The low permeability of healthy meniscus and labrum limit articular cartilage consolidation and maintain fluid load support in the knee and hip

The knee meniscus and hip labrum appear to be important for joint health, but the mechanisms by which these structures perform their functions are not fully understood. The fluid phase of articular cartilage provides compressive stiffness and aids in maintaining a low friction articulation. Healthy fibrocartilage, the tissue of meniscus and labrum, has a lower fluid permeability than articular cartilage. In this study we hypothesized that an important function of the knee meniscus and the hip labrum is to augment fluid retention in the articular cartilage of a mechanically loaded joint. Axisymmetric hyperporoelastic finite element models were analyzed for an idealized knee and an idealized hip. The results indicate that the meniscus maintained fluid pressure and inhibited fluid exudation in knee articular cartilage. Similar, but smaller, effects were seen with the labrum in the hip. Increasing the fibrocartilage permeability relative to that of articular cartilage gave a consolidation rate and loss of fluid load support comparable to that predicted by meniscectomy or labrectomy. The reduced articular cartilage fluid pressure that was calculated for the joint periphery is consistent with patterns of endochondral ossification and osteophyte formation in knee and hip osteoarthritis. High articular central strains and loss of fluid load support after meniscectomy could lead to fibrillation. An intact low-permeability fibrocartilage is important for limiting fluid exudation from articular cartilage in the hip and knee. This may be an important aspect of the role of fibrocartilage in protecting these joints from osteoarthritis.     

Development of a preclinical natural porcine knee simulation model for the tribological assessment of osteochondral grafts in vitro

In order to pre-clinically evaluate the performance and efficacy of novel osteochondral interventions, physiological and clinically relevant whole joint simulation models, capable of reproducing the complex loading and motions experienced in the natural knee environment are required. The aim of this study was to develop a method for the assessment of tribological performance of osteochondral grafts within an in vitro whole natural joint simulation model.The study assessed the effects of osteochondral allograft implantation (existing surgical intervention for the repair of osteochondral defects) on the wear, deformation and damage of the opposing articular surfaces. Tribological performance of osteochondral grafts was compared to the natural joint (negative control), an injury model (focal cartilage defects) and stainless steel pins (positive controls). A recently developed method using an optical profiler (Alicona Infinite Focus G5, Alicona Imaging GmbH, Austria) was used to quantify and characterise the wear, deformation and damage occurring on the opposing articular surfaces. Allografts inserted flush with the cartilage surface had the lowest levels of wear, deformation and damage following the 2 h test; increased levels of wear, deformation and damage were observed when allografts and stainless steel pins were inserted proud of the articular surface. The method developed will be applied in future studies to assess the tribological performance of novel early stage osteochondral interventions prior to in vivo studies, investigate variation in surgical precision and aid in the development of stratified interventions for the patient population.     

The effects of knee joint kinematics on anterior cruciate ligament injury and articular cartilage damage

This study determined which knee joint motions lead to anterior cruciate ligament (ACL) rupture with the knee at 25° of flexion. The knee was subjected to internal and external rotations, as well as varus and valgus motions. A failure locus representing the relationship between these motions and ACL rupture was established using finite element simulations. This study also considered possible concomitant injuries to the tibial articular cartilage prior to ACL injury. The posterolateral bundle of the ACL demonstrated higher rupture susceptibility than the anteromedial bundle. The average varus angular displacement required for ACL failure was 46.6% lower compared to the average valgus angular displacement. Femoral external rotation decreased the frontal plane angle required for ACL failure by 27.5% compared to internal rotation. Tibial articular cartilage damage initiated prior to ACL failure in all valgus simulations. The results from this investigation agreed well with other experimental and analytical investigations. This study provides a greater understanding of the various knee joint motion combinations leading to ACL injury and articular cartilage damage.     

