Objective

To analyze the short-term outcome after medial open-wedge high tibial osteotomy with a 3D-printing technology in early medial keen osteoarthritis and varus malalignment.

Varus malalignment increases the susceptibility of cartilage to mechanical overloading, which stimulates catabolic metabolism to break down the extracellular matrix and lead to osteoarthritis (OA). The altered mechanical axis from the hip, knee to ankle leads to knee joint pain and ensuing cartilage wear and deterioration, which impact millions of the aged population. Stabilization of the remaining damaged cartilage, and prevention of further deterioration, could provide immense clinical utility and prolong joint function. Our previous work showed that high tibial osteotomy (HTO) could shift the mechanical stress from an imbalanced status to a neutral alignment. However, the underlying mechanisms of endogenous cartilage stabilization after HTO remain unclear. We hypothesize that cartilage-resident mesenchymal stem cells (MSCs) dampen damaged cartilage injury and promote endogenous repair in a varus malaligned knee. The goal of this study is to further examine whether HTO-mediated off-loading would affect human cartilage-resident MSCs' anabolic and catabolic metabolism. This study was approved by IACUC at Xi'an Jiaotong University. Patients with medial compartment OA (52.75±6.85 yrs, left knee 18, right knee 20) underwent open-wedge HTO by the same surgeons at one single academic sports medicine center. Clinical data was documented by the Epic HIS between the dates of April 2019 and April 2022 and radiographic images were collected with a minimum of 12 months of follow-up. Medial compartment OA with/without medial meniscus injury patients with unilateral Kellgren /Lawrence grade 3–4 was confirmed by X-ray. All incisions of the lower extremity healed well after the HTO operation without incision infection. Joint space width (JSW) was measured by uploading to ImageJ software. The Knee injury and Osteoarthritis Outcome Score (KOOS) toolkit was applied to assess the pain level. Outerbridge scores were obtained from a second-look arthroscopic examination. RNA was extracted to quantify catabolic targets and pro-inflammatory genes (QiaGen). Student's t test for two group comparisons and ANOVA analysis for differences between more than 2 groups were utilized. To understand the role of mechanical loading-induced cartilage repair, we measured the serial changes of joint space width (JSW) after HTO for assessing the state of the cartilage stabilization. Our data showed that HTO increased the JSW, decreased the VAS score and improved the KOOS score significantly. We further scored cartilage lesion severity using the Outerbridge classification under a second-look arthroscopic examination while removing the HTO plate. It showed the cartilage lesion area decreased significantly, the full thickness of cartilage increased and mechanical strength was better compared to the pre-HTO baseline. HTO dampened medial tibiofemoral cartilage degeneration and accelerate cartilage repair from Outerbridge grade 2 to 3 to Outerbridge 0 to 1 compared to untreated varus OA. It suggested that physical loading was involved in HTO-induced cartilage regeneration. Given that HTO surgery increases joint space width and creates a physical loading environment, we hypothesize that HTO could increase cartilage composition and collagen accumulation. Consistent with our observation, a group of cartilage-resident MSCs was identified. Our data further showed decreased expression of RUNX2, COL10 and increased SOX9 in MSCs at the RNA level, indicating that catabolic activities were halted during mechanical off-loading. To understand the role of cartilage-resident MSCs in cartilage repair in a biophysical environment, we investigated the differentiation potential of MSCs under 3-dimensional mechanical loading conditions. The physical loading inhibited catabolic markers (IL-1 and IL-6) and increased anabolic markers (SOX9, COL2). Knee-preserved HTO intervention alleviates varus malalignment-related knee joint pain, improves daily and recreation function, and repairs degenerated cartilage of medial compartment OA. The off-loading effect of HTO may allow the mechanoregulation of cartilage repair through the differentiation of endogenous cartilage-derived MSCs

