For chondral damage in younger patients, surgical best practice is microfracture, which involves drilling into the bone to liberate the bone marrow. This leads to a mechanically inferior fibrocartilage formed over the defect as opposed to the desired hyaline cartilage that properly withstands joint loading. While some devices have been developed to aid microfracture and enable its use in larger defects, fibrocartilage is still produced and there is no clear clinical improvement over microfracture alone in the long term. Our goal is to develop 3D printed devices, which surgeons can implant with a minimally invasive technique. The scaffolds should match the functional properties of cartilage and expose endogenous marrow cells to suitable mechanobiological stimuli in-situ, in order to promote healing of articular cartilage lesions before they progress to osteoarthritis, and rapidly restore joint health and mobility. Importantly, scaffolds should direct a physiological host reaction, instead of a foreign body reaction, associated with chronic inflammation and fibrous capsule formation, negatively influencing the regenerative outcome.

Our novel silica/polytetrahydrofuran/polycaprolactone hybrids were prepared by sol-gel synthesis and scaffolds were 3D printed by direct ink writing. 3D printed hybrid scaffolds with pore channels of ~250 µm mimic the compressive behaviour of cartilage. Our results show that these scaffolds support human bone marrow stem/stromal cell (hMSC) differentiation towards chondrogenesis in vitro under hypoxic conditions to produce markers integral to articular cartilage-like matrix evaluated by immunostaining and gene expression analysis. Macroscopic and microscopic evaluation of subcutaneously implanted scaffolds in mice showed that scaffolds caused a minimal resolving inflammatory response. Our findings show that 3D printed hybrid scaffolds have the potential to support cartilage regeneration.

Acknowledgements: Authors acknowledge funding provided by EPSRC grant EP/N025059/1.

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Abstract

Autologous osteochondral grafting has demonstrated positive outcomes for treating articular cartilage defects by replacing the damaged region with a cylindrical graft consisting of bone with a layer of cartilage, taken from a non-loadbearing region of the knee. Despite positive clinical use, factors that cause graft subsidence or poor integration are relatively unknown. The aim of this study was to develop finite element (FE) models of osteochondral grafts within a tibiofemoral joint and to investigate parameters affecting osteochondral graft stability.

Initial experimental tests on cadaveric femurs were performed to calibrate the bone properties and graft-bone frictional forces for use in corresponding FE models, generated from µCT scan data. The effects of cartilage defects and osteochondral graft repair were measured by examining contact pressure changes using in vitro tests on a single cadaveric human tibiofemoral joint. Six defects were created in the femoral condyles which were subsequently treated with osteochondral autografts or metal pins. Matching µCT scan-based FE models were created, and the contact patches were compared. Sensitivity to graft bone properties was investigated.

The bone material properties and graft-bone frictional forces were successfully calibrated from the initial tests with good resulting levels of agreement (CCC=0.87). The tibiofemoral joint experiment provided a range of cases to model. These cases were well captured experimentally and represented accurately in the FE models. Graft properties relative to host bone had large effects on immediate graft stability despite limited changes to resultant cartilage contact pressure.

Model confidence was built through extensive validation and sensitivity testing, and demonstrated that specimen-specific properties were required to accurately represent graft behaviour. The results indicate that graft bone properties affect the immediate stability, which is important for the selection of allografts and design of future synthetic grafts.

Non-optimal clinical alignment of components in total hip replacements (THRs) may lead to edge loading of the acetabular cup liner. This has the potential to cause changes to the liner rim not accounted for in standard wear models. A greater understanding of the material behaviours could be beneficial to design and surgical guidance for THR devices. The aim of this research was to combine finite element (FE) modelling and experimental simulation with microstructural assessment to examine material behaviour changes during edge loading.

A dynamic deformable FE model, matching the experimental conditions, was created to simulate the stress strain environment within liners. Five liners were tested for 4Mc (million cycles) of standard loading (ISO14242:1) followed by 3Mc of edge loading with dynamic separation (ISO14242:4) in a hip simulator. Microstructural measurements by Raman spectroscopy were taken at unloaded and highly loaded rim locations informed by FE results. Gravimetric and geometric measurements were taken every 1Mc cycles.

