Exploiting light-based 3D-printing for the fabrication of mechanically enhanced, patient-specific aortic grafts.

Despite polyester vascular grafts being routinely used in life-saving aortic aneurysm surgeries, they are less compliant than the healthy, native human aorta. This mismatch in mechanical behaviour has been associated with disruption of haemodynamics contributing to several long-term cardiovascular complications. Moreover, current fabrication approaches mean that opportunities to personalise grafts to the individual anatomical features are limited. Various modifications to graft design have been investigated to overcome such limitations; yet optimal graft functionality remains to be achieved. This study reports on the development and characterisation of an alternative vascular graft material. An alginate:PEGDA (AL:PE) interpenetrating polymer network (IPN) hydrogel has been produced with uniaxial tensile tests revealing similar strength and stiffness (0.39 ± 0.05 MPa and 1.61 ± 0.19 MPa, respectively) to the human aorta. Moreover, AL:PE tubular conduits of similar geometrical dimensions to segments of the aorta were produced, either via conventional moulding methods or stereolithography (SLA) 3D-printing. While both fabrication methods successfully demonstrated AL:PE hydrogel production, SLA 3D-printing was more easily adaptable to the fabrication of complex structures without the need of specific moulds or further post-processing. Additionally, most 3D-printed AL:PE hydrogel tubular conduits sustained, without failure, compression up to 50% their outer diameter and returned to their original shape upon load removal, thereby exhibiting promising behaviour that could withstand pulsatile pressure in vivo. Overall, these results suggest that this AL:PE IPN hydrogel formulation in combination with 3D-printing, has great potential for accelerating progress towards personalised and mechanically-matched aortic grafts.

Is the mechanical function of meniscal tissue altered in osteoarthritic knees?

BACKGROUND: Deteriorating meniscal function is thought to play a role in knee osteoarthritis. Meniscal proteoglycans maintain mechanical stiffness of the tissue through electrostatic effects. This study aimed to investigate whether the mechanical properties of macroscopically intact meniscus are preserved in osteoarthritis. METHODS: Discs of lateral meniscal tissue two millimetres thick and of five millimetres diameter from osteoarthritic knees and from healthy donors were placed within a confined compression chamber, mounted in a materials testing machine and bathed in isotonic 0.14M PBS, hypotonic deionised water or hypertonic 3M PBS. Following equilibrium, a 10% ramp compressive strain was applied followed by a 7200 second hold. Resultant stress relaxation curves were fitted to a nonlinear poroviscoelastic model with strain dependent permeability using finite element modelling to determine mechanical parameters. All samples were assayed for proteoglycan content. Comparison of results was undertaken using multivariate ANOVA. RESULTS: Thirty samples from osteoarthritic knees and 18 samples from healthy donors were tested. No significant differences in mechanical parameters or proteoglycan content was observed between groups. In both groups Young's modulus (E) was significantly greater, and zero-strain permeability significantly reduced, in samples tested in deionised water compared to samples tested in 0.14M or 3M PBS (all p < 0.05). CONCLUSION: Mechanical parameters of intact lateral meniscus in osteoarthritic knees are similar to those found in healthy knees. Proteoglycan concentration and their electrostatic contribution to mechanical stiffness of the meniscus is maintained in menisci derived from osteoarthritic knees. Whilst macroscopic tears in the meniscal ultrastructure may contribute to osteoarthritis, intact meniscal tissue maintains its function.

Genome-wide association study identifies genetic variants which predict the response of bone mineral density to teriparatide therapy.

OBJECTIVES: Teriparatide (TPTD) is an effective treatment for osteoporosis but the individual response to therapy is variable for reasons that are unclear. This study aimed to determine whether the response to TPTD might be influenced by genetic factors. METHODS: We searched for predictors of the response of bone mineral density (BMD) to TPTD using a two-stage genome-wide association study in 437 patients with osteoporosis from three referral centres. Demographic and clinical data including the response of BMD to treatment at the lumbar spine and hip were extracted from the medical records of each participant. RESULTS: Allelic variation at rs6430612 on chromosome 2, close to the CXCR4 gene was associated with the response of spine BMD to TPTD at a genome wide significant level (p=9.2×10-9 beta=-0.35 (-0.47 to -0.23)). The increase in BMD was almost twice as great in AA homozygotes at rs6430612 as compared with GG homozygotes with intermediate values in heterozygotes. The same variant was also associated with response of femoral neck and total hip BMD (p=0.007). An additional locus on chromosome 19 tagged by rs73056959 was associated with the response of femoral neck BMD to TPTD (p=3.5×10-9, beta=-1.61 (-2.14 to -1.07)). CONCLUSIONS: Genetic factors influence the response to TPTD at the lumbar spine and hip with a magnitude of effect that is clinically relevant. Further studies are required to identify the causal genetic variants and underlying mechanisms as well as to explore how genetic testing for these variants might be implemented in clinical practice.