High tibial osteotomy (HTO) is an effective surgical treatment for isolated medial compartment knee osteoarthritis; however, widespread adoption is limited due to difficulty in achieving the planned correction, and patient dissatisfaction due to soft tissue irritation. A new HTO system – Tailored Osteotomy Knee Alignment (TOKA®, 3D Metal Printing Ltd, Bath, UK) could potentially address these barriers having a custom titanium plate and titanium surgical guides featuring a unique mechanism for precise osteotomy opening as well as saw cutting and drilling guides. The aim of this study was to assess the accuracy of this novel HTO system using cadaveric specimens; a preclinical testing stage ahead of first-in-human surgery according to the ‘IDEAL-D’ framework for device innovation. Local ethics committee approval was obtained. The novel opening wedge HTO procedure was performed on eight cadaver leg specimens. Whole lower limb CT scans pre- and post-operatively provided geometrical assessment quantifying the discrepancy between pre-planned and post-operative measurements for key variables: the gap opening angle and the patient specific surgical instrumentation positioning and rotation - assessed using the implanted plate. The average discrepancy between the pre-operative plan and the post-operative osteotomy correction angle was: 0.0 ± 0.2°. The R2 value for the regression correlation was 0.95. The average error in implant positioning was −0.4 ± 4.3 mm, −2.6 ± 3.4 mm and 3.1 ± 1.7° vertically, horizontally, and rotationally respectively. This novel HTO surgery has greater accuracy and smaller variability in correction angle achieved compared to that reported for conventional or other patient specific methods with published data available. This system could potentially improve the accuracy and reliability of osteotomy correction angles achieved surgically

High tibial osteotomy (HTO) is a joint preserving alternative to knee replacement for medial tibiofemoral osteoarthritis in younger, more active patients. The procedure is technically challenging and limited also by ‘one size fits all’ plates which can result in patient discomfort necessitating plate removal. This clinical trial evaluated A novel custom-made HTO system – TOKA (3D Metal Printing LTD, Bath, UK) for accuracy of osteotomy correction and improvements in clinical outcome scores. The investigation was a single-arm single-centre prospective clinical trial (IRCCS Istituto Ortopedico Rizzoli; ClinicalTrials.gov NCT04574570), with recruitment of 25 patients (19M/6F; average age: 54.4 years; average BMI: 26.8), all of whom received the TOKA HTO 3D planning and surgery. All patients were predominantly diagnosed with isolated medial knee osteoarthritis and with a varus deformity under 20°. Patients were CT scanned pre- and post-operatively for 3D virtual planning and correctional assessment. All surgeries were performed by the lead clinical investigator – a consultant knee surgeon with a specialist interest in and clinical experience of HTO. On average, Knee Society Scores (KSS) improved significantly (p<0.001) by 27.6, 31.2 and 37.2 percentage points respectively by 3-, 6- and 12-months post-surgery respectively. Other measures assessed during the study (KOOS, EQ5D) produced similar increases. Our early experience using custom implants is extremely promising. We believe the reduced profile of the plate, as well as the reduced invasiveness and ease of surgery contributed to faster patient recovery, and improved outcome scores compared to conventional techniques. These clinical outcome results compare very favourably other case-series with published KOOS scores using different devices

Unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) are well-established operative interventions in the treatment of knee osteoarthritis (KOA). However, which of these interventions is more beneficial, to patients with KOA, is not known and remains a topic of much debate. Aims: (i) To determine whether UKA or HTO is more beneficial in the treatment of isolated medial compartment KOA, via an assessment of patient-reported outcome measures (PROMs). (ii) To investigate the relationship between PROMs and radiographic parameters of knee joint orientation/alignment. This longitudinal observational study assessed a total of 42 patients that had undergone UKA (n=23) or HTO (n=19) to treat isolated medial compartment KOA. The PROMs assessed, pre-operatively and 1-year post-operatively, consisted of the: self-administered comorbidity questionnaire; short form-12; oxford knee score; knee injury and osteoarthritis outcome score; and the EQ-5D-5L. The radiographic parameters of knee joint alignment/orientation assessed, pre-operatively and 8-weeks post-operatively, included the: hip-knee-ankle angle; mechanical axis deviation; and the angle of the Mikulicz line. Statistical analysis demonstrated an overall significant (p<0.001), pre-operative to post-operative, improvement in the PROM scores of both groups. There were no significant differences in the post-operative PROM scores of the UKA and HTO group. Correlation analyses revealed that pre-operatively, a more distolaterally angled Mikulicz line was associated with worse knee function (p<0.05) and overall health (p<0.05); a relationship that, until now, has not been investigated nor commented upon within the literature. UKAs and HTOs are both efficacious operations that provide a comparable degree of clinical benefit to patients with isolated medial compartment KOA. To further the scientific/medical community's understanding of the factors that impact upon health-outcomes in KOA, future research should seek to investigate the mechanism underlying the relationship, between Mikulicz line and PROMs, observed within the current study

