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The meniscus tissue is crucial for knee joint biomechanics and is frequently susceptible to injuries resulting in early-onset osteoarthritis. Consequently, the need for meniscal substitutes spurs ongoing development. The meniscus is a composite tissue reinforced with circumferential and radial collagenous fibers; the mechanical role of the latter has yet to be fully unveiled. Here, we investigated the role of radial fibers using a synergistic methodology combining meniscal tissue structure imaging, a computational knee joint model, and the fabrication of simple biomimetic composite laminates. These laminates mimic the basic structural units of the meniscus, utilizing longitudinal and transverse fibers equivalent to the circumferential and radial fibers in meniscal tissue. In the computational model, the absence of radial fibers resulted in stress concentration within the meniscus matrix and up to 800 % greater area at the same stress level. Furthermore, the contact pressure on the tibial cartilage increased drastically, affecting up to 322 % larger areas. Conversely, in models with radial fibers, we observed up to 25 % lower peak contact pressures and width changes of less than 0.1 %. Correspondingly, biomimetic composite laminates containing transverse fibers exhibited minor transverse deformations and smaller Poisson's ratios. They demonstrated structural shielding ability, maintaining their mechanical performance with the reduced amount of fibers in the loading direction, similar to the ability of the torn meniscus to carry and transfer loads to some extent. These results indicate that radial fibers are essential to distribute contact pressure and tensile stresses and prevent excessive deformations, suggesting the importance of incorporating them in novel designs of meniscal substitutes. STATEMENT OF SIGNIFICANCE: The organization of the collagen fibers in the meniscus tissue is crucial to its biomechanical function. Radially oriented fibers are an important structural element of the meniscus and greatly affect its mechanical behavior. However, despite their importance to the meniscus mechanical function, radially oriented fibers receive minor attention in meniscal substitute designs. Here, we used a synergistic methodology that combines imaging of the meniscal tissue structure, a structural computational model of the knee joint, and the fabrication of simplistic biomimetic composite laminates that mimic the basic structural units of the meniscus. Our findings highlight the importance of the radially oriented fibers, their mechanical role in the meniscus tissue, and their importance as a crucial element in engineering novel meniscal substitutes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Characterizing the ultimate tensile strength (UTS) of the meniscus is critical in studying knee damage and pathology. This study aims to determine the UTS of the meniscus with an emphasis on its heterogeneity and anisotropy. We performed tensile tests to failure on the menisci of six month old Yorkshire pigs at a low strain rate. Specimens from the anterior, middle and posterior regions of the meniscus were tested in the radial and circumferential directions. Then the UTS was obtained for each specimen and the data were analyzed statistically, leading to a comprehensive view of the variations in porcine meniscal strength. The middle region has the highest average strength in the circumferential (43.3 ± 4.7 MPa) and radial (12.6 ± 2.2 MPa) directions. This is followed by the anterior and posterior regions, which present similar average values (about 34.0MPa) in circumferential direction. The average strength of each region in the radial direction is approximately one-fourth to one-third of the value in the circumferential direction. This study is novel as it is the first work to focus on the experimental methods to investigate the heterogeneity and anisotropy only for porcine meniscus., Competing Interests: Declaration of competing interest I certify that there is no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives:  The aim of the study was to investigate the contact mechanics and kinematic changes in the stifle in different standing angles., Study Design:  We performed a biomechanical ex vivo study using pairs of canine cadaver hindlimbs. Motion sensors were fixed to the tibia and the femur for kinematic data acquisition. Pressure mapping sensors were placed between the femur and both menisci. Thirty percent bodyweight was applied to the limbs with the stifle in 125, 135, or 145 degrees of extension., Results:  Stifle flexion angle influences femoromeniscal contact mechanics significantly. The load on both menisci was significantly higher for 125 and 135 degrees in comparison to 145 degrees. Additionally, the center of force was located significantly more caudal when comparing 125 to 145 degrees in the medial meniscus as well as in both menisci combined., Conclusion:  The angle of knee flexion significantly impacts the contact mechanics between the femur and the meniscus. As the knee flexes, the load on both menisci increases., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The meniscus plays a crucial role in the proper functioning of the knee joint, and when it becomes damaged, partial removal or replacement is necessary to restore proper function. Understanding the stress and deformation of the meniscus during various movements is essential for developing effective materials for meniscus repair. However, accurately estimating the contact mechanics of the knee joint can be challenging due to its complex shape and the dynamic changes it undergoes during movement. To address this issue, the open-source software SCONE can be used to establish a kinematics model that monitors the different states of the knee joint during human motion and obtains relevant gait kinematics data. To evaluate the stress and deformation of the meniscus during normal human movement, values of different states in the movement gait can be selected for finite element analysis (FEA) of the knee joint. This analysis enables researchers to assess changes in the meniscus. To evaluate meniscus damage, it is necessary to obtain changes in its mechanical behavior during abnormal movements. This information can serve as a reference for designing and optimizing the mechanical performance of materials used in meniscus repair and replacement.