Under edge loading, peak Mises stress and plastic deformation occur below the surface of the rim during heel strike. After 7Mc, microstructural analysis determined edge loaded regions had an increased crystalline mass fraction compared to unloaded regions (p<0.05). Gravimetric wear rates of 12.5mm³/Mc and 22.3mm³/Mc were measured for standard and edge loading respectively. A liner penetration of 0.37mm was measured after 7Mc.

Edge loading led to an increase in gravimetric wear rate indicating a different wear mechanism is occurring. FE and Raman results suggest that changes to material behaviour at the rim could be possible. These methods will now be used to assess more liners and over a larger number of cycles. They have potential to explore the impact of edge loading on different surgical and patient variables.

The aim of this work was to develop a novel, accessible and low-cost method, which is sufficient to measure changes in meniscal position in a whole-knee joint model performing dynamic motion in a knee simulator.

An optical tracking method using motion markers, MATLAB (MATLAB, The MathWorks Inc.) and a miniature camera system (Raspberry Pi, UK) was developed. Method feasibility was assessed on porcine whole joint knee samples (n = 4) dissected and cemented to be used in the simulator (1). Markers were placed on three regions (medial, posterior, anterior) of the medial meniscus with corresponding reference markers on the tibial plateau, so the relative meniscal position could be calculated. The Leeds high kinematics gait profile scaled to the parameters of a pig (1, 2) was driven in displacement control at 0.5 Hz. Videos were recorded at cycle-3 and cycle-50. Conditions tested were the capsule retained (intact), capsule removed and a medial posterior root tear. Mean relative displacement values were taken at time-points relating to the peaks of the axial force and flexion-extension gait inputs, as well as the range between the maximum and minimum values. A one-way ANOVA followed by Tukey post hoc analysis were used to assess differences (p = 0.05).

The method was able to measure relative meniscal displacement for all three meniscal regions. The medial region showed the greatest difference between the conditions. A significant increase (p < 0.05) for the root tear condition was found at 0.28s and 0.90s (axial load peaks) during cycle-3. Mean relative displacement for the root tear condition decreased by 0.29 mm between cycle-3 and cycle-50 at the 0.28s time-point. No statistically significant differences were found when ranges were compared at cycle-3 and cycle-50.

The method was sensitive to measure a substantial difference in medial-lateral relative displacement between an intact and a torn state. Meniscus extrusion was detected for the root tear condition throughout test duration. Further work will progress onto human specimens and apply an intervention condition.

Cam-type femoroacetabular impingement is caused by bone excess on the femoral neck abutting the acetabular rim. This can cause cartilage and labral damage due to increased contact pressure as the cam moves into the acetabulum. However, the damage mechanism and the influence of individual mechanical factors (such as sliding distance) are poorly understood. The aim of this study was to identify the cam sliding distance during impingement for different activities in the hip joint.

Motion data for 12 different motion activities from 18 subjects, were applied to a hip shape model (selected as most likely to cause damage, anteriorly positioned with a maximum alpha angle of 80°). The model comprised of a pointwise representation of the acetabular rim and points on the femoral head and neck where the shape deviated from a sphere (software:Matlab).

The movement of each femoral point was tracked in 3D while an activity motion was applied, and impingement recorded when overlap between a cam point and the acetabular rim occurred. Sliding distance was recorded during impingement for each relevant femoral point.

Angular sliding distances varied for different activities. The highest mean (±SD) sliding distance was for leg-crossing (42.62±17.96mm) and lowest the trailing hip in golf swing (2.17±1.11mm). The high standard deviation in the leg crossing sliding distances, indicates subjects may perform this activity in a different manner.

This study quantified sliding distance during cam impingement for different activities. This is an important parameter for determining how much the hip moves during activities that may cause damage and will provide information for future experimental studies.

Multiple biochemical biomarkers have been previously investigated for the diagnosis, prognosis and response to treatment of articular cartilage damage, including osteoarthritis (OA). Synovial fluid (SF) biomarker measurement is a potential method to predict treatment response and effectiveness. However, the significance of different biomarkers and their correlation to clinical outcomes remains unclear. This systematic review evaluated current SF biomarkers used in investigation of cartilage degeneration or regeneration in the knee joint and correlated these biomarkers with clinical outcomes following cartilage repair or regeneration interventions.