Introduction and Objective. After anterior cruciate ligament reconstruction one of the risk factors for graft (re-)rupture is an increased posterior tibial slope (PTS). The current treatment for PTS is a high tibial osteotomy (HTO). This is a free-hand method, with 1 degree of tibial slope correction considered to be equal to 1 or even 1.67 mm of the anterior wedge resection. Error rates in the frontal plane reported in literature vary from 1 – 8.6 degrees, and in the sagittal plane outcomes in a range of 2 – 8 degrees are reported when planned on PTSs of 3 – 5 degrees. Therefore, the free-hand method is considered to have limited accuracy. It is expected that HTO becomes more accurate with patient specific saw guides (PSGs), with an accuracy margin reported in literature of 2 degrees. This proof of concept porcine cadaver case study aimed to investigate whether the use of PSGs improves the accuracy of HTO to less than 2 degrees. Secondly, the reproducibility of tibial slope measurement was evaluated. Materials and Methods. Preoperative MRI images of porcine cadaver knees (n = 3) were used to create 3D anatomical bone models (Mimics, Materialise, Belgium). These 3D models were subsequently used to develop PSGs (3-Matic, Materialise, Belgium) to correct all tibias for 3 degrees PTS and 4 degrees varus. The PSG mediated HTOs were performed by an experienced orthopaedic surgeon, after which postoperative MRI images were obtained. 3D anatomical models of postoperative tibias were created, and tibial slopes were assessed on both pre- and postoperative tibias. The tibial slope was defined as the angle between the mechanical axis and 3D tibial reference plane in the frontal and sagittal plane. The accuracy of the PSG mediated HTO (median and range) was defined as the difference in all possible combinations of the preoperatively planned and postoperatively obtained tibial slopes. To ensure reproducibility, the pre- and postoperative tibial slopes were measured thrice by one observer. The intra-class correlation coefficients (ICCs) were subsequently calculated to assess the intra-rater reliability (SPSS, IBM Corp., Armonk, N.Y., USA). Results. An accuracy within 2 degrees was achieved in all three cases. The median and range in accuracy for each specimen were +0.46 (−0.57 – 1.45), +0.60 (−1.07 – 1.00), and +0.45 (−0.16 – 0.71) degrees in the frontal plane, and −0.45 (−1.97 – 1.22), −0.80 (−2.42 – 1.77), and 0.00 (−2.19 – 1.93) degrees in the sagittal plane. The pre- and postoperatively planned tibial slopes in the frontal and sagittal plane were measured with a good up to excellent reproducibility. The ICCs of the preoperative planned tibial slopes were 0.82 (95% CI, 0.11 – 1.0), and 0.77 (95% CI, 0.17 – 1.0) for the frontal and sagittal plane, respectively. Postoperative, the ICC for the frontal plane was 0.92 (95% CI, 0.43 – 1.0), and 0.67 (95% CI, −0.06 – 0.99) for the sagittal plane. Conclusions. This proof of concept porcine case study showed an accuracy for the PSG mediated HTO within 2 degrees for each specimen. Moreover, the tibial slopes were measured with a good up to excellent reproducibility. Therefore, the PSG mediated HTO seems to be accurate and might be better than the current used free-hand HTO method. These results offer perspective for implementation of PSG mediated HTO to correct PTS and metaphyseal varus