A finite deformation theory for cartilage and other soft hydrated connective tissues--I. Equilibrium results

The determination of valid stress-strain relations for articular cartilage under finite deformation conditions is a prerequisite for constructing models for synovial joint lubrication. Under physiological conditions of high strain rates and/or high stresses in the joint, large strains occur in cartilage. A finite deformation theory valid for describing cartilage, as well as other soft hydrated connective tissues under large loads, has been developed. This theory is based on the choice of a specific Helmholtz energy function which satisfies the generalized Coleman-Noll (GCN0) condition and the Baker-Ericksen (B-E) inequalities established in finite elasticity theory. In addition, the finite deformation biphasic theory includes the effects of strain-dependent porosity and permeability. These nonlinear effects are essential for properly describing the biomechanical behavior of articular cartilage, even when strain rates are low and strains are infinitesimal. The finite deformation theory describes the large strain behavior of cartilage observed in one-dimensional confined compression experiments at equilibrium, and it reduces to the linear biphasic theory under infinitesimal strain and slow strain rate conditions. Using this theory, we have determined the material coefficients of both human and bovine articular cartilages under large strain conditions at equilibrium. The theory compares very well with experimental results.     

In vivo tibiofemoral cartilage deformation during the stance phase of gait

The knowledge of articular cartilage contact biomechanics in the knee joint is important for understanding the joint function and cartilage pathology. However, the in vivo tibiofemoral articular cartilage contact biomechanics during gait remains unknown. The objective of this study was to determine the in vivo tibiofemoral cartilage contact biomechanics during the stance phase of treadmill gait. Eight healthy knees were magnetic resonance (MR) scanned and imaged with a dual fluoroscopic system during gait on a treadmill. The tibia, femur and associated cartilage were constructed from the MR images and combined with the dual fluoroscopic images to determine in vivo cartilage contact deformation during the stance phase of gait. Throughout the stance phase of gait, the magnitude of peak compartmental contact deformation ranged between 7% and 23% of the resting cartilage thickness and occurred at regions with thicker cartilage. Its excursions in the anteroposterior direction were greater in the medial tibiofemoral compartment as compared to those in the lateral compartment. The contact areas throughout the stance phase were greater in the medial compartment than in the lateral compartment. The information on in vivo tibiofemoral cartilage contact biomechanics during gait could be used to provide physiological boundaries for in vitro testing of cartilage. Also, the data on location and magnitude of deformation among non-diseased knees during gait could identify where loading and later injury might occur in diseased knees.     

The influence and biomechanical role of cartilage split line pattern on tibiofemoral cartilage stress distribution during the stance phase of gait

This study presents an evaluation of the role that cartilage fibre ‘split line’ orientation plays in informing femoral cartilage stress patterns. A two-stage model is presented consisting of a whole knee joint coupled to a tissue-level cartilage model for computational efficiency. The whole joint model may be easily customised to any MRI or CT geometry using free-form deformation. Three ‘split line’ patterns (medial–lateral, anterior–posterior and random) were implemented in a finite element model with constitutive properties referring to this ‘split line’ orientation as a finite element fibre field. The medial–lateral orientation was similar to anatomy and was derived from imaging studies. Model predictions showed that ‘split lines’ are formed along the line of maximum principal strains and may have a biomechanical role of protecting the cartilage by limiting the cartilage deformation to the area of higher cartilage thickness.     

Application of a semi-automatic cartilage segmentation method for biomechanical modeling of the knee joint

Manual segmentation of articular cartilage from knee joint 3D magnetic resonance images (MRI) is a time consuming and laborious task. Thus, automatic methods are needed for faster and reproducible segmentations. In the present study, we developed a semi-automatic segmentation method based on radial intensity profiles to generate 3D geometries of knee joint cartilage which were then used in computational biomechanical models of the knee joint. Six healthy volunteers were imaged with a 3T MRI device and their knee cartilages were segmented both manually and semi-automatically. The values of cartilage thicknesses and volumes produced by these two methods were compared. Furthermore, the influences of possible geometrical differences on cartilage stresses and strains in the knee were evaluated with finite element modeling. The semi-automatic segmentation and 3D geometry construction of one knee joint (menisci, femoral and tibial cartilages) was approximately two times faster than with manual segmentation. Differences in cartilage thicknesses, volumes, contact pressures, stresses, and strains between segmentation methods in femoral and tibial cartilage were mostly insignificant (p > 0.05) and random, i.e. there were no systematic differences between the methods. In conclusion, the devised semi-automatic segmentation method is a quick and accurate way to determine cartilage geometries; it may become a valuable tool for biomechanical modeling applications with large patient groups.     

