 15, respectively. The repaired entheses in the HF-CD group had a significantly lower load to failure (P = .0278) at 12 weeks after surgery compared with the CD group, while the load to failure in the HFD group was low but not significantly different (P = .0960). There were no differences in the biomechanical and histological results between the groups at 2 weeks after surgery. Body mass at the time of surgery, plasma leptin concentration, and body fat percentage were negatively correlated with histology scores and plasma leptin concentration was correlated with load to failure at 12 weeks after surgery. CONCLUSION: DIO impaired enthesis healing in this rat RC repair model, with inferior biomechanical and histological outcomes. Restoring a normal weight with dietary changes after surgery did not improve healing outcomes. CLINICAL RELEVANCE: Obesity is a potentially modifiable factor that impairs RC healing and increases the risk of failure after surgery. Exploring interventions that improve the metabolic state of obese patients and counseling patients appropriately about their modest expectations after repair should be considered.

A Maternal High Fat Diet Leads to Sex-Specific Programming of Mechanical Properties in Supraspinatus Tendons of Adult Rat Offspring.

Background: Over half of women of reproductive age are now overweight or obese. The impact of maternal high-fat diet (HFD) is emerging as an important factor in the development and health of musculoskeletal tissues in offspring, however there is a paucity of evidence examining its effects on tendon. Alterations in the early life environment during critical periods of tendon growth therefore have the potential to influence tendon health that cross the lifespan. We hypothesised that a maternal HFD would alter biomechanical, morphological and gene expression profiles of adult offspring rotator cuff tendon. Materials and Methods: Female Sprague-Dawley rats were randomly assigned to either: control diet (CD; 10% kcal or 43 mg/g from fat) or HFD (45% kcal or 235 mg/g from fat) 14 days prior to mating and throughout pregnancy and lactation. Eight female and male offspring from each maternal diet group were weaned onto a standard chow diet and then culled at postnatal day 100 for tissue collection. Supraspinatus tendons were used for mechanical testing and histological assessment (cellularity, fibre organisation, nuclei shape) and tail tendons were collected for gene expression analysis. Results: A maternal HFD increased the elasticity (Young's Modulus) in the supraspinatus tendon of male offspring. Female offspring tendon biomechanical properties were not affected by maternal HFD. Gene expression of SCX and COL1A1 were reduced in male and female offspring of maternal HFD, respectively. Despite this, tendon histological organisation were similar between maternal diet groups in both sexes. Conclusion: An obesogenic diet during pregnancy increased tendon elasticity in male, but not female, offspring. This is the first study to demonstrate that maternal diet can modulate the biomechanical properties of offspring tendon. A maternal HFD may be an important factor in regulating adult offspring tendon homeostasis that may predispose offspring to developing tendinopathies and adverse tendon outcomes in later life.

A Novel In Vitro and In Silico System for Analyzing Complex Mechanobiological Behavior of Chondrocytes in Three-Dimensional Hydrogel Constructs.

Physiological loading is essential for the maintenance of articular cartilage through the regulation of tissue remodeling. To correctly understand the behavior of chondrocytes in their native environment, cell stimulating devices and bioreactors have been developed to examine the effect of mechanical stimuli on chondrocytes. This study describes the design and validation of a novel system for analyzing chondrocyte deformation patterns. This involves an in vitro mechanical device for a controlled application of multi-axial-loading regimes to chondrocyte-seeded agarose constructs and in silico models for analyzing chondrocyte deformation patterns. The computer-controlled device precisely applies compressive, tensile, and shear strains to hydrogel constructs using a customizable macro-based program. The synchronization of the displacements is shown to be accurate with a 1.2% error and is highly reproducible. The device design allows housing for up to eight novel designed free-swelling three-dimensional hydrogel constructs. Constructs include mesh ends and are optimized to withstand the application of up to 7% mechanical tensile and 15% shear strains. Constructs were characterized through mapping the strain within as mechanical load was applied and was validated using light microscopy methods, chondrocyte viability using live/dead imaging, and cell deformation strains. Images were then analyzed to determine the complex deformation strain patterns of chondrocytes under a range of dynamic mechanical stimulations. This is one of the first systems that have characterized construct strains to cellular strains. The features in this device make the system ideally suited for a systematic approach for the investigation of the response of chondrocytes to a complex physiologically relevant deformation profile.