Abstract. OBJECTIVES. Valgus high tibial osteotomy (HTO) represents an effective treatment for patients with medial compartment osteoarthritis (OA) in a varus knee. However, the mechanisms which cause this clinical improvement are unclear. Previous studies suggest a wider stance gait can reduce medial compartment loading via reduction in the external knee adduction moment (KAM); a measure implicated in progression of medial compartment OA. This study aimed to measure whether valgus HTO is associated with a postoperative increase in static stance width. METHODS. 32 patients, recruited in the Biomechanics and Bioengineering Centre Versus Arthritis HTO study, underwent valgus (medial opening wedge) HTO. Weightbearing pre- and post- operative radiographs were taken showing both lower limbs. The horizontal distance, measured from a fixed point on the right talus to the corresponding point on the left, was divided by the talus width to give a standardised “stance width” for each radiograph. The difference between pre- and post- operative stance width was compared for each patient using a paired sample t-test. RESULTS. Preoperatively, mean stance was 4.00 talar-widths but postoperatively this increased to 5.41. This mean increase of 1.42 talar-widths was statistically significant (p=0.001) and represents a mean proportional increase in stance width of 35.5% following HTO. Of the 32 patients, 23 showed increased stance width and 9 decreased (range −4.64 to 6.00 talar-widths). CONCLUSIONS. These findings indicate an association of frontal plane surgical realignment at the proximal tibia via a medial opening wedge HTO with an increased stance width on postoperative radiographs. Considering both wider stance gait and HTO have been shown to affect the progression of medial compartment OA, these results may explain one mechanism contributing to the efficacy of HTO surgery. However, the range of changes in stance width suggests significant variability in how patients adapt at a whole-limb and whole-body level following HTO. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Introduction and Objective. Medial Knee Osteoarthritis (MKO) is associated with abnormal knee varism, this resulting in altered locomotion and abnormal loading at tibio-femoral condylar contacts. To prevent end-stage MKO, medial compartment decompression is selectively considered and, when required, executed via High Tibial Osteotomy (HTO). This is expected to restore normal knee alignment, load distribution and locomotion. In biomechanics, HTO efficacy may be investigated by a thorough analysis of the ground reaction forces (GRF), whose orientation with respect to patient-specific knee morphology should reflect knee misalignment. Although multi-instrumental assessments are feasible, a customized combination of medical imaging and gait analysis (GA), including GRF data, rarely is considered. The aim of this study was to report an original methodology merging Computed-Tomography (CT) with GA and GFR data in order to depict a realistic patient-specific representation of the knee loading status during motion before and after HTO. Materials and Methods. 25 MKO-affected patients were selected for HTO. All patients received pre-operative clinical scoring, and radiological/instrumental assessments; so far, these were also executed post-operatively at 6-month follow-up on 7 of these patients. State-of-the-art GA was performed during walking and more demanding motor tasks, like squatting, stair-climbing/descending, and chair-rising/sitting. An 8-camera motion capture system, combined with wireless electromyography, and force platforms for GRF tracking, was used together with an own established protocol. This marker-set was enlarged with 4 additional skin-based non-collinear markers, attached around the tibial-plateau rim. While still wearing these markers, all analyzed patients received full lower-limb X-ray in standing posture a CT scan of the knee in weight-bearing Subsequently, relevant DICOMs were segmented to reconstruct the morphological models of the proximal tibia and the additional reference markers, for a robust anatomical reference frame to be defined on the tibia. These marker trajectories during motion were then registered to the corresponding from CT-based 3D reconstruction. Relevant registration matrices then were used to report GRF data on the reconstructed tibial model. Intersection paths of GRF vectors with respect to the tibial-plateau plane were calculated, together with their centroids. Results. Pre-operative clinical and radiological scoring confirmed MKO and associated abnormal varism. The morphological characterization of GRF was successfully achieved pre- and post- HTO on patient-specific tibial plateau. Pre-operative GFR patterns and peaks, including those related to knee joint moments, were observed medially on the knee, as expected. In post-HTO, these resulted lateralized and much closer to the tibial plateau spine, as desired. In detail, when post- is compared to pre-op, the difference of the centroids were, on average, 54.6±18.1 mm (min÷max: 36.7÷72.8 mm) more lateral during walking and 52.5±28.5 mm (24.7÷87.6 mm) during stair climbing. When reported in % of the tibial plateau width, these values became 69.2±20.1 (46.1÷81.4) and 78.1±30.1 (43.4÷98.0), respectively. Post-op also clinical scores and GA revealed a considerable overall improvement, especially in functional performances. Conclusions. The reported novel approach allows a combination of motion data, including GFR, and tibial-plateau morphology. Relevant pre- and post-operative routine application offer a quantification of the effect of the original deformity and executed joint realignment, and an assistance for surgical planning in case of HTO as well as ideally in other orthopedic treatments