Characterisation of native and decellularised porcine tendon under tension and compression: A closer look at glycosaminoglycan contribution to tendon mechanics.

Decellularised porcine superflexor tendon (pSFT) has been characterised as a suitable scaffold for anterior cruciate ligament replacement, with dimensions similar to hamstring tendon autograft. However, decellularisation of tissues may reduce or damage extracellular matrix components, leading to undesirable biomechanical changes at a whole tissue scale. Although the role of collagen in tendons is well established, the mechanical contribution of glycosaminoglycans (GAGs) is less evident and could be altered by the decellularisation process. In this study, the contribution of GAGs to the tensile and compressive mechanical properties of pSFT was determined and whether decellularisation affected these properties by reducing GAG content or functionality. PSFTs were either enzymatically treated using chondroitinase ABC to remove GAGs or decellularised using previously established methods. Native, GAG-depleted and decellularised pSFT groups were then subjected to quantitative assays and biomechanical characterisation. In tension, specimens underwent stress relaxation and strength testing. In compression, specimens underwent confined compression testing. The GAG-depleted group was found to have circa 86% reduction of GAG content compared to native and decellularised groups. There was no significant difference in GAG content between native (3.75 ± 0.58 µg/mg) and decellularised (3.40 ± 0.37 µg/mg) groups. Stress relaxation testing discovered the time-independent and time-dependent relaxation moduli of the decellularised group were reduced ≥50% compared to native and GAG-depleted groups. However, viscoelastic behaviour of native and GAG-depleted groups resulted similar. Strength testing discovered no differences between native and GAG-depleted group's properties, albeit a reduction ∼20% for decellularised specimens' linear modulus and tensile strength compared to native tissue. In compression testing, the aggregate modulus was found to be circa 74% lower in the GAG-depleted group than the native and decellularised groups, while the zero-strain permeability was significantly higher in the GAG-depleted group (0.86 ± 0.65 mm4/N) than the decellularised group (0.03 ± 0.04 mm4/N). The results indicate that GAGs may significantly contribute to the mechanical properties of pSFT in compression, but not in tension. Furthermore, the content and function of GAGs in pSFTs are unaffected by decellularisation and the mechanical properties of the tissue remain comparable to native tissue.

Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout.

OBJECTIVE: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. METHODS: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. RESULTS: The PRS was associated with earlier age at gout onset in men (ß = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; ß = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; ß = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (ß = 0.07 [95% CI -2.32, 2.45] in European women; ß = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; ß -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (ß = -2.42 [95% CI -3.37, -1.46] and ß = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (ß = -1.79 [95% CI -4.74, 1.16]). CONCLUSION: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.

Incorporating gout guideline advice into urate reports is associated with reduced hospital admissions: results of an observational study.

OBJECTIVE: To evaluate the impact of incorporating treatment guidance into reporting of urate test results. METHODS: Urate targets for clinically confirmed gout were added to urate results above 0.36 mmol/l requested after September 2014 within NHS Lothian. Scotland-wide data on urate-lowering therapy prescriptions and hospital admissions with gout were analysed between 2009 and 2020. Local data on urate tests were analysed between 2014 and 2015. RESULTS: Admissions with a primary diagnosis of gout in Lothian reduced modestly following the intervention from 111/year in 2010-2014 to 104/year in 2015-2019, a non-significant difference (P = 0.32). In contrast there was a significant increase in admissions to remaining NHS Scotland health boards (556/year vs 606/year, P < 0.01). For a secondary diagnosis of gout the number of admissions in NHS Lothian reduced significantly (58/year vs 39/year, P < 0.01) contrasting with a significant increase in remaining Scottish health boards (220/year vs 290/year, P < 0.01). The relative rate of admissions to NHS Lothian compared with remaining Scottish boards using a 2009 baseline were significantly reduced for both primary diagnosis of gout (1.06 vs 1.25, P < 0.001) and secondary diagnoses of gout (0.64 compared with 1.4, P < 0.001) after the intervention; however, there was no difference before the intervention. A relative increase in the prescription rates of allopurinol 300 mg tablets and febuxostat 120 mg tablets may have contributed to the improved outcomes seen. CONCLUSION: Incorporation of clinical guideline advice into routine reporting of urate results was associated with reduced rates of admission with gout in NHS Lothian, in comparison with other Scottish health boards.