Finite element studies of the tibiofemoral joint have increased use in research, with attention often placed on the material models. Few studies assess the effect of meniscus modelling assumptions in image-based models on contact mechanics outcomes. This work aimed to assess the effect of modelling assumptions of the meniscus on knee contact mechanics and meniscus kinematics. A sensitivity analysis was performed using three specimen-specific tibiofemoral models and one generic knee model. The assumptions in representing the meniscus attachment on the tibia (shape of the roots and position of the attachment), the material properties of the meniscus, the shape of the meniscus and the alignment of the joint were evaluated, creating 40 model instances. The values of material parameters for the meniscus and the position of the root attachment had a small influence on the total contact area but not on the meniscus displacement or the force balance between condyles. Using 3D shapes to represent the roots instead of springs had a large influence in meniscus displacement but not in knee contact area. Changes in meniscus shape and in knee alignment had a significantly larger influence on all outcomes of interest, with differences two to six times larger than those due to material properties. The sensitivity study demonstrated the importance of meniscus shape and knee alignment on meniscus kinematics and knee contact mechanics, both being more important than the material properties or the position of the roots. It also showed that differences between knees were large, suggesting that clinical interpretations of modelling studies using single geometries should be avoided., (© 2024. The Author(s).)

The complex fibrillar architecture of native meniscus is essential for proper function and difficult to recapitulate in vitro. In the native meniscus, proteoglycan content is low during the development of collagen fibers and progressively increases with aging. In vitro, fibrochondrocytes produce glycosaminoglycans (GAGs) early in culture, in contrast to native tissue, where they are deposited after collagen fibers have formed. This difference in the timing of GAG production hinders the formation of a mature fiber network in such in vitro models. In this study, we removed GAGs from collagen gel-based tissue engineered constructs using chondroitinase ABC (cABC) and evaluated the effect on the formation and alignment of collagen fibers and the subsequent effect on tensile and compressive mechanical properties. Removal of GAGs during maturation of in vitro constructs improved collagen fiber alignment in tissue engineered meniscus constructs. Additionally, removal of GAGs during maturation improved fiber alignment without compromising compressive strength, and this removal improved not only fiber alignment and formation but also tensile properties. The increased fiber organization in cABC-treated groups also appeared to influence the size, shape, and location of defects in these constructs, suggesting that treatment may prevent the propagation of large defects under loading. This data gives another method of modulating the ECM for improved collagen fiber formation and mechanical properties in tissue engineered constructs.

The meniscus is a fibrocartilaginous structure of the knee joint that serves a crucial role in joint health and biomechanics. Degeneration or removal of the meniscus is known to lead to a chronic and debilitating disease known as knee osteoarthritis, whose prevalence is expected to increase in the next few decades. Meniscus bioengineering has been developed as a potential alternative to current treatment methods, wherein meniscus-like tissues are engineered using cells, materials, and biomechanical stimuli. The application of mechanical stimulation in meniscus bioengineering has presented varied results but, for the most part, it has been shown to enhance meniscus-like tissue formation. In this review, we summarized literature over the last 10 years of various mechanical stimuli applied in bioengineering meniscus tissues. The role of individual loading types is examined, and the effects on engineered meniscus are evaluated on both molecular and tissue levels. In addition, simulated microgravity is highlighted as a new area of interest in meniscus engineering, and its potential use as a disease-driving platform is discussed. Taken together, with the increased understanding of the effects of mechanical stimulation on bioengineered meniscus tissues, the most suitable loading regime could be developed for meniscus tissue engineering and osteoarthritis modeling.

There are few studies investigate morphologic changes of knee meniscus in vivo mechanical loading and three-dimensions (3D) deformation and displacement of the whole meniscus between in vivo mechanical loading and unloading conditions are still unclear. To investigate the displacements and 3D morphological changes of the menisci under knee weight-bearing and early flexion conditions in healthy adults using a Magnetic Resonance Imaging (MRI)-compatible loading device (a 3.0 T MR imaging system) combined with a newly developed 3D comparison technique. Fifteen healthy volunteers were recruited in this cross-sectional observational study. Each subject underwent MRIs of their dominant right knee in eight different scanning conditions using a 3.0-T MRI scanner with a custom-made MRI-compatible loading device. The knee meniscus images were 3D reconstructed, and dimensional comparisons were made for each meniscal model with baseline (0°-unloaded model). The morphologic changes of the meniscal-anterior horn (AH), body (BD), and posterior horn (PH) regions were expressed as mean positive and negative deviations. The displacements were further investigated, and the meniscal extrusions of different subregions were measured. The morphologic changing patterns of human meniscus under loading and flexions were presented using 3D chromatic maps. The bilateral menisci were generally shifting laterally and posteriorly in most flexion angles and were changing medially and anteriorly under fully extended knee loading conditions. The mean deviations were more significant with loading at 0° of knee flexion, while the PH region in the lateral side changed further posteriorly with loading in 30° flexion. Most of the differences were not significant in other flexion angles between loading conditions. The extrusion of meniscus's medial body was greater in full extension compared to any other flexing angles. Mechanical loading can significantly deform the menisci in knee extension; however, this effect is limited during knee flexion. Current study can be used as a reference for the evaluations of the integrity in meniscal functions., (© 2021. The Author(s).)