Abstract. Objective. Explore whether high tibial osteotomy (HTO) changes knee contact forces and to explore the relationship between the external knee adduction moment (EKAM) pre and 12 months post HTO. Methods. Three-dimensional gait analysis was performed on 17 patients pre and 12-months post HTO using a modified Cleveland marker-set. Tibiofemoral contact forces were calculated in SIMM. The scaled musculoskeletal model integrated an extended knee model allowing for 6 degrees of freedom in the tibiofemoral and patellofemoral joint. Joint angles were calculated using inverse kinematics then muscle and contact forces and secondary knee kinematics were estimated using the COMAC algorithm. Paired samples t-test were performed using SPSS version 25 (SPSS Inc., USA). Testing for normality was undertaken with Shapiro-Wilk. Pearson correlations established the relationships between EKAM1 to medial KCF1, and EKAM2 to medial KCF2, pre and post HTO. Results. Total knee contact force peak 1 significantly reduced from 2.6 x body weight pre-HTO to 2.3 x body weight 12-months post-HTO. Medial contact force peak 1 significantly reduced from 1.7 x body weight pre-HTO to 1.5 x body weight 12-months post-HTO. Second peak lateral knee contact force significantly increased from 0.9 body weight pre-HTO to 1.1 x body weight 12-months post-HTO. Furthermore, this study found very strong correlations between EKAM1 and medial KCF1 pre-HTO (r=0.85) as well as post-HTO (r=0.91). There was a significantly moderate relationship between EKAM2 and medial KCF2 pre-HTO (r=0.625). Conclusion. HTO significantly reduced overall and medial KCF during the first half of stance whilst increasing second half of stance peak lateral knee contact force. This study demonstrated a strong relationship between EKAM peaks and respective medial KCF peaks, supporting the usefulness of EKAM as a surrogate measure of medial compartment tibiofemoral contact forces. This demonstrates HTO successfully offloads the tibiofemoral joint overall, as well as offloading the medial compartment

Abstract. Objectives. Principal Component Analysis (PCA) is a useful method for analysing human motion data. The objective of this study was to use PCA to quantify the biggest variance in knee kinematics waveforms between a Non-Pathological (NP) group and individuals awaiting High Tibial Osteotomy (HTO) surgery. Methods. Thirty knees (29 participants) who were scheduled for HTO surgery were included in this study. Twenty-eight NP volunteers were recruited into the study. Human motion analysis was performed during level gait using a modified Cleveland marker set. Subjects walked at their self-selected speed for a minimum of 6 successful trials. Knee kinematics were calculated within Visual3D (C-Motion). The first three Principal Components (PCs) of each input variable were selected. Single-component reconstruction was performed alongside representative extremes of each PC to aid interpretation of the biomechanical feature reconstructed by each component. Results. Pre-operatively patient demographics included (age: 50.70 (8.71) years; height: 1.75 (.11) m; body mass: 90.57 (20.17) kg; mTFA: 7.75 (3.72) degrees varus; gait speed: 1.06 (0.23) m/s). The HTO cohort was significantly older and had a higher mass than the NP control participants. For knee kinematics the first three PCs explained 88%, 95% and 89% of the sagittal, frontal, and transverse planes, respectively. The main variances can be explained by sagittal plane magnitude differences, peak swing is associated with toe-off, a reduced knee flexion angle is associated with a longer time spent in stance, pre-HTO remain adducted during stance and pre-HTO patients remain more externally rotated during stance and latter part of swing. Conclusions. This study has introduced PCA in trying to better understand the biomechanical differences between a control group and a cohort with medial knee osteoarthritis varus deformity awaiting HTO. Further analysis will be undertaken using PCA comparing pre- and post-surgery which will be of importance in clinical decision making

The medial opening-wedge high tibial osteotomy (OW-HTO) is an accepted option to treat the isolated medial compartment osteoarthritis (OA) in varus knee. Despite satisfactory outcomes were described in literature, consistent complication rate has been reported and the provided accuracy of coronal alignment correction using conventional HTO techniques falls short. Patient specific instrumentations has been introduced with the aim to reduce complications and to improve the intra-operative accuracy according to the pre-operative plan, which is responsible for the clinical result of the surgery. In this talk, an overview of the clinical results of HTO patient specific instrumentation available in literature will be performed. Moreover, preliminary intra-operative and clinical results of a new customised 3-D printed cutting guide and fixation plate for OW-HTO will be presented

