Inflammation in knee osteoarthritis (OA) is mediated primarily by synovial tissue macrophages, but non-invasive measurement of macrophage activity in vivo is a challenge. Activated macrophages markedly increase expression of the translocator protein (TSPO). In the context of other diseases TSPO-PET using the [18F]FEPPA tracer (binding to TSPO) has been reported to be an effective method for imaging macrophages in vivo. The goal of this study was to validate the use of [18F]FEPPA PET radiotracer to accurately measure macrophage activation in knee synovial tissue.
Ten participants with late-stage OA scheduled for knee replacement surgery were recruited. Prior to surgery, 5 of the participants underwent a clinical [18F]FEPPA PET/MRI scan and the standard uptake value (SUV) in the suprapatellar synovial region was calculated. Suprapatellar synovial tissue samples were collected from all participants at the time of surgery and were imaged ex vivo with [18F]FEPPA autoradiography. Tracer uptake was compared to TSPO antibody immunostaining in serial tissue sections. The correlation between the [18F]FEPPA uptake and gold standard TSPO fluorescent intensity was measured.
The autoradiography [18F]FEPPA signal in the synovial lining was correlated with the TSPO signal in the. lining macrophages measured by immunohistochemistry (r = 0.81, p = 0.0040, CI [0.37, 0.95]). Similarly, PET/MRI scans demonstrated similar correlation between SUV in synovial tissues in vivo and in situ TSPO signal in lining macrophages {r = 0.90, p = 0.083, CI [0.086, 0.99])
[18F]FEPPA uptake in knee synovial tissue is strongly correlated to the expression of TSPO in synovial lining macrophages, suggesting that clinical [18F]FEPPA PET/MRI may be a valid measure of true macrophage activity in synovial tissues in knee OA. [18F]FEPPA may be an effective tool to assess macrophage activation both ex vivo and in vivo, and should be investigated further to assess its performance and measurement properties in different clinical contexts of knee OA including disease states and responses to treatment.
Model calculations of knee joint loading range from an assumption of perfectly rigid articular surfaces to more realistic simulations of cartilage and meniscal deformation. Rigid-body musculoskeletal models simulate knee contact mechanics using the ‘bed of springs’ method from elastic foundation theory whereas finite-element models discretise each structure into a series of interconnected elements and ascribe material properties to each element. This mini-review describes some of the most recent developments in computational modelling of knee contact mechanics and suggests possible avenues for future improvements.
Narrative mini-review.
Muscle and joint contact forces can be calculated synchronously at a reasonable computational cost (typically a few hours of CPU time) using rigid-body models and elastic foundation theory whereas similar calculations using fully deformable finite-element models can take several days and even weeks. The main computational expense incurred in finite-element musculoskeletal modelling is the solution of a muscle-force optimization problem.
Calculation of muscle and joint contact forces within the framework of a finite-element musculoskeletal model remains challenging. Integrating biomechanical data from human motion experiments with fully deformable finite-element models to simulate knee contact mechanics during dynamic activity is an evolving science. Future work should explore the use of efficient methods such as direct collocation to perform muscle-driven dynamic optimization simulations of movement using finite-element musculoskeletal models. Dynamic optimization may be combined with finite-element modelling to enable predictive simulations of movement so that the effects of changes in musculoskeletal anatomy on knee contact mechanics can be studied more systematically.
Our aims were to 1) introduce the semi-quantitative CT Osteoarthritis Knee Score (COAKS); and 2) report intra- and inter-observer reproducibility.
Weight-bearing CT (WBCT) images of 106 participants were reviewed to develop the COAKS system and create a standardized atlas. Images of 10 knees were used to train musculoskeletal radiologists with the atlas. Once trained, two radiologists independently scored 35 knees on two occasions using reformatted images in orthogonal planes. Joint space narrowing (JSN), osteophytes, subchondral cysts and subchondral sclerosis were scored (0–3 scale) in the medial tibiofemoral, lateral tibiofemoral, patellofemoral, and proximal tibiofibular compartments. Weighted kappa statistics were calculated for intra- and inter-observer reliability. Compartment feature scores were plotted as heat maps for each knee to illustrate OA severity and location.