Evaluation of supported self-management in gout (GoutSMART): a randomised controlled feasibility trial.

BACKGROUND: Improved outcomes for patients with gout are associated with the control of urate levels; yet, less than 40% of patients in the UK are currently offered urate lowering therapy, and it is typically offered without titration to target. Supported self-management has been shown to benefit patients with chronic health conditions; therefore, we aimed to determine whether a supported gout self-management approach, incorporating treatment-to-target urate, helped participants reach target urate levels. METHODS: In this randomised controlled feasibility study, conducted in one hospital in Edinburgh, UK, we included patients (aged ≥18 years) with gout and a physician recommendation for initiation or escalation of urate lowering therapy. We randomised participants in a 2:1 ratio to a supported self-management group or a usual care group using the GoutSMART smartphone app. Participants in the self-management group were given a urate self-testing meter and received direct advice from clinicians on escalation of urate lowering therapy through the app. Participants were identified following referral to rheumatology, or using the Scottish Health Research Register, and they were screened and offered a detailed management plan before randomisation. Participants in the usual care group had a limited version of the app, which only allowed it to function as a health diary, and their gout management plan was implemented by their general practitioner. The primary outcome was the percentage of participants achieving a urate target of 0·30 mmol/L or less at 24 weeks, and analysis was by intent to treat. The trial was registered with ClinicalTrials.gov, NCT03274063, and there is an extension study ongoing. There was no masking of participants or assessors. FINDINGS: Between April 5, 2019, and March 19, 2020, 60 (65%) of 92 patients screened were enrolled to the study. The mean age was 52.8 years (SD 14.6); 56 (93%) of the participants were male, and 4 (7%) were female. 58 (97%) of participants were White. 40 participants were assigned to the self-supported management group and 20 participants were assigned to the usual care group. A urate target of 0·30 mmol/L or less at 24 weeks was reached by 29 (73%) participants in the supported self-management group compared with 3 (15%) participants in the usual care group (risk difference 0·58 [95% CI 0·37-0·78]; p<0·0001). 90% of participants completed the study with no difference in the drop-out rate or adverse events between the two groups. INTERPRETATION: Supported self-management of gout results in substantially improved attainment of urate targets compared with usual care, and it is well tolerated. Larger trials will be needed to fully evaluate the clinical and cost-effectiveness of this approach. FUNDING: Edinburgh & Lothians Health Foundation.

Dynamic stability during stair negotiation after total knee arthroplasty.

BACKGROUND: The assessment of dynamic stability is crucial for the prevention of falls in the elderly and people with functional impairments. Evidence that total knee arthroplasty improves balance in patients with severe osteoarthritis is scarce and no information exists about how the surgery affects dynamic stability during stair negotiation. METHODS: This study aims to investigate if patients before and one year after surgery are less stable compared to asymptomatic controls. Seventeen control and twenty-seven patient participants with end-stage knee osteoarthritis that were scheduled to undergo unilateral total knee arthroplasty were recruited in this study. Participants' assessment was carried out by means of marker-based optical full-body motion capture with force platforms. The extrapolated Centre of mass and the margin of stability metrics were used to examine dynamic stability during stair ascent and descent. FINDINGS: Patient participants, during both pre-operative and post-operative assessments, were equally balanced to the asymptomatic controls during stair gait (p > .188). Additionally, the patients' overall stability did not improve significantly one year after arthroplasty surgery (p > .252). INTERPRETATION: Even if pain from arthritis and fear of falling is decreased following surgery, our results indicate that stability in stair walking in not affected by osteoarthritis and total knee arthroplasty. CLINICAL TRIAL REGISTRATION NUMBER: NCT02422251.

Review of Current Real-World Experience with Teriparatide as Treatment of Osteoporosis in Different Patient Groups.

Teriparatide has proven effective in reducing both vertebral and non-vertebral fractures in clinical trials of post-menopausal and glucocorticoid-induced osteoporosis. Widespread adoption of Teriparatide over the last two decades means that there is now substantial experience of its use in routine clinical practice, which is summarized in this paper. Extensive real-world experience of Teriparatide in post-menopausal osteoporosis confirms the fracture and bone density benefits seen in clinical trials, with similar outcomes identified also in male and glucocorticoid-induced osteoporosis. Conversely, very limited experience has been reported in pre-menopausal osteoporosis or in the use of Teriparatide in combination with other therapies. Surveillance studies have identified no safety signals relating to the possible association of Teriparatide with osteosarcoma. We also review the evidence for predicting response to Teriparatide in order to inform the debate on where best to use Teriparatide in an increasingly crowded therapeutic landscape.