In situ chondrocyte deformation with physiological compression of the feline patellofemoral joint

The mechanical environment is an important factor affecting the maintenance and adaptation of articular cartilage, and thus the function of the joint and the progression of joint degeneration. Recent evidence suggests that cartilage deformation caused by mechanical loading is directly associated with deformation and volume changes of chondrocytes. Furthermore, in vitro experiments have shown that these changes in the mechanical states of chondrocytes correlate with a change in the biosynthetic activity of cartilage cells. The purpose of this study was to apply our knowledge of contact forces within the feline patellofemoral joint to quantify chondrocyte deformation in situ under loads of physiological magnitude. A uniform, static load of physiological magnitude was applied to healthy articular cartilage still fully intact and attached to its native bone. The compressed cartilage was then chemically fixed to enable the evaluation of cartilage strain, chondrocyte deformation and chondrocyte volumetric fraction. Patella and femoral groove articular cartilages differ in thickness, chondrocyte aspect ratio, and chondrocyte volumetric fraction in both magnitude and depth distribution. Furthermore, when subjected to the same compressive loads, changes to all of these parameters differ in magnitude and depth distribution between patellar and femoral groove articular cartilage. This evidence suggests that significant chondrocyte deformation likely occurs during in vivo joint loading, and may influence chondrocyte biosynthetic activity. Furthermore, we hypothesise that the contrasts between patella and femoral groove cartilages may explain, in part, the site-specific progression of osteoarthritis in the patellofemoral joint of the feline anterior cruciate ligament transected knee.     

A chondral modeling theory revisited

The mechanical environment of limb joints constantly changes during growth due to growth-related changes in muscle and tendon lengths, long bone dimensions, and body mass. The size and shape of limb joint surfaces must therefore also change throughout post-natal development in order to maintain normal joint function. Frost's (1979, 1999) chondral modeling theory proposed that joint congruence is maintained in mammalian limbs throughout postnatal ontogeny because cartilage growth in articular regions is regulated in part by mechanical load. This paper incorporates recent findings concerning the distribution of stress in developing articular units, the response of chondrocytes to mechanically induced deformation, and the development of articular cartilage in order to expand upon Frost's chondral modeling theory. The theory presented here assumes that muscular contraction during post-natal locomotor development produces regional fluctuating, intermittent hydrostatic pressure within the articular cartilage of limb joints. The model also predicts that peak levels of hydrostatic pressure in articular cartilage increase between birth and adulthood. Finally, the chondral modeling theory proposes that the cell-cell and cell-extracellular matrix interactions within immature articular cartilage resulting from mechanically induced changes in hydrostatic pressure regulate the metabolic activity of chondrocytes. Site-specific rates of articular cartilage growth are therefore regulated in part by the magnitude, frequency, and orientation of prevailing loading vectors. The chondral modeling response maintains a normal kinematic pathway as the magnitude and direction of joint loads change throughout ontogeny. The chondral modeling theory also explains ontogenetic scaling patterns of limb joint curvature observed in mammals. The chondral modeling response is therefore an important physiological mechanism that maintains the match between skeletal structure, function, and locomotor performance throughout mammalian ontogeny and phylogeny.     

The effects of femoral graft placement on cartilage thickness after anterior cruciate ligament reconstruction

Altered joint motion has been thought to be a contributing factor in the long-term development of osteoarthritis after ACL reconstruction. While many studies have quantified knee kinematics after ACL injury and reconstruction, there is limited in vivo data characterizing the effects of altered knee motion on cartilage thickness distributions. Thus, the objective of this study was to compare cartilage thickness distributions in two groups of patients with ACL reconstruction: one group in which subjects received a non-anatomic reconstruction that resulted in abnormal joint motion and another group in which subjects received an anatomically placed graft that more closely restored normal knee motion. Ten patients with anatomic graft placement (mean follow-up: 20 months) and 12 patients with non-anatomic graft placement (mean follow-up: 18 months) were scanned using high-resolution MR imaging. These images were used to generate 3D mesh models of both knees of each patient. The operative and contralateral knee models were registered to each other and a grid sampling system was used to make site-specific comparisons of cartilage thickness. Patients in the non-anatomic graft placement group demonstrated a significant decrease in cartilage thickness along the medial intercondylar notch in the operative knee relative to the intact knee (8%). In the anatomic graft placement group, no significant changes were observed. These findings suggest that restoring normal knee motion after ACL injury may help to slow the progression of degeneration. Therefore, graft placement may have important implications on the development of osteoarthritis after ACL reconstruction.     

Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice

IntroductionPrevious studies in animal models of osteoarthritis suggest that alendronate (ALN) has antiresorptive and chondroprotective effects, and can reduce osteophyte formation. However, these studies used non-physiologic injury methods, and did not investigate early time points during which bone is rapidly remodeled prior to cartilage degeneration. The current study utilized a non-invasive model of knee injury in mice to investigate the effect of ALN treatment on subchondral bone changes, articular cartilage degeneration, and osteophyte formation following injury.MethodsNon-invasive knee injury via tibial compression overload or sham injury was performed on a total of 90 mice. Mice were treated with twice weekly subcutaneous injections of low-dose ALN (40 μg/kg/dose), high-dose ALN (1,000 μg/kg/dose), or vehicle, starting immediately after injury until sacrifice at 7, 14 or 56 days. Trabecular bone of the femoral epiphysis, subchondral cortical bone, and osteophyte volume were quantified using micro-computed tomography (μCT). Whole-joint histology was performed at all time points to analyze articular cartilage and joint degeneration. Blood was collected at sacrifice, and serum was analyzed for biomarkers of bone formation and resorption.ResultsμCT analysis revealed significant loss of trabecular bone from the femoral epiphysis 7 and 14 days post-injury, which was effectively prevented by high-dose ALN treatment. High-dose ALN treatment was also able to reduce subchondral bone thickening 56 days post-injury, and was able to partially preserve articular cartilage 14 days post-injury. However, ALN treatment was not able to reduce osteophyte formation at 56 days post-injury, nor was it able to prevent articular cartilage and joint degeneration at this time point. Analysis of serum biomarkers revealed an increase in bone resorption at 7 and 14 days post-injury, with no change in bone formation at any time points.ConclusionsHigh-dose ALN treatment was able to prevent early trabecular bone loss and cartilage degeneration following non-invasive knee injury, but was not able to mitigate long-term joint degeneration. These data contribute to understanding the effect of bisphosphonates on the development of osteoarthritis, and may support the use of anti-resorptive drugs to prevent joint degeneration following injury, although further investigation is warranted.     

Vasculature of the normal and arthritic synovial joint

The vasculature of the normal and arthritic knee is described. The joint contains a number of different tissues, many of which are heterogeneous and each with varying degrees of vascularization. In the normal joint the vasculature is highly organised, some tissues are highly vascular with well defined vascular organisation, whilst other tissues are avascular. During arthritis vascular turnover is increased. This vascular plasticity leads to redistribution of the vascular bed and may compromise its functional ability. The normal joint is able to regulate its blood flow, but this ability may be compromised by the inflammation and increased synovial fluid volume that are associated with joint disease. Growth of the subchondral vasculature into the articular cartilage may also occur, leading to ossification of the articular cartilage.     

A computationally efficient strategy to estimate muscle forces in a finite element musculoskeletal model of the lower limb

Concurrent multiscale simulation strategies are required in computational biomechanics to study the interdependence between body scales. However, detailed finite element models rarely include muscle recruitment due to the computational burden of both the finite element method and the optimization strategies widely used to estimate muscle forces. The aim of this study was twofold: first, to develop a computationally efficient muscle force prediction strategy based on proportional-integral-derivative (PID) controllers to track gait and chair rise experimental joint motion with a finite element musculoskeletal model of the lower limb, including a deformable knee representation with 12 degrees of freedom; and, second, to demonstrate that the inclusion of joint-level deformability affects muscle force estimation by using two different knee models and comparing muscle forces between the two solutions. The PID control strategy tracked experimental hip, knee, and ankle flexion/extension with root mean square errors below 1°, and estimated muscle, contact and ligament forces in good agreement with previous results and electromyography signals. Differences up to 11% and 20% in the vasti and biceps femoris forces, respectively, were observed between the two knee models, which might be attributed to a combination of differing joint contact geometry, ligament behavior, joint kinematics, and muscle moment arms. The tracking strategy developed in this study addressed the inevitable tradeoff between computational cost and model detail in musculoskeletal simulations and can be used with finite element musculoskeletal models to efficiently estimate the interdependence between muscle forces and tissue deformation.     