Meniscus tears of the knee are among the most common orthopedic knee injury. Specifically, tears of the posterior root can result in abnormal meniscal extrusion leading to decreased function and progressive osteoarthritis. Despite contemporary surgical treatments of posterior meniscus root tears, there is a low rate of healing and an incidence of residual meniscus extrusion approaching 30%, illustrating an inability to recapitulate native meniscus function. Here, we characterized the differential functional behavior of the medial and lateral meniscus during axial compression load and dynamic knee motion using a cadaveric model. We hypothesized essential differences in extrusion between the medial and lateral meniscus in response to axial compression and knee range of motion. We found no differences in the amount of meniscus extrusion between the medial and lateral meniscus with a competent posterior root (0.338mm vs. 0.235mm; p-value = 0.181). However, posterior root detachment resulted in a consistently increased meniscus extrusion for the medial meniscus compared to the lateral meniscus (2.233mm vs. 0.4705mm; p-value < 0.0001). Moreover, detachment of the posterior root of the medial meniscus resulted in an increase in extrusion at all angles of knee flexion and was most pronounced (4.00mm ± 1.26mm) at 30-degrees of knee flexion. In contrast, the maximum mean extrusion of the lateral meniscus was 1.65mm ± 0.97mm, occurring in full extension. Furthermore, only the medial meniscus extruded during dynamic knee flexion after posterior root detachment. Given the differential functional behaviors between the medial and lateral meniscus, these findings suggest that posterior root repair requires reducing overall meniscus extrusion and recapitulating the native functional responses specific to each meniscus., Competing Interests: B.E.W. is a consultant for AlloSource and G.S.B. is a consultant for Conmed. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The commercial organizations did not play a role in the study design, data collection and analysis, decision to publish, preparation of the manuscript, and provided no financial support or compensation.

Meniscus regeneration could be enhanced by targeting meniscus cells and mesenchymal stromal cells (MSCs) with the right growth factors. Combining these growth factors with the Collagen Meniscus Implant (CMI®) could accelerate cell ingrowth and tissue formation in the implant and thereby improve clinical outcomes. Using a transwell migration assay and a micro-wound assay, the effect of insulin-like growth factor-1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-β1), fibroblast growth factor, and platelet lysate (PL) on migration and proliferation of meniscus cells and MSCs was assessed. The formation of extracellular matrix under influence of the above-mentioned growth factors was assessed after 28 days of culture of both MSCs and meniscus cells. As a proof of concept, the CMI® was functionalized with a VEGF binding peptide and coated with platelet-rich plasma (PRP) for clinical application. Our results demonstrate that PDGF, TGF-β1, and PL stimulate migration, proliferation, and/or extracellular matrix production of meniscus cells and MSCs. Additionally, the CMI® was successfully functionalized with a VEGF binding peptide and PRP which increased migration of meniscus cell and MSC into the implant. This study demonstrates proof of concept of functionalizing the CMI® with growth factor binding peptides. A CMI® functionalized with the right growth factors holds great potential for meniscus replacement after partial meniscectomy., (© 2021 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons Ltd.)

Changes in stress transferred across articular joints have been described as a substantial factor in the initiation and progression of joint disease such as post-traumatic osteoarthritis and have thus been of interest to biomechanical researchers. However, to date, stress magnitudes within the menisci have not been successfully measured. In this study, a novel method for measuring stress within the menisci is presented. Small Fibre Bragg Grating (FBG) sensors were inserted inside menisci and used to measure mechanical stress during replicated gait cycles. In-vitro stress measurements within the menisci were preformed for healthy gait and gait following surgical damage to the joints. Together with our capability to reproduce in vivo motions accurately, the improvements in fibre optic technology have allowed for the first direct measurement of mechanical stress in menisci.

Tensile testing is an essential experiment to assess the mechanical integrity of musculoskeletal soft tissues, yet standard test methods have not been developed to ensure the quality and reproducibility of these experiments. The ASTM International standards organization has created tensile test standards for common industry materials that specify geometric dimensions of test specimens (coupons) that promote valid failures within the gage section (midsubstance), away from the grips. This study examined whether ASTM test standards for plastics, elastomers, and fiber-reinforced composites are suitable for tensile testing of bovine meniscus along the circumferential fiber direction. We found that dumbbell (DB) shaped coupons based on ASTM standards for elastomers and plastics had an 80% and 60% rate of midsubstance failures, respectively. The rate of midsubstance failures dropped to 20% when using straight (ST) coupons based on ASTM standards for fiber-reinforced composites. The mechanical properties of dumbbell shaped coupons were also significantly greater than straight coupons. Finite element models of the test coupons revealed stress distributions that supported our experimental findings. In addition, we found that a commercial deli-slicer was able to slice meniscus to uniform layer thicknesses that were within ASTM dimensional tolerances. This study provides methods, recommendations, and insights that can advance the standardization of tensile testing in meniscus and other soft fibrous tissues., (Copyright © 2021 by ASME.)

Meniscus degeneration is closely related to the progression of knee osteoarthritis (OA). However, there is currently a lack of quantitative and objective metrics to assess OA meniscal cell phenotypes. In this study we investigated the phenotypic markers and chondrogenic potency of avascular and vascular meniscal cells and chondrocytes from medial OA knee joints (n = 10). Flow cytometry results showed that a significantly greater percentage of meniscal cells were positive for CD49b, CD49c and CD166 compared to donor-matched chondrocytes after 14 days in monolayer culture. The integrins, CD49b and CD29, were expressed at a significantly higher level on avascular meniscal cells derived from tissues with a more degenerated inner border than non-degenerate menisci, suggesting that the integrin family may play an important role in meniscus OA pathology. Collagen fibres arranged in a "tree-like" formation within the meniscus appeared to have less blood vessels associated with them in the vascular region of the most degenerate menisci, which may indicate that such structures are involved in the pathological process. We have demonstrated that meniscal cells derived from the lateral meniscus in medial OA patients have chondrogenic capacity in vitro and hence could represent a potential cell source to consider for meniscus tissue engineering.

