Though dentin matrix protein 1 (Dmp1) is known to play critical role in mediating bone mineralization, it has also been validated to be expressed in brain and helps maintain blood brain barrier (BBB). Our study aims to clarify the expression pattern of Dmp1 in mouse brain and explore whether intercellular mitochondrial transfer occurs between Dmp1 positive astrocytes (DPAs) and endothelial cells, and thus acting as a mechanism in maintaining BBB during aging.

Single cell RNA sequencing (scRNAseq) of 1 month, 6 month, and 20 month old mice brain (n=1, respectively) was employed to identify Dmp1 positive cell types. Dmp1^Cre-mGmT and Dmp1^Cre-COX8a fluorescent mice were generated to visualize DPAs and investigate their mitochondrial activities. A 3D noncontact coculture system and mitochondrial transplantation were applied to study the role of mitochondrial transfer between astrocytes and bEnd.3 endothelial cells. Dmp1^Cre-Mfn2^f/f mice were generated by depleting the ER-mitochondria tethering protein Mfn2 in DPAs.

Dmp1 was mainly expressed in astrocytes at different ages. GO analysis revealed that cell projection and adhesion of DPAs were upregulated. Confocal imaging on Dmp1^Cre-mGmT mice indicated that DPAs are a cluster of astrocytes that closely adhere to blood vessels (n=3). Bioinformatics analysis revealed that mitochondrial activity of DPAs were compromised during aging. Enriched scRNAseq of fluorescent cells from Dmp1^Cre-COX8a mice (n=2) and immunofluorescent imaging (n=3) validated the acquisition of extrinsic mitochondria in endothelial cells. 3D coculture of astrocytes and bEnd.3 and direct mitochondrial transplantation revealed the rescue effect of mitochondrial transfer on damaged bEnd.3. BBB was impaired after depleting Mfn2 in DPAs, expressing a similar phenotype with aging brain.

Astrocytes that express Dmp1 play a significant role in maintaining BBB via transferring mitochondria to vascular endothelial cells. Compromised mitochondrial transfer between DPAs and endothelial cells might be the potential mechanism of impaired BBB during aging.

One out of nine Canadian males would suffer prostate cancer (PC) during his lifetime. Life expectancy of males with PC has increased with modern therapy and 90% live >10 years. However, 20% of PC-affected males would develop incurable metastatic diseases. Bone metastases (BM) are present in ~80% of metastatic PC patients, and are the most severe complication of PC, generating severe pain, fractures, spinal cord compression, and death. Interestingly, PC-BMs are mostly osteoblastic. However, the structure of this newly formed bone and how it relates to pain and fracture are unknown. Due to androgen antagonist treatment, different PC phenotypes develop with differential dependency on androgen receptor (AR) signaling: androgen-dependent (AR+), double negative (AR-) and neuroendocrine. How these phenotypes are related to changes in bone structure has not been studied. Here we show a state-of-the-art structural characterization of PCBM and how PC phenotypes are associated to abnormal bone formation in PCBM.

Cadaveric samples (n=14) obtained from metastases of PC in thoracic or lumbar vertebrae (mean age 74yo) were used to analyze bone structure. We used micro-computed tomography (mCT) to analyze the three-dimensional structure of the bone samples. After imaging, the samples were sectioned and one 3mm thick section was embedded in epoxy-resin, ground and polished. Scanning electron microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDS) and quantitative backscattering electron (qBSE) imaging were used to determine mineral morphology and composition. Another section was used for histological analysis of the PC-affected bone. Collagen structure, fibril orientation and extracellular matrix composition were characterized using histochemistry. Additionally, we obtained biopsies of 3 PCBM patients undergoing emergency decompression surgery following vertebral fracture and used them for immunohistological characterization.