PubMed, Institute of Science Index, Scopus, Cochrane Central Register of Controlled Trials, and Embase databases were searched. Studies evaluating SF biomarkers and clinical outcomes following cartilage repair intervention were included. Two researchers independently performed data extraction and QUADAS-2 analysis. Biomarker inclusion, change following intervention and correlation with clinical outcome was compared.

9 studies were included. Study heterogeneity precluded meta-analysis. There was significant variation in sampling and analysis. 33 biomarkers were evaluated in addition to microRNA and catabolic/anabolic ratios. Five studies reported on correlation of biomarkers with six biomarkers significantly correlated with clinical outcomes following intervention. However, correlation was only demonstrated in isolated studies.

This review demonstrates significant difficulties in drawing conclusions regarding the importance of SF biomarkers based on the available literature. Improved standardisation for collection and analysis of SF samples is required. Future publications should also focus on clinical outcome scores and seek to correlate biomarkers with progression to further understand the significance of identified markers in a clinical context.

Stimulation of the mechanosensitive ion channel, Piezo1 promotes bone anabolism and SNPs in the Piezo1 locus are associated with changes in fracture risk. Osteocytes function as critical regulators of bone homeostasis by sensing mechanical signals. The current study used a human, cell-based physiological, 3D in vitro model of bone to determine whether loading of osteocytes in vitro results in upregulation of the Piezo1 pathway.

Human Y201 MSCs, embedded in type I collagen gels and differentiated to osteocytes for 7-days, were subjected to pathophysiological load (5000 µstrain, 10Hz, 5 mins; n=6) with unloaded cells as controls (n=4). RNA was extracted 1-hr post load and assessed by RNAseq analysis. To mimic mechanical load and activate Piezo1, cells were differentiated to osteocytes for 13 days and treated ± Yoda1 (5µM, 2- and 24-hs, n=4); vehicle treated cells served as controls (n=4). RNA was subjected to RT-qPCR and data normalised to the housekeeping gene, YWHAZ. Media was analysed for IL6 release by ELISA.

Mechanical load upregulated Piezo1 gene expression (16.5-fold, p<0.001) and expression of the transcription factor NFATc1, and matricellular protein CYR61, known regulators of Piezo1 mechanotransduction (3-fold; p= 5.0E-5 and 6.8-fold; p= 6.0E-5, respectively). After 2-hrs, Yoda1 increased the expression of the early mechanical response gene, cFOS (11-fold; p=0.021), mean Piezo1 expression (2.3-fold) and IL-6 expression (103-fold, p<0.001). Yoda1 increased the release of IL6 protein after 24 hours (7.5-fold, p=0.001).

This study confirms Piezo1 as an important mechanosensor in osteocytes. Piezo1 activation mediated an increase in IL6, a cytokine that drives inflammation and bone resorption providing a direct link between mechanical activation of Piezo1, bone remodeling and inflammation, which may contribute to mechanically induced joint degeneration in diseases such as osteoarthritis. Mechanistically, we hypothesize this may occur through promoting Ca2+ influx and activation of the NFATc1 signaling pathway.

Osteoarthritis (OA) is a common cause of chronic pain. Subchondral bone is highly innervated, and bone structural changes directly correlate with pain in OA. Mechanisms underlying skeletal–neural interactions are under-investigated. Bone derived axon guidance molecules are known to regulate bone remodelling. Such signals in the nervous system regulate neural plasticity, branching and neural inflammation. Perturbation of these signals during OA disease progression may disrupt sensory afferents activity, affecting tissue integrity, nociception, and proprioception.

Osteocyte mechanical loading and IL-6 stimulation alters axon guidance signalling influencing innervation, proprioception, and nociception.