Background: Proteoglycans contribute to mechanical stiffness in articular cartilage, aiding load transmission. The magnitude of the ionic contribution of proteoglycans to the stiffness of human meniscal tissue has not been established., Methods: Thirty-six discs of human meniscal tissue were placed within a custom confined compression chamber and bathed in three solutions of increasing ionic concentration. Following a 0.3 N preload, at equilibrium, a 10% ramp compressive strain was followed by a 7200 s hold phase. A nonlinear poroviscoelastic model with strain dependent permeability was fitted to resultant stress relaxation curves. All samples were assayed for proteoglycan content. Model parameters were analysed using multivariate analysis of variance whilst proteoglycan content was compared using a univariate analysis of variance model., Findings: A significant difference (p < .05) was observed in the value of the Young's modulus (E) between samples tested in deionised water compared to those tested in solutions of high ionic concentration. No differences were observed in the zero-strain permeability or the exponential strain dependent stiffening coefficient. Proteoglycan content was not found to differ with solution; but was found to be significantly increased in the middle meniscal region of both menisci., Interpretation: Proteoglycans make a significant ionic contribution to mechanical stiffness of the meniscus, increasing it by 58% in the physiological condition. It is therefore critical that meniscal regeneration strategies attempt to recreate the function of proteoglycans to ensure normal meniscal function., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Abnormal mechanical loading is essential in the onset and progression of knee osteoarthritis. Combined musculoskeletal (MS) and finite element (FE) modeling is a typical method to estimate load distribution and tissue responses in the knee joint. However, earlier combined models mostly utilize static-optimization based MS models and muscle force driven FE models typically use elastic materials for soft tissues or analyze specific time points of gait. Therefore, here we develop an electromyography-assisted muscle force driven FE model with fibril-reinforced poro(visco)elastic cartilages and menisci to analyze knee joint loading during the stance phase of gait. Moreover, since ligament pre-strains are one of the important uncertainties in joint modeling, we conducted a sensitivity analysis on the pre-strains of anterior and posterior cruciate ligaments (ACL and PCL) as well as medial and lateral collateral ligaments (MCL and LCL). The model produced kinematics and kinetics consistent with previous experimental data. Joint contact forces and contact areas were highly sensitive to ACL and PCL pre-strains, while those changed less cartilage stresses, fibril strains, and fluid pressures. The presented workflow could be used in a wide range of applications related to the aetiology of cartilage degeneration, optimization of rehabilitation exercises, and simulation of knee surgeries.

Joint motion and postnatal stress of weight bearing are the principal factors that determine the phenotypical and architectural changes that characterize the maturation process of the meniscus. In this study, the effect of compressive forces on the meniscus will be evaluated in a litter of 12 Dobermann Pinschers, of approximately 2 months of age, euthanized as affected by the quadriceps contracture muscle syndrome of a single limb focusing on extracellular matrix remodeling and cell-extracellular matrix interaction (i.e., meniscal cells maturation, collagen fibers typology and arrangement). The affected limbs were considered as models of continuous compression while the physiologic loaded limbs were considered as controls. The results of this study suggest that a compressive continuous force, applied to the native meniscal cells, triggers an early maturation of the cellular phenotype, at the expense of the proper organization of collagen fibers. Nevertheless, an application of a compressive force could be useful in the engineering process of meniscal tissue in order to induce a faster achievement of the mature cellular phenotype and, consequently, the earlier production of the fundamental extracellular matrix (ECM), in order to improve cellular viability and adhesion of the cells within a hypothetical synthetic scaffold., Competing Interests: The authors declare no conflict of interest.