Fragmentation of decorin, biglycan, lumican and keratocan is elevated in degenerate human meniscus, knee and hip articular cartilages compared with age-matched macroscopically normal and control tissues

Introduction

The small leucine-rich proteoglycans (SLRPs) modulate tissue organization, cellular proliferation, matrix adhesion, growth factor and cytokine responses, and sterically protect the surface of collagen type I and II fibrils from proteolysis. Catabolism of SLRPs has important consequences for the integrity of articular cartilage and meniscus by interfering with their tissue homeostatic functions.

Methods

SLRPs were dissociatively extracted from articular cartilage from total knee and hip replacements, menisci from total knee replacements, macroscopically normal and fibrillated knee articular cartilage from mature age-matched donors, and normal young articular cartilage. The tissue extracts were digested with chondroitinase ABC and keratanase-I before identification of SLRP core protein species by Western blotting using antibodies to the carboxyl-termini of the SLRPs.

Results

Multiple core-protein species were detected for all of the SLRPs (except fibromodulin) in the degenerate osteoarthritic articular cartilage and menisci. Fibromodulin had markedly less fragments detected with the carboxyl-terminal antibody compared with other SLRPs. There were fewer SLRP catabolites in osteoarthritic hip than in knee articular cartilage. Fragmentation of all SLRPs in normal age-matched, nonfibrillated knee articular cartilage was less than in fibrillated articular cartilage from the same knee joint or total knee replacement articular cartilage specimens of similar age. There was little fragmentation of SLRPs in normal control knee articular cartilage. Only decorin exhibited a consistent increase in fragmentation in menisci in association with osteoarthritis. There were no fragments of decorin, biglycan, lumican, or keratocan that were unique to any tissue. A single fibromodulin fragment was detected in osteoarthritic articular cartilage but not meniscus. All SLRPs showed a modest age-related increase in fragmentation in knee articular and meniscal cartilage but not in other tissues.

Conclusion

Enhanced fragmentation of SLRPs is evident in degenerate articular cartilage and meniscus. Specific decorin and fibromodulin core protein fragments in degenerate meniscus and/or human articular cartilage may be of value as biomarkers of disease. Once the enzymes responsible for their generation have been identified, further research may identify them as therapeutic targets.     

A theoretical model of the knee and ACL: theory and experimental verification.

A three-dimensional mathematical model of the human knee joint was developed to examine the role of single ligaments, such as an anterior cruciate ligament (ACL) graft in ACL reconstruction, on joint motion and tissue forces. The model is linear and valid for small motions about an equilibrium position. The knee joint is modeled as two rigid bodies (the femur and the tibia) interconnected by deformable structures, including the ACL or ACL graft, the cartilage layer, and the remainder of the knee tissues (modeled as a single element). The model was demonstrated for the equilibrium condition of the knee in extension with an anterior tibial force, causing anterior drawer and hyperextension. The knee stiffness matrix for this condition was measured for a human right knee in vitro. Predicted model response was compared with experimental observations. Qualitative agreement was found between model and experiment, validating the model and its assumptions. The model was then used to predict the change in graft and cartilage forces and joint motion of the knee due to an increment of load in the normal joint both after ACL removal and with various altered states simulating ACL reconstructions. Results illustrate the interdependence between loads in the ACL graft, other knee structures, and contact force. Stiffer grafts and smaller maximum unloaded length of the ligament lead to higher graft and contact forces. Changes in cartilage stiffness alter load sharing between ACL graft and other joint tissues.     