By using mCT, we observed three dysmorphic bone patterns: osteolytic pattern with thinned trabecula of otherwise well-organized structures, osteoblastic pattern defined as accumulation of disorganized matrix deposited on pre-existing trabecula, and osteoblastic pattern with minimum residual trabecula and bone space dominated by accumulation of disorganized mineralized matrix. Comparing mCT data with patho/clinical parameters revealed a trend for higher bone density in males with larger PSA increase. Through histological sections, we observed that PC-affected bone, lacks collagen alignment structure, have a higher number of lacunae and increased amount of proteoglycans as decorin.

Immunohistochemistry of biopsies revealed that PC-cells inside bone organize into two manners: i) glandular-like structures where cells maintain their polarization in the expression of prostate markers, ii) diffuse infiltrate that spreads along bone surfaces, with loss of cell polarity. These cells take direct contact with osteoblasts in the surface of trabecula. We define that PCBM are mostly composed by AR+ with some double negative cells. We did not observe neuroendocrine phenotype cells.

PCBMs generate predominantly osteoblastic lesions that are characterized by high lacunar density, lack of collagen organization and elevated proteoglycan content. These structural changes are associated with the infiltration of PC cells that are mostly androgen-dependent but have lost their polarization and contact directly with osteoblasts, perhaps altering their function. These changes could be associated with lower mechanical properties that led to fracture and weakness of the PCBM affected bone.

Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by joint pain and physical disability. Aberrant subchondral bone induces pathological changes and is a major source of pain in OA. In the subchondral bone, which is highly innervated, nerves have dual roles in pain sensation and bone homeostasis regulation. The interaction between peripheral nerves and target cells in the subchondral bone, and the interplay between the sensory and sympathetic nervous systems, allow peripheral nerves to regulate subchondral bone homeostasis. Alterations in peripheral innervation and local transmitters are closely related to changes in nociception and subchondral bone homeostasis, and affect the progression of OA. Recent literature has substantially expanded our understanding of the physiological and pathological distribution and function of specific subtypes of neurones in bone. This review summarizes the types and distribution of nerves detected in the tibial subchondral bone, their cellular and molecular interactions with bone cells that regulate subchondral bone homeostasis, and their role in OA pain. A comprehensive understanding and further investigation of the functions of peripheral innervation in the subchondral bone will help to develop novel therapeutic approaches to effectively prevent OA, and alleviate OA pain.

Cite this article: Bone Joint Res 2022;11(7):439–452.

Introduction

Variation in resection thickness of the femur in Total Knee Arthroplasty (TKA) impacts the flexion and extension tightness of the knee. Less well investigated is how variation in patient anatomy drives flexion or extension tightness pre- and post- operatively. Extension and flexion stability of the post TKA knee is a function of the tension in the ligaments which is proportional to the strain. This study sought to investigate how femoral ligament offset relates to post-operative navigation kinematics and how outcomes are affected by component position in relation to ligament attachment sites.

Introduction

Knee ligament laxity and soft tissue balance are important pre- and intra- operative balancing factors in total knee arthroplasty (TKA). Laxity can be measured pre-operatively from short-leg radiographs using a stress device to apply a reproducible force to the knee, whereas intra-operative laxity is routinely measured using a navigation system in which a variable surgeon-applied force is applied. The relationship between these two methods and TKA outcome however, has not been investigated. This study aims to determine how intra-operative assessments of laxity relate to functional radiographic assessments performed on pre-operatively. We also investigate how laxity relates to short-term patient-reported outcomes.

Introduction

Provision of prehabilitation prior to total knee arthroplasty (TKA) through a digital mobile application is a novel concept. The primary aim of our research is to determine whether provision of prehabilitation through a mobile digital application impacts length of stay (LOS), requirement for inpatient rehabilitation and hospital-associated costs after TKA. Our study hypothesis is that a mobile digital application provides a low resource, cost effective method of delivering prehabilitation prior to TKA.

Provision of prehabilitation prior to total knee arthroplasty (TKA) through a digital mobile application is a novel concept. Our research evaluates a resource effective and cost effective method of delivering prehabilitation. The primary aim of our research is to determine whether provision of prehabilitation through a mobile digital application impacts inpatient LOS after TKA. The secondary objective is to understand the effect of digital prehabilitation on hospital costs.