Response to loading of soft tissues as assessed by advanced magnetic resonance imaging (MRI) techniques is a promising approach to evaluate tissue functionality beyond (statically obtained) structural and compositional features. As cartilage and meniscus pathologies are closely intertwined in osteoarthritis (OA) and beyond, both tissues should ideally be studied to elucidate further the underlying mechanisms involved in load transmission and its failure leading to OA. Hence, we devised, constructed and validated a dedicated MRI-compatible pneumatic force-controlled loading device to study cartilage and meniscus functionality in a standardized and reproducible manner and in reference to alternative tissue evaluation methods. Mechanical reference measurements using digital force sensors confirmed the reproducible application of forces in the range of 0-76N. To demonstrate the device's utility in a basic research context, MRI measurements of human articular cartilage (obtained from the lateral femoral condyle, n = 5) and meniscus (obtained from lateral meniscus body, n = 5) were performed in the unloaded (δ 0 ) and loaded configurations (δ 1 : [cartilage] 0.75 bar corresponding to 15.1 N, [meniscus] 2 bar corresponding to 37.1 N; δ 2 : [cartilage] 1.5 bar corresponding to 28.6 N, [meniscus] 4 bar corresponding to 69.1 N). Cartilage samples were directly indented, while meniscus samples were subject to torque-induced compression using a dedicated lever compression device. Morphological MR Imaging using Proton Density-weighted sequences and quantitative MR Imaging using T2 and T1ρ mapping were performed serially and at high resolution. For reference, samples underwent subsequent biomechanical and histological reference evaluation. In conclusion, the force-controlled loading device has been validated for the non-invasive response-to-loading assessment of human cartilage and meniscus samples by advanced MRI techniques. Hereby, both tissues may be functionally evaluated in combination, beyond mere static analysis and in reference to histological and biomechanical measures., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Despite the fact that type III collagen is the second most abundant collagen type in the body, its contribution to the physiologic maintenance and repair of skeletal tissues remains poorly understood. This study queried the role of type III collagen in the structure and biomechanical functions of two structurally distinctive tissues in the knee joint, type II collagen-rich articular cartilage and type I collagen-dominated meniscus. Integrating outcomes from atomic force microscopy-based nanomechanical tests, collagen fibril nanostructural analysis, collagen cross-link analysis and histology, we elucidated the impact of type III collagen haplodeficiency on the morphology, nanostructure and biomechanical properties of articular cartilage and meniscus in Col3a1 +/- mice. Reduction of type III collagen leads to increased heterogeneity and mean thickness of collagen fibril diameter, as well as reduced modulus in both tissues, and these effects became more pronounced with skeletal maturation. These data suggest a crucial role of type III collagen in mediating fibril assembly and biomechanical functions of both articular cartilage and meniscus during post-natal growth. In articular cartilage, type III collagen has a marked contribution to the micromechanics of the pericellular matrix, indicating a potential role in mediating the early stage of type II collagen fibrillogenesis and chondrocyte mechanotransduction. In both tissues, reduction of type III collagen leads to decrease in tissue modulus despite the increase in collagen cross-linking. This suggests that the disruption of matrix structure due to type III collagen deficiency outweighs the stiffening of collagen fibrils by increased cross-linking, leading to a net negative impact on tissue modulus. Collectively, this study is the first to highlight the crucial structural role of type III collagen in both articular cartilage and meniscus extracellular matrices. We expect these results to expand our understanding of type III collagen across various tissue types, and to uncover critical molecular components of the microniche for regenerative strategies targeting articular cartilage and meniscus repair., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mimicking the ultrastructural morphology of the meniscus with nanofiber scaffolds, coupled with controlled growth-factor delivery to the appropriate cells, can help engineer tissue with the potential to grow, mature, and regenerate after in vivo implantation. We electrospun nanofibers encapsulating platelet-derived growth factor (PDGF-BB), which is a potent mitogen and chemoattractant in a core of serum albumin contained within a shell of polylactic acid. We controlled the local PDGF-BB release by adding water-soluble polyethylene glycol to the polylactic acid shell to serve as a porogen. The novel core-shell nanofibers generated 3D scaffolds with an interconnected macroporous structure, with appropriate mechanical properties and with high cell compatibility. Incorporating PDGF-BB increased cell viability, proliferation, and infiltration, and upregulated key genes involved in meniscal extracellular matrix synthesis in human meniscal and synovial cells. Our results support proof of concept that these core-shell nanofibers can create a cell-favorable nanoenvironment and can serve as a system for sustained release of bioactive factors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Meniscal injuries have posed a challenging problem for many years, especially considering that historically the meniscus was considered to be a structure with no important role in the knee joint. This led to earlier treatments aiming at the removal of the entire structure in a procedure known as a meniscectomy. However, with the current understanding of the function and roles of the meniscus, meniscectomy has been identified to accelerate joint degradation significantly and is no longer a preferred treatment option in meniscal tears. Current therapies are now focused to regenerate, repair, or replace the injured meniscus to restore its native function. Repairs have improved in technique and materials over time, with various implant devices being utilized and developed. More recently, strategies have applied stem cells, tissue engineering, and their combination to potentiate healing to achieve superior quality repair tissue and retard the joint degeneration associated with an injured or inadequately functioning meniscus. Accordingly, the purpose of this current review is to summarize the current available pre-clinical and clinical literature using stem cells and tissue engineering for meniscal repair and regeneration.

Fibrillar collagens are highly prevalent in the extracellular matrix of all connective tissues and therefore commonly used as a biomaterial in tissue engineering applications. In the native environment, collagen fibers are arranged in a complex hierarchical structure that is often difficult to recreate in a tissue engineered construct. Small leucine rich proteoglycans as well as hyaluronan binding proteoglycans, aggrecan and versican, have been implicated in regulating fiber formation. In this study, we modified proteoglycan production in vitro by altering culture medium glucose concentrations (4500, 1000, 500, 250, and 125 mg/L), and evaluated its effect on the formation of collagen fibers inside tissue engineered meniscal constructs. Reduction of extracellular glucose resulted in a dose dependent decrease in total sulfated glycosaminoglycan (GAG) production, but minimal decreases of decorin and biglycan. However, fibromodulin doubled in production between 125 and 4500 mg/L glucose concentration. A peak in fiber formation was observed at 500 mg/L glucose concentration and corresponded with reductions in total GAG production. Fiber formation reduction at 125 and 250 mg/L glucose concentrations are likely due to changes in metabolic activity associated with a limited supply of glucose. These results point to proteoglycan production as a means to manipulate fiber architecture in tissue engineered constructs. STATEMENT OF SIGNIFICANCE: Fibrillar collagens are highly prevalent in the extracellular matrix of all connective tissues; however achieving appropriate assembly and organization of collagen fibers in engineered connective tissues is a persistent challenge. Proteoglycans have been implicated in regulating collagen fiber organization both in vivo and in vitro, however little is known about methods to control proteoglycan production and the subsequent fiber organization in tissue engineered menisci. Here, we show that media glucose content can be optimized to control proteoglycan production and collagen fiber assembly, with optimal collagen fiber assembly occurring at sub-physiologic levels of glucose., (Copyright © 2019. Published by Elsevier Ltd.)