Implant design affects walking and stair navigation after total knee arthroplasty: a double-blinded randomised controlled trial.

BACKGROUND: Dissimilar total knee arthroplasty implant designs offer different functional characteristics. This is the first work in the literature to fully assess the Columbus ultra-congruent mobile (UCR) system with a rotating platform. METHODS: This is a double-blinded randomised controlled trial, comparing the functional performance of the low congruent fixed (CR DD), ultra-congruent fixed (UC) and UCR Columbus Total Knee Systems. The pre-operative and post-operative functional performance of twenty-four osteoarthritic patients was evaluated against nine control participants when carrying out everyday tasks. Spatiotemporal, kinematic and kinetic gait parameters in walking and stair navigation were extracted by means of motion capture. RESULTS: The UC implant provided better post-operative function, closely followed by the UCR design. However, both the UC and UCR groups exhibited restricted post-operative sagittal RoM (walking, 52.1 ± 4.4° and 53.2 ± 6.6°, respectively), whilst patients receiving a UCR implant did not show an improvement in their tibiofemoral axial rotation despite the bearing's mobile design (walking, CR DD 13.2 ± 4.6°, UC 15.3 ± 6.7°, UCR 13.5 ± 5.4°). Patients with a CR DD fixed bearing showed a statistically significant post-operative improvement in their sagittal RoM when walking (56.8 ± 4.6°). CONCLUSION: It was concluded that both ultra-congruent designs in this study, the UC and UCR bearings, showed comparable functional performance and improvement after TKA surgery. The CR DD group showed the most prominent improvement in the sagittal RoM during walking. TRIAL REGISTRATION: The study is registered under the clinical trial registration number: NCT02422251 . Registered on April 21, 2015.

3D biofabrication for soft tissue and cartilage engineering.

Soft tissue injuries (STIs) affect patients of all age groups and represent a common worldwide clinical problem, resulting from conditions including trauma, infection, cancer and burns. Within the spectrum of STIs a mixture of tissues can be injured, ranging from skin to underlying nerves, blood vessels, tendons and cartilaginous tissues. However, significant limitations affect current treatment options and clinical demand for soft tissue and cartilage regenerative therapies continues to rise. Improving the regeneration of soft tissues has therefore become a key area of focus within tissue engineering. As an emerging technology, 3D bioprinting can be used to build complex soft tissue constructs "from the bottom up," by depositing cells, growth factors, extracellular matrices and other biomaterials in a layer-by-layer fashion. In this way, regeneration of cartilage, skin, vasculature, nerves, tendons and other bodily tissues can be performed in a patient specific manner. This review will focus on recent use of 3D bioprinting and other biofabrication strategies in soft tissue repair and regeneration. Biofabrication of a variety of soft tissue types will be reviewed following an overview of available cell sources, bioinks and bioprinting techniques.

Changing paradigms in the management of gout.

The incidence and prevalence of gout have increased, as have comorbid obesity, diabetes mellitus, hypertension, chronic kidney and cardiovascular disease. Gout is now the commonest type of inflammatory arthritis despite availability of safe, effective and potentially 'curative' urate-lowering drugs. Modern imaging studies show that gout is a chronic inflammatory crystal deposition disorder even at the first acute attack and they illuminate the need to eliminate urate crystals by continuing reduction of the serum urate below its solubility threshold. Clinical outcomes, adherence to therapy and quality of gout care in primary care and hospital practice can be greatly improved by better use of allopurinol and flare prophylaxis, greater patient engagement, education and follow-up, and by nurse-led models of care that employ a 'treat-to-target' principle (SUA< 360 or 300µmol/l). Advances in understanding the physiology and genetic control of urate transport in the kidney and gut have led to novel, more selective uricosuric drugs, and basic research on mediators of urate crystal-induced inflammation has pointed to alternative therapeutic targets for treating and preventing gout flares. Current guidelines for the management of gout and indications for the use of some more recently introduced drugs; febuxostat, lesinurad, pegloticase and interleukin-1 antagonists are also briefly reviewed.

Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout.

OBJECTIVE: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10-5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry. CONCLUSION: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.

Pleiotropic effect of the ABCG2 gene in gout: involvement in serum urate levels and progression from hyperuricemia to gout.