The aim of this study was to determine whether the clinical outcome of autologous chondrocyte transplantation was dependent on the timing of a high tibial osteotomy in tibio-femoral mal-aligned knees. Between 2000 and 2005, forty-eight patients underwent autologous chondrocyte implantation with HTO performed at varying times relative to the second stage autologous chondrocyte implantation procedure. 24 patients had HTO performed simultaneously with their second stage cartilage transplantation, (the HTO Simultaneous Group). 5 patients had HTO prior to their cartilage procedure, (the HTO pre-ACI Group) and 19 had HTO performed between 1 to 4 years after their second stage cartilage implantation, (the HTO post-ACI Group). There were 29 men and 19 women with a mean age of 37 years (Range 28 to 50) at the time of their second stage procedure. With average follow-up of 72 months we have demonstrated a significant functional benefit in performing the HTO either prior to or simultaneously with the ACI procedure in the mal-aligned knee. The failure rate in the Post-ACI group was 45% compared to the Pre-ACI and Simultaneous group, with failure rates of 20% and 25%, respectively. An HTO performed prior to or simultaneously with an autologous chondrocyte implantation procedure in the mal-aligned knee, provides a significant protective effect by reducing the failure rate by approximately 50%

Introduction. Simultaneous correction of knee varus malalignment with medial open wedge high tibial osteotomy (MOWHTO) combined with anterior cruciate ligament (ACL) surgery aims to address symptomatic unicompartmental osteoarthritis in addition to restore knee stability in order to improve outcomes. The aim of this study is to present at least 5 years results of 32 patients who underwent simultaneous knee realignment osteotomy with ACL surgery. Methods. Patients with symptomatic instability due to chronic ACL deficiency or failed previous ACL surgery together with a varus malalignment of ≥6°, previous medial meniscectomy and symptomatic medial compartment pain who were treated with MOWHTO combined with ACL surgery were enrolled. ACL surgery was performed with the anatomical single bundle all-inside technique using TightRope. ®. RT (Arthrex, Naples, FL, USA) and MOWHTO using TomoFix. ®. medial high tibia plate (DePuy Synthes, Raynham, MA, USA) in all cases. Patients were evaluated preoperatively and at 6 months, 12 months and annually postoperatively using the Knee Injury and Osteoarthritis Outcome Score (KOOS), Oxford Knee Score (OKS) and Euroqol's Visual Analogue Score (VAS) for pain. Results. 32 patients (22 men and 10 women) with a mean age of 41.2 years and mean BMI of 28.6 kg/m. 2. , underwent the combined procedures. Tibiofemoral neutral re-alignment was achieved in all patients with HTO. Complete subjective and objective scores have been obtained in 84.4% of patients with at least 5 years of follow-up (mean 8.7 years). An improvement in total KOOS of 27.1 points (p<0.003), OKS of 15.1 (p<0.003) and VAS for pain of 24.7 points (p<0.001) were detected. No ACL reconstruction failure was noted. Complications consisted of one superficial wound infection and one delayed union. Plate removal was needed in 20 (62.5%) patients due to pes anserinus pain. Conclusions. Simultaneous restoration of coronal knee axis by applying HTO and stability by ACL reconstruction/revision were reported to offer excellent improvement in early outcomes in patients with ACL rupture and symptomatic unicompartmental osteoarthritis. The combined procedure requires careful pre-operative planning and is therefore technically challenging. However, by restoring the neutral axis and providing stability, it represents a good joint preserving alternative to arthroplasty for active middle-aged patients