An observational, retrospective analysis was performed on a consecutive case series of 64 patients who underwent TKA by a single surgeon over a 21 month period. Exercise provision varied from 3 months to 2 weeks prior to TKA. The outcomes of rehabilitation length of stay, total length of stay and total hospital costs were statistically significantly at p=0.5. The rehabilitation length of stay was 3.79 days in the experimental and 7.33 days in the control group (p = 0.045), the total length of stay was 12.00 days in the control and 8.04 days in the experimental group (p=0.03) and the total cost of the hospital stay was $6357.35AUD for the control and $4343.22AUD for the experimental group (p=0.029).

Our research shows a cost saving with this intervention, as measured by a reduction in rehabilitation length of stay. To our knowledge, this is the first piece of research that analyses the impact of the use of a digital mobile application providing prehabilitation prior to TKA.

Despite of the high success of TKA, 20% of recipients remain dissatisfied with their surgery. There is an increasing discordance in the literature on what is an optimal goal for component alignment. Furthermore, the unique patient specific anatomical characteristics will also play a role. The dynamic characteristic of a TKR is a product of the complex interaction between a patient's individual anatomical characteristics and the specific alignment of the components in that patient knee joint. These interactions can be better understood with computational models. Our objective was to characterise ligament characteristics by measuring knee joint laxity with functional radiograph and with the aid of a computational model and an optimisation study to estimate the subject specific free length of the ligaments.

Pre-operative CT and functional radiographs, varus and valgus stressed X-rays assessing the collateral ligaments, were captured for 10 patients. CT scan was segmented and 3D–2D pose estimation was performed against the radiographs. Patient specific tibio-femoral joint computational model was created. The model was virtually positioned to the functional radiograph positions to simulate the boundary conditions when the knee is stressed. The model was simulated to achieve static equilibrium. Optimisation was done on ligament free length and a scaling coefficient, flexion factor, to consider the ligaments wrapping behaviour.

Our findings show the generic values for reference strain differ significantly from reference strains calculated from the optimised ligament parameters, up to 35% as percentage strain. There was also a wide variation in the reference strain values between subjects and ligaments, with a range of 37% strain between subjects. Additionally, the knee laxity recorded clinically shows a large variation between patients and it appears to be divorced from coronal alignment measured in CT. This suggests the ligaments characteristics vary widely between subjects and non-functional imaging is insufficient to determine its characteristics. These large variations necessitate a subject-specific approach when creating knee computational models and functional radiographs may be a viable method to characterise patient specific ligaments.

INTRODUCTION

Despite that computer-assisted orthopaedic surgery (CAOS) has been shown to offer increased accuracy to the bony resections compared to the conventional techniques [1], previous studies of CAOS have mostly focused on alignment outcomes based on a small number of patients [1]. Although several recent meta-analyses on the CAOS outcomes have been reported [2], these analyses did not differentiate between systems, while system-dependency has been reported to influence alignment parameters [3]. To date, no study has benchmarked a specific CAOS system based on a large number of clinical cases. The purpose of this study is to assess the accuracy and precision of bony resection in more than 4000 cases using a specific contemporary CAOS system.

Introduction

Surgical planning for Patient Specific Instrumentation (PSI) in total knee arthroplasty (TKA) is based on static non-functional imaging (CT or MRI). Component alignment is determined prior to any assessment of clinical soft tissue laxity. This leads to surgical planning where assumptions of correctability of preoperative deformity are false and a need for intraoperative variation or abandonment of the PSI blocks occurs. The aim of this study is to determine whether functional radiology complements pre-surgical planning by identifying non-predictable patient variation in laxity.

Introduction

Total Knee Replacement (TKR) alignment measured intra-operatively with Navigation has been shown to differ from that observed in long leg radiographs (Deep 2011). Potential explanations for this discrepancy may be the effect of weight bearing or the dynamic contributions of soft tissue loads.