BACKGROUND: The ABCG2 Q141K (rs2231142) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~ 60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls. METHODS: We analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables. RESULTS: In Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR = 1.85, P = 3.8E- 21 and ORmeta = 1.85, P = 1.3E- 03, respectively). There was evidence for an effect of 141K in determining HU in European (OR = 1.56, P = 1.7E- 18) but not in Polynesian (ORmeta = 1.49, P = 0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR = 1.37, P = 4.7E- 06), however significantly weaker than ABCG2 rs2231142 141K (PHet = 0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P = 0.009) and 2.6-fold in European (P = 9.9E- 06). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (Pmeta = 2.5E- 03). CONCLUSION: These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus.

OBJECTIVE: The aim of this study was to examine whether serum urate-associated genetic variants are associated with early-onset gout. METHODS: Participants with gout in the Genetics of Gout in Aotearoa study with available genotyping were included (n = 1648). Early-onset gout was defined as the first presentation of gout <40 years of age. Single nucleotide polymorphisms (SNPs) for the 10 loci most strongly associated with serum urate were genotyped. Allelic association of the SNPs with early-onset gout was tested using logistic regression in an unadjusted model and in a model adjusted for sex, body mass index, tophus presence, flare frequency, serum creatinine and highest serum urate. The analysis was also done in two replication cohorts: Eurogout (n = 704) and Ardea (n = 755), and data were meta-analysed. RESULTS: In the Genetics of Gout in Aotearoa study, there were 638 (42.4%) participants with early-onset gout. The ABCG2 rs2231142 gout risk T-allele was present more frequently in participants with early-onset gout compared with the later-onset group. For the other SNPs tested, no differences in risk allele number were observed. In the allelic association analysis, the ABCG2 rs2231142 T-allele was associated with early-onset gout in unadjusted and adjusted models. Analysis of the replication cohorts confirmed the association of early-onset gout with the ABCG2 rs2231142 T-allele, but not with other serum urate-associated SNPs. In the meta-analysis, the odds ratio (95% CI) for early-onset gout for the ABCG2 rs2231142 T-allele was 1.60 (1.41, 1.83). CONCLUSION: In contrast to other serum urate-raising variants, the ABCG2 rs2231142 T-allele is strongly associated with early-onset gout.

Identifying car ingress movement strategies before and after total knee replacement.

Background: Post-operative performance of knee bearings is typically assessed in activities of daily living by means of motion capture. Biomechanical studies predominantly explore common tasks such as walking, standing and stair climbing, while overlooking equally demanding activities such as embarking a vehicle. Aims: The aim of this work is to evaluate changes in the movement habits of patients after total knee arthroplasty surgery in comparison to healthy age-matched control participants. Methods: A mock-up car was fabricated based on the architecture of a common vehicle. Ten control participants and 10 patients with severe osteoarthritis of the knee attended a single- and three-motion capture session(s), respectively. Participants were asked to enter the car and sit comfortably adopting a driving position. Three trials per session were used for the identification of movement strategies by means of hierarchical clustering. Task completion time was also measured. Results: Patients' movement behaviour didn't change significantly following total knee arthroplasty surgery. Control participants favoured different movement strategies compared to patients post-operatively. Group membership, height and sidedness of the affected joint were found to be non-significant in task completion time. Conclusion: This study describes an alternative movement identification technique for the analysis of the ingress movement that may be used to clinically assess knee bearings and aid in movement simulations and vehicle design.

On the relationships between applied force, photography technique, and the quantification of bruise appearance.

Bruising is an injury commonly observed within suspect cases of assault or abuse, yet how a blunt impact initiates bruising and influences its severity is not fully understood. Furthermore, the standard method of documenting a bruise with colour photography is known to have limitations which influence the already subjective analysis of a bruise. This research investigated bruising using a standardised blunt impact, delivered to 18 volunteers. The resulting bruise was imaged using colour, cross polarised (CP) and infrared photography. Timelines of the L*a*b* colour space were determined from both colour and CP images for up to 3 weeks. Overall, no single photographic technique out-performed the others, however CP did provide greater contrast than colour photography. L*a*b* colour space timelines were not attributable any physiological characteristics. Whilst impact force negatively correlated with BMI (R2 = 0.321), neither were associated with any measure of bruise appearance. Due to the inter-subject variability in the bruise response to a controlled infliction, none of the methods in the current study could be used to reliably predict the age of a bruise or the severity of force used in creating a bruise. A more comprehensive approach combining impact characteristics, tissue mechanics, enhanced localised physiological measures and improvements in quantifying bruise appearance is likely to be essential in removing subjectivity from their interpretation.