Regeneration of an injured meniscus continues to be a scientific challenge due to its poor self-healing potential. Tissue engineering provides an avenue for regenerating a severely damaged meniscus. In this study, we first investigated the superiority of five concentrations (0%, 0.5%, 1%, 2%, and 4%) of meniscus extracellular matrix (MECM)-based hydrogel in promoting cell proliferation and the matrix-forming phenotype of meniscal fibrochondrocytes (MFCs). We found that the 2% group strongly enhanced chondrogenic marker mRNA expression and cell proliferation compared to the other groups. Moreover, the 2% group showed the highest glycosaminoglycan (GAG) and collagen production by day 14. We then constructed a hybrid scaffold by 3D printing a wedge-shaped poly(ε-caprolactone) (PCL) scaffold as a backbone, followed by injection with the optimized MECM-based hydrogel (2%), which served as a cell delivery system. The hybrid scaffold (PCL-hydrogel) clearly yielded favorable biomechanical properties close to those of the native meniscus. Finally, PCL scaffold, PCL-hydrogel, and MFCs-loaded hybrid scaffold (PCL-hydrogel-MFCs) were implanted into the knee joints of New Zealand rabbits that underwent total medial meniscectomy. Six months postimplantation we found that the PCL-hydrogel-MFCs group exhibited markedly better gross appearance and cartilage protection than the PCL scaffold and PCL-hydrogel groups. Moreover, the regenerated menisci in the PCL-hydrogel-MFCs group had similar histological structures, biochemical contents, and biomechanical properties as the native menisci in the sham operation group. In conclusion, PCL-MECM-based hydrogel hybrid scaffold seeded with MFCs can successfully promote whole meniscus regeneration, and cell-loaded PCL-MECM-based hydrogel hybrid scaffold may be a promising strategy for meniscus regeneration in the future.

Meniscus regeneration is an unmet clinical need as damage to the meniscus is common and causes early osteoarthritis. The aim of the present study was to investigate the feasibility of a one-stage cell-based treatment for meniscus regeneration by augmenting a resorbable collagen-based implant with a combination of recycled meniscus cells and mesenchymal stromal cells (MSCs). Cell communication and fate of the different cell types over time in co-culture were evaluated by connexin 43 staining for gap junctions and polymerase chain reaction (PCR) to discriminate between meniscus cells and MSCs, based on a Y-chromosome gene. To define optimal ratios, human meniscus cells and bone-marrow-derived MSCs were cultured in different ratios in cell pellets and type I collagen hydrogels. In addition, cells were seeded on the implant in fibrin glue by static seeding or injection. Cellular communication by gap junctions was shown in co-culture and a decrease in the amount of MSCs over time was demonstrated by PCR. 20 : 80 and 10 : 90 ratios showed significantly highest glycosaminoglycan and collagen content in collagen hydrogels. The same statistical trend was found in pellet cultures. Significantly more cells were present in the injected implant and cell distribution was more homogenous as compared to the statically seeded implant. The study demonstrated the feasibility of a new one-stage cell-based procedure for meniscus regeneration, using 20 % meniscus cells and 80 % MSCs seeded statically on the implant. In addition, the stimulatory effect of MSCs towards meniscus cells was demonstrated by communication through gap junctions.

Aim: To investigate whether platelet-rich gel (PRG) incorporation could promote meniscal regeneration of the silk scaffold. Materials & methods: A PRG-incorporated silk sponge was fabricated for reconstruction of the meniscus in a rabbit meniscectomy model. Subsequently, characterization of the scaffold, as well as the in vitro cytocompatibility and in vivo function was evaluated. Results: Our results showed that the PRG-incorporated silk scaffold provided a sustained release of TGF-β1 over 1 week. The PRG enhanced the cytocompatibility in vitro and cell infiltration in vivo of the silk sponge. Meanwhile, the implantation of the composite in situ ameliorated the cartilage degeneration in knee at 3 months. Conclusion: These findings indicated that PRG-incorporated silk scaffold could promote functional regeneration of the meniscus and effectively prevented subsequent osteoarthritis after meniscectomy.

Recently, the scientific community has shown considerable interest in engineering tissues with organized compositional and structural gradients to mimic hard-to-soft tissue interfaces. This effort is hindered by an incomplete understanding of the construction of native tissue interfaces. In this work, we combined Raman microscopy and confocal elastography to map compositional, structural, and mechanical features across the stiff-to-compliant interface of the attachments of the meniscus in the knee. This study provides new insight into the methods by which biology mediates multiple orders of magnitude changes in stiffness over tens of microns. We identified how the nano- to mesoscale architecture mediates complex microscale transitional regions across the interface: two regions defined by chemical composition, five distinguished by structural features, and three mechanically distinct regions. We identified three major components that lead to a robust interface between a soft tissue and bone: mobile collagen fiber units, a continuous interfacial region, and a local stiffness gradient. This tissue architecture allows for large displacements of collagen fibers in the attachments, enabling meniscal movement without localizing strains to the soft tissue-to-bone interface. The interplay of these regions reveals a method relying on hierarchical structuring across multiple length scales to minimize stress concentrators between highly dissimilar materials. These insights inspire new design strategies for synthetic soft tissue-to-bone attachments and biomimetic material interfaces.