Human Y201 MSC cells, embedded in 3D type I collagen gels (0.05 × 106 cell/gel) in 48 well plastic or silicone (load) plates, were differentiated to osteocytes for 7 days before stimulation with IL-6 (5ng/ml) with soluble IL-6 receptor (sIL-6r (40ng/ml) or unstimulated (n=5/group), or mechanically loaded (5000 μstrain, 10Hz, 3000 cycles) or not loaded (n=5/group). RNA extracted 1hr and 24hrs post load was quantified by RNAseq whole transcriptome analysis (NovaSeq S1 flow cell 2 × 100bp PE reads and differentially expressed neurotransmitters identified (>2-fold change in DEseq2 analysis on normalised count data with FDR p<0.05). After 24 hours, extracted IL-6 stimulated RNA was quantified by RT-qPCR for neurotrophic factors using 2–∆∆Ct method (efficiency=94-106%) normalised to reference gene GAPDH (stability = 1.12 REfinder). Normally distributed data with homogenous variances was analysed by two-tailed t test.

All detected axonal guidance genes were regulated by mechanical load. Axonal guidance genes were both down-regulated (Netrin1 0.16-fold, p=0.001; Sema3A 0.4-fold, p<0.001; SEMA3C (0.4-fold, p<0.001), and up-regulated (SLIT2 2.3-fold, p<0.001; CXCL12 5-fold, p<0.001; SEMA3B 13-fold, p<0.001; SEMA4F 2-fold, p<0.001) by mechanical load. IL6 and IL6sR stimulation upregulated SEMA3A (7-fold, p=0.01), its receptor Plexin1 (3-fold, p=0.03). Neutrophins analysed in IL6 stimulated RNA did not show regulation.

Here we show osteocytes regulate multiple factors which may influence innervation, nociception, and proprioception upon inflammatory or mechanical insult. Future studies will establish how these factors may combine and affect nerve activity during OA disease progression.

Mechanical loading of joints with osteoarthritis (OA) results in pain-related functional impairment, altered joint mechanics and physiological nociceptor interactions leading to an experience of pain. However, the current tools to measure this are largely patient reported subjective impressions of a nociceptive impact. A direct measure of nociception may offer a more objective indicator. Specifically, movement-induced physiological responses to nociception may offer a useful way to monitor knee OA. In this study, we gathered preliminary data on healthy volunteers to analyse whether integrated biomechanical and physiological sensor datasets could display linked and quantifiable information to a nociceptive stimulus.

Following ethical approval, 15 healthy volunteers completed 5 movement and stationary activities in 2 conditions; a control setting and then repeated with an applied quantified thermal pain stimulus to their right knee. An inertial measurement unit (IMU) and an electromyography (EMG) lower body marker set were tested and integrated with ground reaction force (GRF) data collection. Galvanic skin response electrodes for skin temperature and conductivity and photoplethysmography (PPG) sensors were manually timestamped to the integrated system.

Pilot data showed EMG, GRF and IMU fluctuations within 0.5 seconds of each other in response to a thermal trigger. Preliminary analysis on the 15 participants tested has shown skin conductance, PPG, EMG, GRFs, joint angles and kinematics with varying increases and fluctuations during the thermal condition in comparison to the control condition.

Preliminary results suggest physiological and biomechanical data outputs can be linked and identified in response to a defined nociceptive stimulus. Study data is currently founded on healthy volunteers as a proof-of-concept. Further exploratory statistical and sensor readout pattern analysis, alongside early and late-stage OA patient data collection, can provide the information for potential development of wearable nociceptive sensors to measure disease progression and treatment effectiveness.

To determine the risk of total knee replacement (TKR) for primary osteoarthritis (OA) associated with overweight/obesity in the Australian population.

This population-based study analyzed 191,723 cases of TKR collected by the Australian Orthopaedic Association National Joint Registry and population data from the Australian Bureau of Statistics. The time-trend change in incidence of TKR relating to BMI was assessed between 2015-2018. The influence of obesity on the incidence of TKR in different age and gender groups was determined. The population attributable fraction (PAF) was then calculated to estimate the effect of obesity reduction on TKR incidence.

The greatest increase in incidence of TKR was seen in patients from obese class III. The incidence rate ratio for having a TKR for obesity class III was 28.683 at those aged 18-54 years but was 2.029 at those aged >75 years. Females in obesity class III were 1.7 times more likely to undergo TKR compared to similarly classified males. The PAFs of TKR associated with overweight or obesity was 35%, estimating 12,156 cases of TKR attributable to obesity in 2018. The proportion of TKRs could be reduced by 20% if overweight and obese population move down one category.