Dynamic 3D culture: Models of chondrogenesis and endochondral ossification

The formation of cartilage from stem cells during development is a complex process which is regulated by both local growth factors and biomechanical cues, and results in the differentiation of chondrocytes into a range of subtypes in specific regions of the tissue. In fetal development cartilage also acts as a precursor scaffold for many bones, and mineralization of this cartilaginous bone precursor occurs through the process of endochondral ossification. In the endochondral formation of bones during fetal development the interplay between cell signalling, growth factors, and biomechanics regulates the formation of load bearing bone, in addition to the joint capsule containing articular cartilage and synovium, generating complex, functional joints from a single precursor anlagen. These joint tissues are subsequently prone to degeneration in adult life and have poor regenerative capabilities, and so understanding how they are created during development may provide useful insights into therapies for diseases, such as osteoarthritis, and restoring bone and cartilage lost in adulthood. Of particular interest is how these tissues regenerate in the mechanically dynamic environment of a living joint, and so experiments performed using 3D models of cartilage development and endochondral ossification are proving insightful. In this review, we discuss some of the interesting models of cartilage development, such as the chick femur which can be observed in ovo, or isolated at a specific developmental stage and cultured organotypically in vitro. Biomaterial and hydrogel‐based strategies which have emerged from regenerative medicine are also covered, allowing researchers to make informed choices on the characteristics of the materials used for both original research and clinical translation. In all of these models, we illustrate the essential importance of mechanical forces and mechanotransduction as a regulator of cell behavior and ultimate structural function in cartilage. Birth Defects Research (Part C) 105:19–33, 2015. © 2015 Wiley Periodicals, Inc.     

Chondroitin sulphate and heparan sulphate sulphation motifs and their proteoglycans are involved in articular cartilage formation during human foetal knee joint development

Novel sulphation motifs within the glycosaminoglycan chain structure of chondroitin sulphate (CS) containing proteoglycans (PGs) are associated with sites of growth, differentiation and repair in many biological systems and there is compelling evidence that they function as molecular recognition sites that are involved in the binding, sequestration or presentation of soluble signalling molecules (e.g. morphogens, growth factors and cytokines). Here, using monoclonal antibodies 3B3(-), 4C3 and 7D4, we examine the distribution of native CS sulphation motifs within the developing connective tissues of the human foetal knee joint, both during and after joint cavitation. We show that the CS motifs have broad, overlapping distributions within the differentiating connective tissues before the joint has fully cavitated; however, after cavitation, they all localise very specifically to the presumptive articular cartilage tissue. Comparisons with the labelling patterns of heparan sulphate (HS), HS-PGs (perlecan, syndecan-4 and glypican-6) and FGF-2, molecules with known signalling roles in development, indicate that these also become localised to the future articular cartilage tissue after joint cavitation. Furthermore, they display interesting, overlapping distributions with the CS motifs, reflective of early tissue zonation. The overlapping expression patterns of these molecules at this site suggests they are involved, or co-participate, in early morphogenetic events underlying articular cartilage formation; thus having potential clinical relevance to mechanisms involved in its repair/regeneration. We propose that these CS sulphation motifs are involved in modulating the signalling gradients responsible for the cellular behaviours (proliferation, differentiation, matrix turnover) that shape the zonal tissue architecture present in mature articular cartilage.     

Comparison of nonlinear mechanical properties of bovine articular cartilage and meniscus

Nonlinear, linear and failure properties of articular cartilage and meniscus in opposing contact surfaces are poorly known in tension. Relationships between the tensile properties of articular cartilage and meniscus in contact with each other within knee joints are also not known. In the present study, rectangular samples were prepared from the superficial lateral femoral condyle cartilage and lateral meniscus of bovine knee joints. Tensile tests were carried out with a loading rate of 5 mm/min until the tissue rupture. Nonlinear properties of the toe region, linear properties in larger strains, and failure properties of both tissues were analysed. The strain-dependent tensile modulus of the toe region, Young's modulus of the linear region, ultimate tensile stress and toughness were on average 98.2, 8.3, 4.0 and 1.9 times greater (p<0.05) for meniscus than for articular cartilage. In contrast, the toe region strain, yield strain and failure strain were on average 9.4, 3.1 and 2.3 times greater (p<0.05) for cartilage than for meniscus. There was a significant negative correlation between the strain-dependent tensile moduli of meniscus and articular cartilage samples within the same joints (r=−0.690, p=0.014). In conclusion, the meniscus possesses higher nonlinear and linear elastic stiffness and energy absorption capability before rupture than contacting articular cartilage, while cartilage has longer nonlinear region and can withstand greater strains before failure. These findings point out different load carrying demands that both articular cartilage and meniscus have to fulfil during normal physiological loading activities of knee joints.