Background: While a primary goal of anterior cruciate ligament (ACL) reconstruction is to reduce pathologically increased anterior and rotational knee laxity, the relationship between knee laxity after ACL reconstruction and patient-reported knee function remains unclear., Hypothesis: There would be no significant correlation between the degree of residual anterior and rotational knee laxity and patient-reported outcomes (PROs) 2 years after primary ACL reconstruction., Study Design: Cross-sectional study; Level of evidence, 3., Methods: From a prospective multicenter nested cohort of patients, 433 patients younger than 36 years of age injured in sports with no history of concomitant ligament surgery, revision ACL surgery, or surgery of the contralateral knee were identified and evaluated at a minimum 2 years after primary ACL reconstruction. Each patient underwent Lachman and pivot-shift evaluation as well as a KT-1000 arthrometer assessment along with Knee injury and Osteoarthritis Outcome Score and subjective International Knee Documentation Committee (IKDC) scores. A proportional odds logistic regression model was used to predict each 2-year PRO score, controlling for preoperative score, age, sex, body mass index, smoking, Marx activity score, education, subsequent surgery, meniscal and cartilage status, graft type, and range of motion asymmetry. Measures of knee laxity were independently added to each model to determine correlation with PROs., Results: Side-to-side manual Lachman differences were IKDC A in 246 (57%) patients, IKDC B in 183 (42%) patients, and IKDC C in 4 (<1%) patients. Pivot-shift was classified as IKDC A in 209 (48%) patients, IKDC B in 183 (42%) patients, and IKDC C in 11 (2.5%) patients. The mean side-to-side KT-1000 difference was 2.0 ± 2.6 mm. No significant correlations were noted between pivot-shift or anterior tibial translation as assessed by Lachman or KT-1000 and any PRO. All predicted differences in PROs based on IKDC A versus B pivot-shift and anterior tibial translation were less than 4 points., Conclusion: Neither the presence of IKDC A versus B pivot-shift nor increased anterior tibial translation of up to 6 mm is associated with clinically relevant decreases in PROs 2 years after ACL reconstruction.

Rigid-body knee models have gained popularity thanks to computational speed and ease of setup compared to finite element models-showing exciting potential for clinical patient-specific models in the future. However, Rigid-body studies in general have encountered difficulty in modeling cartilage and especially meniscus material properties, often relying on computationally costly optimization techniques. This paper presents two new methods to alleviate the difficulty-one to define model contact pressure and one to define meniscus internal forces-and is the first to our knowledge to use experimental pressure-strain curves from the literature to simulate cartilage and meniscus behavior in a rigid body model. This paper describes the methodology to derive the proof of concept model and preliminary results from a gait simulation based on ISO 14243-1.

Reconstruction of the anisotropic structure and proper function of the knee meniscus remains an important challenge to overcome, because the complexity of the zonal tissue organization in the meniscus has important roles in load bearing and shock absorption. Current tissue engineering solutions for meniscus reconstruction have failed to achieve and maintain the proper function in vivo because they have generated homogeneous tissues, leading to long-term joint degeneration. To address this challenge, we applied biomechanical and biochemical stimuli to mesenchymal stem cells seeded into a biomimetic scaffold to induce spatial regulation of fibrochondrocyte differentiation, resulting in physiological anisotropy in the engineered meniscus. Using a customized dynamic tension-compression loading system in conjunction with two growth factors, we induced zonal, layer-specific expression of type I and type II collagens with similar structure and function to those present in the native meniscus tissue. Engineered meniscus demonstrated long-term chondroprotection of the knee joint in a rabbit model. This study simultaneously applied biomechanical, biochemical, and structural cues to achieve anisotropic reconstruction of the meniscus, demonstrating the utility of anisotropic engineered meniscus for long-term knee chondroprotection in vivo., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Most previous studies investigated the remarkably low and complex friction properties of meniscus and cartilage under constant loading and motion conditions. However, both load and relative velocity within the knee joint vary considerably during physiological activities. Hence, the question arises how friction of both tissues is affected by physiological testing conditions occurring during gait. As friction properties are of major importance for meniscal replacement devices, the influence of these simulated physiological testing conditions was additionally tested for a potential meniscal implant biomaterial. Using a dynamic friction testing device, three different friction tests were conducted to investigate the influence of either just varying the motion conditions or the normal load and also to replicate the physiological gait conditions. It could be shown for the first time that the friction coefficient during swing phase was statistically higher than during stance phase when varying both loading and motion conditions according to the physiological gait pattern. Further, the friction properties of the exemplary biomaterial were also higher, when tested under dynamic gait parameters compared to static conditions, which may suggest that static conditions can underestimate the friction coefficient rather than reflecting the in vivo performance.

The aim of this study was to review aspects of the pathobiology of the meniscus in health and disease and show how degeneration of the meniscus can contribute to deleterious changes in other knee joint components. The menisci, distinctive semilunar weight bearing fibrocartilages, provide knee joint stability, co-ordinating functional contributions from articular cartilage, ligaments/tendons, synovium, subchondral bone and infra-patellar fat pad during knee joint articulation. The meniscus contains metabolically active cell populations responsive to growth factors, chemokines and inflammatory cytokines such as interleukin-1 and tumour necrosis factor-alpha, resulting in the synthesis of matrix metalloproteases and A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS)-4 and 5 which can degrade structural glycoproteins and proteoglycans leading to function-limiting changes in meniscal and other knee joint tissues. Such degradative changes are hall-marks of osteoarthritis (OA). No drugs are currently approved that change the natural course of OA and translate to long-term, clinically relevant benefits. For any pharmaceutical therapeutic intervention in OA to be effective, disease modifying drugs will have to be developed which actively modulate the many different cell types present in the knee to provide a global therapeutic. Many individual and combinatorial approaches are being developed to treat or replace degenerate menisci using 3D printing, bioscaffolds and hydrogel delivery systems for therapeutic drugs, growth factors and replacement progenitor cell populations recognising the central role the menisci play in knee joint health., Competing Interests: The author declares no conflict of interest.