Introduction

Despite generally excellent patient outcomes for Total Knee Arthroplasty (TKA), there remains a contingent of patients, up to 20%, who are not satisfied with the outcome of their procedure. (Beswick, 2012) There has been a large amount of research into identifying the factors driving these poor patient outcomes, with increasing recognition of the role of non-surgical factors in predicting achieved outcomes. However, most of this research has been based on single database or registry sources and so has inherited the limitations of its source data. The aim of this work is to develop a predictive model that uses expert knowledge modelling in conjunction with data sources to build a predictive model of TKR patient outcomes.

Introduction

Total Knee Arthroplasty (TKA) is an established procedure for relieving patients of pain and functional degradation associated with end-stage osteoarthritis of the knee. Historically, alignment of components in TKA has focused on a ‘reconstructive’ approach neutral to the mechanical axes of the femur and tibia coupled with ligament balancing to achieve a balanced state. More recently, Howell et al. have proposed an alternate approach to TKA alignment, called kinematic alignment. (Howell, 2012) This approach seeks to position the implants to reproduce underlying, pre-disease state femoral condylar and tibial plateau morphology, and in doing is ‘restorative’ of the patients underlying knee kinematic behaviour rather than ‘reconstructive’. While some promising early clinical results have been reported at the RCT level (Dosset, 2014), in vivo comparisons of the kinematic outcome achieved at patient specific levels with the two alignment techniques remain an impossibility. The aim of this research is to develop and report preliminary findings of a means of simulating both alignment techniques on a number of patients.

Fixed flexion contracture is often present in association with osteoarthritis of the knee and correction is one of the key surgical goals in total knee replacement. Surgical strategies to correct flexion contracture include removal of posterior osteophytes, posterior capsular release and additional distal femoral bone resection.

Traditional teaching indicates 2 mm of additional distal femoral bone resection will correct 10 degrees of flexion deformity. However some studies have questioned this figure and removing excessive distal femoral bone results in elevation of the joint line, potentially causing patella baja, alteration in collateral ligament tension through the flexion arc and mid-flexion instability.

The aim of our study is to determine the relationship between distal bone resection of the femur and passive knee extension in total knee arthroplasty.

A cohort of 50 patients, undergoing total knee arthroplasty, was recruited. Following complete femoral and tibial bone preparation, to simulate the effect of distal femoral bone resection, augments of 2 mm increments (2 mm, 4 mm, 6 mm, 8 mm) were placed onto the trial femoral component. The degree of flexion contracture with each augment was measured using computer navigation.

The results showed a 2 mm augment produced an average of 3.37 degrees of flexion deformity. A 4 mm augment led to an average of 6.68 degrees fixed flexion, whilst a 6 mm augment produced 11.38 degrees. To correct 10 degrees flexion deformity, an additional 6 mm distal femoral bone resection is required.

In conclusion, additional distal femoral bone resection may not be as an effective strategy as previously believed to correct fixed flexion deformity in total knee arthroplasty.

Recent emphasis in total knee arthroplasty has been on accelerated rehabilitation and recovery. Minimally invasive and quadriceps sparing techniques have been developed to expediate return to normal function. The aim of this study was to evaluate the effect of the tourniquet on post-operative pain and quadriceps function in total knee arthroplasty.

This study involved a randomised, blinded, prospective trial of 20 patients undergoing total knee arthroplasty by a single surgeon. All patients received a general anaesthetic, identical prosthesis and post-operative protocol. Patients were randomly allocated to one of two group: (a) tourniquet group or (b) no tourniquet group. A standard surgical tourniquet was applied to all patients but only inflated in the tourniquet group.

Outcomes included Oxford knee scores, post-operative pain scores, post-operative drainage and transfusion requirements, thigh and knee circumference measurements, range of motion, and surface EMG measurements at intervals of two weeks, six weeks, six months and twelve months.