Abstract. OBJECTIVE. Knee varus malalignment increases medial knee compartment loading and is associated with knee osteoarthritis (OA) progression and severity. 1. Altered biomechanical loading and dysregulation of joint tissue biology drive OA progression, but mechanistic links between these factors are lacking. Subchondral bone structural changes are biomechanically driven, involve bone resorption, immune cell influx, angiogenesis, and sensory nerve invasion, and contribute to joint destruction and pain. 2. We have investigated mechanisms underlying this involving RANKL and alkaline phosphatase (ALP), which reflect bone resorption and mineralisation respectively. 3. and the axonal guidance factor Sema3A. Sema3A is osteotropic, expressed by mechanically sensitive osteocytes, and an inhibitor of sensory nerve, blood vessel and immune cell invasion. 4. Sema3A is also differentially expressed in human OA bone. 5. HYPOTHESIS: Medial knee compartment overloading in varus knee malalignment patients causes dysregulation of bone derived Sema3A signalling directly linking joint biomechanics to pathology and pain. METHODS. Synovial fluid obtained from 30 subjects with medial knee OA (KL grade II-IV) undergoing high tibial osteotomy surgery (HTO) was analysed by mesoscale discovery and ELISA analysis for inflammatory, neural and bone turnover markers. 11 of these patients had been previously analysed in a published patient-specific musculoskeletal model. 6. of gait estimating joint contact location, pressure, forces, and medial-lateral condyle load distribution in a published data set included in analyses. Data analysis was performed using Pearson's correlation matrices and principal component analyses. Principal Components (PCs) with eigenvalues greater than 1 were analysed. RESULTS. PC1 (32.94% of variation) and PC2 (25.79% of variation) from PCA analysis and correlation matrices separated patients according to correlated clusters of established inflammatory markers of OA pain and progression (IL6/IL8, r=0.754, p<0.001) and anti-inflammatory mediators (IL4/IL10, r=0.469, p=0.005). Bone turnover marker ALP was positively associated with KL grade (r=0.815, p=0.002) and negatively associated with IL10 (r=−0.402, p=0.018) and first peak knee loading pressures (r=−0.688, p=0.019). RANKL was positively associated with IL4 (r=0.489, p=0.003). Synovial fluid Sema3A concentrations showed separate clustering from all OA progression markers and was inversely correlated with TNF-α (r=−0.423, p=0.022) in HTO patients. Sema3A was significantly inversely correlated with total predicted force in the medial joint compartment (r=−0.621, p=0.041), mean (r=−0.63, p=0.038) and maximum (r=−0.613, p=0.045) calculated medial compartment joint pressures during the first phase and mean (r=−0.618, p=0.043) and maximum (r=−0.641, p=0.034) medial compartment joint pressures during midstance outputs of patient-specific musculoskeletal model. CONCLUSIONS. This study shows joint inflammatory status and mechanical overloading influence subchondral bone-remodelling. Synovial Sema3A concentrations are inversely correlated to patient-specific musculoskeletal model estimations of pathological medial overloading. This study reveals Sema3A as a biological mediator with capacity to induce OA pain and disease progression that is directly regulated by gait mechanical loading. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

BACKGROUND. High tibial Osteotomy (HTO) realigns the forces in the knee to slow the progression of osteoarthritis. This study relates the changes in knee joint biomechanics during level gait to glutamate signalling in the subchondral bone of patients pre and post HTO. Glutamate transmits mechanical signals in bone and activates glutamate receptors to influence inflammation, degeneration and nociception in arthritic joints. Thus glutamate signalling is a mechanism whereby mechanical load can directly modulate joint pathology and pain. METHODS. 3D motion analysis was used to assess level gait prior to HTO (n=5) and postoperatively (n=2). A biomechanical model of each subject was created in Visual3D (C-motion. Inc) and used for biomechanical analysis. Gene expression was analysed by RT-PCR from bone cores from anterior and posterior drill holes, subdivided according to medial or lateral proximal tibia from HTO patients (n=5). RESULTS. Knee adduction moment is a clinical marker of medial compartment loading. Pre-operatively the mean peak adduction moment was 3.8 ± 1.8 % body weight times height (BW.h). One subject maintained a consistent peak adduction moment pre (1.8 %BW.h) and post-operatively (1.9 %BW.h) with a reduction in the second moment peak. Another subjects peak adduction moment was significantly reduced from 6.7 %BW.h pre-operatively to 1.4 %BW.h postoperatively. GAPDH, osteocalcin, EAAT-1, EAAT1ex9skip, NR2A, KA1, OPG and RANKL mRNA expression was detected in HTO bone cores. In one patient, where HTO reduced medial compartment loading, differential expression of EAAT1ex9skip and KA1 was observed in pre and post HTO bone cores. CONCLUSION. Changes in knee adduction moments following HTO have been identified indicating altered medial compartmental loading. This is being investigated further in larger cohorts in a 5 year study. We have demonstrated that glutamate transporters and receptors are expressed in human subchondral bone and that glutamate transporter mRNA expression may vary after HTO surgery. In arthritis, glutamate concentrations in the synovial fluid are increased, activating receptors in joint tissues and nerves to influence pathology and nociception. Thus glutamatergic signals represent a direct mechanism linking mechanical loading through the joint to pathology and pain in human arthritis