Scoring for nearly all features in all compartments had substantial to near-perfect reliability (0.61–1.00). Both inter- and intra-observer results combined across all compartments demonstrated near-perfect agreement for JSN (0.87 and 0.86) and subchondral cysts (0.84 for both) and substantial agreement for osteophytes (0.79 and 0.74) and subchondral sclerosis (0.66 and 0.67).
COAKS is a feasible, multiplanar, semi-quantitative, compartment-by-compartment WBCT-based knee OA scoring system that demonstrates substantial to near-perfect intra- and inter-observer reliability. The capacity of COAKS to characterize the location and severity of OA in the weight-bearing knee could enable patient stratification, selection, and longitudinal monitoring of structural disease severity in clinical trials and cohort studies.
This mini review delves into the mechanisms of [18F]Sodium Fluoride positron emission tomography ([18F]NaF PET), which, by interrogating areas of newly mineralizing bone, provides a valuable tool to study the joint response to loading and areas of altered whole-joint function in osteoarthritis (OA).
The review consolidates and discusses findings from both preclinical and clinical studies that utilize [18F]NaF PET to evaluate the bone response to various loading paradigms. It also briefly reviews technical considerations for PET imaging and discusses its strong potential as a tool in the quest to understand bone metabolism in the context of loading and osteoarthritis.
While considering previous studies, technical considerations and potential new applications of this methodology are also discussed. [18F]NaF PET/MRI reveals localized, load-related bone responses after exercise, providing insights into early OA progression. In human studies, significant increases in tracer uptake are observed in areas affected by OA pathology, driven by bone perfusion and blood volume. Future work to examine the relationship between metabolic bone response to exercise and the bone loading environment is needed.
Integrating [18F]NaF PET/MRI with advanced biomechanical modeling holds promise for guiding clinical management of OA, primarily by examining the relationship between bone, soft tissues of the joint, and loading forces.
Since its introduction, four dimensional computed tomography (4D CT) has improved the precision of a variety of diagnostic challenges such as radiation therapy in oncology and has also been expanded into cardiovascular assessments as well. Its use in musculoskeletal imaging marks a breakthrough in peripheral joint imaging, enabling detailed analysis of joint biomechanics and stability across various joints such as the knee, wrist, shoulder, and ankle. Studies employing 4D CT have offered new insights into normative and altered joint biomechanics, contributing to the diagnosis of joint pathologies and aiding in surgical planning. Looking ahead, artificial intelligence and photon-counting CT systems are poised to further refine 4D CT's capabilities, potentially leading to personalized diagnostic and therapeutic approaches based on individualized biomechanical characteristics. This review delves into the transformative role of four-dimensional computed tomography in musculoskeletal imaging, particularly its applications in understanding joint biomechanics.
Knowledge of joint biomechanics is crucial for understanding the pathophysiology of osteoarthritis (OA). Biomechanical changes, especially in early-stage OA, are subtle and therefore require highly accurate and precise ways of measuring joint loading (i.e., forces) and kinematics (i.e., motion). Most OA research investigating kinematics to date using conventional measurement methods, has been restricted either to measures of functional, weight-bearing activities with limited precision, or to highly precise measures of non-functional activities. X-ray fluoroscopy, however, is a medical imaging modality that can be used to precisely measure high-speed dynamic human movement in vivo under weight-bearing conditions.
To illustrate the potential of fluoroscopy to measure human movement and study joint biomechanics in OA by highlighting several exemplary applications in studies on knee OA.
We searched PubMed to identify a selection of relevant studies with fluoroscopic evaluation of joint mechanics in individuals with, or at risk of developing, knee OA.
Fluoroscopy has been utilized in biomechanical studies in populations with early stages of knee OA or at risk of developing knee OA, as well as in studies evaluating conservative treatment strategies for knee OA. Due to its ability to capture highly accurate and precise kinematic measures, fluoroscopy holds great promise in providing new insights in the role of biomechanics in OA pathogenesis.
The use of fluoroscopy in larger cohorts and longitudinal (interventional) studies may lead to more robust and generalizable results and could clarify the mediation pathways of joint biomechanics in the onset and progression of OA.