Computer assisted orthopaedic surgery: Past, present and future.

Computer technology is ubiquitous and relied upon in virtually all professional activities including neurosurgery, which is why it is surprising that it is not the case for orthopaedic surgery with fewer than 5% of surgeons using available computer technology in their procedures. In this review, we explore the evolution and background of Computer Assisted Orthopaedic Surgery (CAOS), delving into the basic principles behind the technology and the changes in the discussion on the subject throughout the years and the impact these discussions had on the field. We found evidence that industry had an important role in driving the discussion at least in knee arthroplasty-a leading field of CAOS-with the ratio between patents and publications increased from approximately 1:10 in 2004 to almost 1:3 in 2014. The adoption of CAOS is largely restrained by economics and ergonomics with sceptics challenging the accuracy and precision of navigation during the early years of CAOS moving to patient functional improvements and long term survivorship. Nevertheless, the future of CAOS remains positive with the prospect of new technologies such as improvements in image-guided surgery, enhanced navigation systems, robotics and artificial intelligence.

3D bioprinting of mature bacterial biofilms for antimicrobial resistance drug testing.

The potential to bioprint and study 3D bacterial biofilm constructs could have great clinical significance at a time when antimicrobial resistance is rising to dangerously high levels worldwide. In this study, clinically relevant bacterial species including Escherichia coli, Staphylococcus aureus (MSSA), Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa were 3D bioprinted using a double-crosslinked alginate bioink to form mature bacteria biofilms, characterized by confocal laser scanning microscopy (CLSM) and fluorescent staining. Solid and porous bacteria-laden constructs were reproducibly bioprinted with thicknesses ranging from 0.25 to 4 mm. We demonstrated 3D bioprinting of thicker biofilms (>4 mm) than found in currently available in vitro models. Bacterial viability was excellent in the bioprinted constructs, with CLSM observation of bacterial biofilm production and maturation possible for at least 28 d in culture. Importantly, we observed the complete five-step biofilm life cycle in vitro following 3D bioprinting for the first time, suggesting the formation of mature 3D bioprinted biofilms. Bacterial growth was faster in thinner, more porous constructs whilst constructs crosslinked with BaCl2 concentrations of above 10 mM had denser biofilm formation. 3D MRSA and MSSA biofilm constructs were found to show greater resistance to antimicrobials than corresponding two-dimensional (2D) cultures. Thicker 3D E. coli biofilms had greater resistance to tetracycline than thinner constructs over 7 d of treatment. Our methodology allowed for the precise 3D bioprinting of self-supporting 3D bacterial biofilm structures that developed biofilms during extended culture. 3D biofilm constructs containing bacterial biofilms produce a model with much greater clinical relevance compared to 2D culture models and we have demonstrated their use in antimicrobial testing.

Health costs and efficiencies of patient-specific and single-use instrumentation in total knee arthroplasty: a randomised controlled trial.

Aim: To investigate whether patient-specific instrumentation (PSI) and single-use instrumentation (SUI) improve operating room efficiency in terms of time and cost to the healthcare provider over conventional/reusable instrumentation (CVR) when performing total knee arthroplasty (TKA). Patients and methods: Patients requiring TKA were randomised into one of four surgical groups: CVR, CVS (conventional/SUI), PSR (PSI/reusable) and PSS (PSI/SUI). All surgical procedures were video recorded to determine specific surgical time intervals. Other variables reported included the number of instrument trays used, missing equipment, direct instrument costs and the weight of the instruments the staff had to handle. Oxford Knee Score (OKS), estimated blood loss and lengths of hospital stay were also recorded as markers of patient experience. Results: PSR was significantly quicker in all the recorded time intervals, used less trays, experienced less missing equipment and resulted in lower blood loss and shorter hospital stays. SUI reported significantly slower operating room times and resulted in higher blood loss, but SUI was 88% lighter and 20% cheaper on average when compared with their reusable counterparts. Despite the economic advantages of PSI and SUI, the patients who reported greatest improvements in OKS were those allocated to the CVR group, but no clinically meaningful difference in OKS was found at any time point. Conclusions: PSI and SUI for TKA have the potential of reducing operating room times over conventional, reusable sets. This reduction will benefit theatre personnel ergonomically, while presenting the healthcare provider with potential cost-saving benefits in terms of reduced sterilisation costs and surgical times.