The study included 16 male and four female patients with 11 right and nine left knees. There was no significant difference pre-operatively between groups in age, degree of deformity or range of motion.

There was no significant difference detected between Oxford knee scores up to twelve months, days to discharge, post-operative drainage and range of motion. However, the pain scores were significantly higher in the tourniquet group. Surface EMG as a measurement of quadriceps activation showed a significant difference between the groups and between time points. The no tourniquet group can support more energy in their quads muscle than the tourniquet group

The use of a tourniquet in total knee arthroplasty has no effect on overall knee function at twelve months as measured by the Oxford knee score and range of motion; however tourniquet use results in higher initial pain scores and reduction in quadriceps function as measured by surface EMG.

This study identified imaging parameter(s) which best predict the mechanical properties of distal tibia. Seventeen human cadaver tibiae were assessed by PQCT at four, eight and ten percent site from distal and tested in compression at the twenty-five percent distal portion. Ultimate compressive loads were recorded with a mean of 8276 ± 2915 N. Spearson rank correlation and stepwise regression analysis revealed that CoA, total BMC, SSI and SSI4-TrA4-CoD4 combination had statistically significant correlations with the failure loads. Among all imaging parameters, SSI had the highest relevance due to its account for geometry, density and material distribution, important factors for structural properties.

Musculoskeletal diseases, especially hip fractures, have huge and growing impact on Canadian society. To develop techniques for identification of high risk population, we needed a link between clinical evaluations and laboratory measures of bone health. This study identified imaging parameter(s) which best predict the mechanical properties of distal tibia.

Seventeen human cadaver tibiae were considered in this study (mean age seventy-four, SD six years). PQCT was used to assess the four, eight and ten percent site. It measured the cross-sectional area, bone mineral content and bone mineral density of the cortical bone, trabecular bone and combined. Strength Strain Index (SSI) was calculated from these measurements. Each tibia was cut at twenty-five percent distal. Compressive force was applied uniaxially through a custom-made PMMA indentor onto the distal plateau along the longitudinal axis of the tibia at a rate of 10mm/s. Load and displacement data were recorded. Spearson rank correlation and stepwise regression analysis were used to identify individual and combination of imaging variables that were related to ultimate failure load.

Ultimate failure loads were recorded with a mean of 8276 ± 2915 N. Cortical area (R_0.72), total BMC (R_0.72) and SSI (R_0.86) had statistically significant correlations with the failure load. Stepwise regression revealed that the combination of SSI, TrA, CoD at 4% site explained the greatest amount of variance (R2 = 0.868) and SSI was the major contributor. SSI takes the polar moment of inertia (geometry), density and distribution of material into account. This explains its relevance towards predicting the ultimate failure load.

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Aim: To compare two approaches to the knee joint for total knee arthroplasty with regard to patient comfort and return of knee function.

Methods: Sixty-six consecutive patients were randomised prospectively to undergo either a medial parapatellar or midvastus approach for total knee arthroplasty. All patients received the same type of prosthesis under the guidance of the same surgeon. A comparison was made of operative time, number of soft tissue releases required, the number of days to reach 60 and 80 degrees of flexion, the time to achieve a straight-leg raise, and the time to discharge from hospital. A subgroup of 34 patients who received the same type of anaesthetic (spinal and femoral nerve blocks) and who also received the same type of post-operative analgesia, were compared for pain and analgesic requirements in the first 48 hours following surgery.

Results: The two groups were similar for number, age, weight, gender and diagnosis. A statistical analysis showed that the midvastus approach was significantly better, with an earlier straight-leg raise and shorter operative time. There was a trend towards improvement in early range of motion but no difference in post-operative pain, number of soft tissue releases or difficulty with surgery.

Conclusions: This trial has shown that the midvastus approach was an effective alternative to the medial parapatellar approach for knee arthroplasty. It produced less tissue damage to the quadriceps mechanism and medial patellar blood supply. It allowed an earlier recovery of knee function and shorter surgery time with no increase in the difficulty of the surgery.