Obesity has resulted in a significant increase in the incidence of TKR in the youngest population in Australia. The impact of obesity is greatest in the young and the female population. Effective strategies to reduce the national obese population could potentially reduce 35% of the TKR, with over 10,000 cases being avoided.

Variations in component positioning of total hip replacements can lead to edge loading of the liner, and potentially affect device longevity. These effects are evaluated using ISO 14242:4 edge loading test results in a dynamic system. Mediolateral translation of one of the components during testing is caused by a compressed spring, and therefore the kinematics will depend on the spring stiffness and damping coefficient, and the mass of the translating component and fixture. This study aims to describe the sensitivity of the liner plastic strain to these variables, to better understand how tests using different simulator designs might produce different amounts of liner rim deformation.

A dynamic explicit deformable finite element model with 36mm Pinnacle metal-on-polyethylene bearing geometry (DePuy Synthes, Leeds, UK) was used with material properties for conventional UHMWPE. Setup was 65° clinical inclination, 4mm mismatch, 70N swing phase load, and 100N/mm spring. Fixture mass was varied from 0.5-5kg, spring damping coefficient was varied from 0-2Ns/mm. They were changed independently, and in combination.

Maximum separation values were relatively insensitive to changes in the mass, damping coefficient, or both. The sensitivity of peak plastic strain, to this range of inputs, was similar to changing the swing phase load from 70N to approximately 150N – 200N. Increasing the fixture mass and/or damping coefficient increased the peak plastic strain, with values from 0.15-0.19.

Liner plastic deformation was sensitive to the spring damping and fixture mass, which may explain some of the differences in fatigue and deformation results in UHMWPE liners tested on different machines or with modified fixtures. These values should be described when reporting the results of ISO14242:4 testing.

Acknowledgements

Funded by EPSRC grant EP/N02480X/1; CAD supplied by DePuy Synthes.

Knee pain is common, representing a significant socioeconomic burden. Caused by a variety of pathologies, its evaluation in primary-care is challenging. Subsequently, an over-reliance on magnetic resonance imaging (MRI) exists. Prior to orthopaedic surgeon referral, many patients receive no, or incorrect, imaging. Electronic-triage (e-triage) tools represent an innovative solution to address this problem. The primary aim of this study was to ascertain whether an e-triage tool is capable of outperforming existing clinical pathways to determine the correct pre-hospital imaging based on knee pain diagnosis.

Patients ≥18 years with a new presentation of knee pain were retrospectively identified. The timing and appropriateness of imaging was assessed. A symptom-based e-triage tool was developed, using the Amazon LEXbotplatform, and piloted to predict five common knee pathologies and suggest appropriate imaging.

1462 patients were identified. 17% of arthroplasty patients received an ‘unnecessary MRI’, whilst 28% of arthroscopy patients did not have a ‘necessary MRI’, thus requiring a follow-up appointment, with a mean delay of three months (SD 2.6, range 0.2-20.2). Using NHS tariffs, a wasted cost through unnecessary/necessary MRIs and subsequent follow-up appointments was estimated at £45,816. The e-triage pilot was trialled with 41 patients (mean age:58.4 years, 58.5% female). Preliminary diagnoses were available for 34 patients. Using the highest proportion of reported symptoms in the corresponding group, the e-triage tool correctly identified three of the four knee pathologies. The e-triage tool did not correctly identify anterior cruciate ligament injuries (n=3). 79.2% of participants would use the tool again.

A significant number of knee pathology patients received incorrect imaging prior to their initial hospital appointment, incurring delays and unnecessary costs. A symptom-based e-triage tool was developed, with promising pilot data and user feedback. With refinement, this tool has the potential to improve wait-times and referral quality, whilst reducing costs.

Abstract

Shoulder replacements have evolved and current 4th generation implants allow intraoperative flexibility to perform anatomic, reverse, trauma, and revision shoulder arthroplasty. Despite high success rates with shoulder arthroplasty, complication rates high as 10–15% have been reported and progressive glenoid loosening remains a concern.

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