Sustained Delivery of Lactoferrin Using Poloxamer Gels for Local Bone Regeneration in a Rat Calvarial Defect Model.

Lactoferrin (LF) is a multifunctional milk glycoprotein that promotes bone regeneration. Local delivery of LF at the bone defect site is a promising approach for enhancement of bone regeneration, but efficient systems for sustained local delivery are still largely missing. The aim of this study was to investigate the potential of the poloxamers for sustained delivery of LF to enhance local bone regeneration. The developed LF/poloxamer formulations were liquid at room temperature (20 °C) transforming to a sustained releasing gel depot at body temperature (37 °C). In vitro release studies demonstrated an initial burst release (~50%), followed by slower release of LF for up to 72 h. Poloxamer, with and without LF, increased osteoblast viability at 72 h (p < 0.05) compared to control, and the immune response from THP-1 cells was mild when compared to the suture material. In rat calvarial defects, the LF/poloxamer group had lower bone volume than the controls (p = 0.0435). No difference was observed in tissue mineral density and lower bone defect coverage scores (p = 0.0267) at 12 weeks after surgery. In conclusion, LF/poloxamer formulations support cell viability and do not induce an unfavourable immune response; however, LF delivery via the current formulation of LF200/poloxamer gel did not demonstrate enhanced bone regeneration and was not compatible with the rat calvarial defect model.

Toxicity of tranexamic acid (TXA) to intra-articular tissue in orthopaedic surgery: a scoping review.

PURPOSE: Intra-articular administration of tranexamic acid (TXA) in orthopaedic arthroplasty and arthroscopic procedures has become increasingly common over the past decade. However, several recent reports have shown that TXA has the potential to be cytotoxic to cartilage, tendon and synovium. Our aim was to review the literature for evidence of toxic effects from TXA exposure to intra-articular tissue. METHODS: A scoping review methodology was used to search for studies assessing the toxic effects of TXA exposure to intra-articular tissues. MEDLINE, EMBASE, SCOPUS and The Cochrane Library were searched. Relevant information was extracted and synthesis of the retrieved data followed a basic content analytical approach. RESULTS: A total of 15 laboratory studies were retrieved. No clinical studies reporting a toxic effect of TXA on intra-articular tissue were identified in our search. Studies were analysed according to species of origin, tissue of origin and study setting (in vitro, ex vivo, or in vivo). There was increasing cytotoxicity to chondrocytes, tenocytes, synoviocytes and periosteum-derived cells with TXA concentrations beyond 20 mg/ml. Monolayer cell cultures appear more susceptible to TXA exposure, than three-dimensional and explant culture models. In vivo studies have not demonstrated a major toxic effect. CONCLUSIONS: Current evidence suggests a dose-dependent toxic effect on cartilage, tendon, and synovial tissue. Concentrations of 20 mg/ml or less are expected to be safe. There is a significant body of evidence to suggest the need for caution with intraarticular administration of TXA. There is a need for further human clinical trials in order to clarify the long-term safety of TXA topical application.

Raman spectroscopy reveals age- and sex-related differences in cortical bone from people with osteoarthritis.

Bone strength in human cortical bone is determined by the composition and structure of both the mineral and collagen matrices and influenced by factors such as age, gender, health, lifestyle and genetic factors. Age-related changes in the bone matrix are known to result in loss of mechanical strength and increased fragility. In this study we show how Raman spectroscopy, with its exquisite sensitivity to the molecular structure of bone, reveals new insights into age- and sex-related differences. Raman analysis of 18 samples of cortical hip bone obtained from people aged between 47-82 years with osteoarthritis (OA) found subtle changes in the lipid and collagen secondary structure, and the carbonate (CO32-) and phosphate (PO43-) mineral ratios in the bone matrix. Significant differences were observed between older and younger bones, and between older female and older male bones; no significant differences were observed between younger male and female bones. Older female bones presented the lowest mineral to matrix ratios (MMR) and highest CO32-/PO43- ratios, and relative to lipid/collagen -CH2 deformation modes at 1450 cm-1 they had lowest overall mineral content, higher collagen cross linking and lipid content but lower levels of α-helix collagen structures than older male and younger male and female bones. These observations provided further insight on bone composition changes observed in the bone volume fraction (BV/TV) for the older female bones from microCT measurements on the same samples, while tissue mineral density (TMD) measurements had shown no significant differences between the samples.