Background. Since 2011, the knee service at the Nuffield Orthopaedic Centre has been offering a neutralising medial opening wedge high tibial osteotomy (HTO) to a group of patients presenting with early medial osteoarthritis of the knee, varus alignment and symptoms for more than 2 years. During development of this practice an association was observed between this phenotype of osteoarthritis and the presence of CAM deformity at the hip. Methods. A retrospective cohort study. All patients who underwent HTO since 2011 were identified (n=30). Comparator groups were used in order to establish whether meaningful observations were being made: Control group: The spouses of a high-risk osteoarthritis cohort recruited for a different study at our unit (n=20) Pre-arthroplasty group: Patients who have undergone uni-compartmental arthroplasty (UKA) for antero-medial osteoarthritis (n=20)All patients had standing bilateral full-length radiographs available for analysis using in house developed Matlab-based software for hip measurements and MediCAD for lower limb alignment measurements. Results. A total of 140 limbs from 70 gender-matched subjects were studied. The HTO group had a significantly higher prevalence of CAM lesions defined by an Alpha angle >650. They also had a significantly greater mean alpha angle than both the pre-arthroplasty and control groups [HTO (Avg. 68.3 (±16.1)) vs Pre-arthroplasty (Avg. 59.5 (±15.5)) P=0.01; HTO vs Control (Avg. 58.2 (±13.9)) P=0.007]. Conclusions. The results of this study confirm that our HTO group have a significantly greater prevalence of CAM lesions. A feature not seen in either pre-arthroplasty or control subjects. This group demonstrate independent predictors for progression of OA in both the hip and the knee. To our knowledge this is a novel observation. Level of evidence. Observational cohort study (III)

Glutamate is a neurotransmitter that transmits mechanical signals in bone (1) and activates glutamate receptors and transporters, in bone, cartilage, meniscus and synovium (2). Glutamate receptor activation influences inflammatory, degenerative and nociceptive pathways in arthritic joints (2). Thus glutamate signalling is a mechanism whereby mechanical load can directly influence joint pathology and pain. We have investigated components of glutamate signalling in the subchondral bone of patients with osteoarthritis to determine which are expressed and whether this varies in anatomical regions subject to different loads. Subchondral bone was sampled from tibial cuts derived from total knee arthroplasty (n=2, TKR, Kellgren Lawrence grade 3) and from tibial drill hole sites from high tibial osteotomy (n=5, HTO, KL grades 2 and 3) for osteoarthritis. RNA was extracted, reverse transcribed and RT-PCR performed for a housekeeping gene GAPDH, a glutamate transporters (EAAT-1, EAAT1ex9skip), glutamate receptors (NR2A and KA1), a bone matrix protein, osteocalcin, and signaling molecules (osteoprotegerin [OPG], RANKL). We found differential mRNA expression in different regions of subchondral bone. In one TKR patient, EAAT-1 expression was significantly reduced in the anterior zone versus the middle or posterior zones of the tibial plateau (ANOVA, p<0.001). HTO bone cores were subdivided medial/lateral and anterior/posterior. Good quality RNA was obtained from bone cores removed from drill holes during HTO surgery, with GAPDH, osteocalcin, EAAT-1, EAAT1ex9skip, NR2A, KA1, OPG and RANKL mRNA expression detected. In one patient, comparison of gene expression in bone cores obtained pre and post HTO revealed that EAAT1ex9skip was rarely detected in post-op bone whereas KA1 was rare in pre-op bone. This differential mRNA expression may be due to the altered loading through the joint caused by the osteotomy, although these on/off differences need to be quantified to confirm this. We have shown that glutamate transporters and receptors are expressed in human subchondral bone. Activation of these receptors and transporters by the increased synovial fluid concentrations of glutamate released in arthritis will influence pathological changes and nociception. In some patients, glutamate transporter mRNA expression appears to vary with anatomical location in bone, or after HTO surgery, consistent with our original discovery of this transporter as mechanically-regulated in bone (1). If glutamatergic signaling is mechanically regulated in the human knee, this will vary during arthritic disease progression and after joint realignment, providing a direct mechanism linking mechanical loading through the joint to pathology and pain in arthritis