Tissue-engineered menisci hold promise as an alternative to allograft procedures but require a means of robust fixation to the native bone. The insertion of the meniscus into bone is critical for meniscal function and inclusion of a soft tissue-to-bone interface in a tissue engineered implant can aid in the fixation process. The native insertion is characterized by gradients in composition, tissue architecture, and cellular phenotype, which are all difficult to replicate. In this study, a soft tissue-to-bone interface is tissue engineered with a cellular gradient of fibrochondrocytes and mesenchymal stem cells and subjected to a biochemical gradient through a custom media diffusion bioreactor. These constructs, consisting of interpenetrating collagen and boney regions, display improved mechanical performance and collagen organization compared to controls without a cellular or chemical gradient. Media gradient exposure produces morphological features in the constructs that appear similar to the native tissue. Collectively, these data show that cellular and biochemical gradients improve integration between collagen and bone in a tissue engineered soft tissue-to-bone construct., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Menisci act like shock absorbers and transmit load across the tibiofemoral joint by increasing congruency during movements or body weight load. This leads to decreasing the resultant stress on the articular cartilages. The meniscus has a dense extracellular matrix (ECM) composed of water, different types of collagens, and proteoglycans, such as decorin, aggrecan and biglycan. Decorin (DCN) regulates collagen fibrillogenesis acting on collagen fibrils diameter and fibrils orientation to achieve the proper assembly of its network. This work investigates the spatial disposition of this fundamental protein in pig meniscus' matrix by immunohistochemistry and western blot analysis. DCN shows an increasing trend, moving from neonatal to adult pig menisci. Adult meniscus, in porcine species, is the only one that could be considered fully mature and functional, and, even if an increasing trend is seen, no precise phenotypical switch points are seen in the age stages considered in this study.

Load transmission is an important function of the meniscus. In articular cartilage, proteoglycans help maintain hydration via negatively charged moieties. We aimed to investigate the influence of electrostatic effects on stiffness of meniscal tissue. Circular discs from bovine menisci of 8 mm diameter and 5 mm thickness were placed within a confined compression chamber. The apparatus was bathed in distilled water, 0.14 M PBS or 3 M PBS before being subjected to 5% ramp compressive strain and held for 300s. FEBio software was used to fit resultant relaxation curves to a non-linear poroviscoelastic model with strain dependent Holmes-Mow permeability. Analysis was conducted using one-way ANOVA with Tukey post-hoc analysis. 10 samples were tested in each solution. Significant differences (p < 0.05) were observed between the values for Young's modulus, zero strain dependent permeability and the viscoelastic coefficient for samples tested in 3 M PBS as compared to deionised water/0.14 M PBS. No significant differences were observed in the strain dependent/stiffening coefficients or the relaxation time. Approximately 79% of the stiffness of the meniscus appears attributable to ionic effects. Ionic effects play a significant role in the mechanical stiffness of the meniscus. It is important to include the influence of ionic effects when developing mathematical models of this tissue., (Copyright © 2018. Published by Elsevier Ltd.)

Tissue engineering is a promising solution for meniscal regeneration after meniscectomy. However, in situ reconstruction still poses a formidable challenge due to multifunctional roles of the meniscus in the knee. In this study, we fabricate a silk sponge from 9% (w/v) silk fibroin solution through freeze drying and then coat its internal space and external surface with collagen sponge. Subsequently, various characteristics of the silk-collagen scaffold are evaluated, and cytocompatibility of the construct is assessed in vitro and subcutaneously. The efficacy of this composite scaffold for meniscal regeneration is evaluated through meniscus reconstruction in a rabbit meniscectomy model. It is found that the internally coated collagen sponge enhances the cytocompatibility of the silk sponge, and the external layer of collagen sponge significantly improves the initial frictional property. Additionally, the silk-collagen composite group shows more tissue ingrowth and less cartilage wear than the pure silk sponge group at 3 months postimplantation in situ. These findings thus demonstrate that the composite scaffold had less damage to the joint surface than the silk alone through promoting functional meniscal regeneration after meniscectomy, which indicates its clinical potential in meniscus reconstruction., (© 2018 John Wiley & Sons, Ltd.)

In this study, porcine fibrochondrocyte-seeded agarose, methacrylated gelatin (GelMA), methacrylated hyaluronic acid (MeHA) and GelMA-MeHA blend hydrogels, and 3D printed PCL scaffolds were tested under dynamic compression for potential meniscal regeneration in vitro. Cell-carrying hydrogels produced higher levels of extracellular matrix (ECM) components after a 35-day incubation than the 3D printed PCL. Cells on GelMA exhibited strong cell adhesion (evidenced with intense paxillin staining) and dendritic cell morphology, and produced an order of magnitude higher level of collagen (p < 0.05) than other materials. On the other hand, cells in agarose exhibited low cell adhesion and round cell morphology, and produced higher levels of glycosaminoglycans (GAGs) (p < 0.05) than other materials. A low level of ECM production and a high level of cell proliferation were observed on the 3D printed PCL. Dynamic compression at 10% strain enhanced GAG production in agarose (p < 0.05), and collagen production in GelMA. These results show that hydrogels have a higher potential for meniscal regeneration than the 3D printed PCL, and depending on the material used, fibrochondrocytes could be directed to proliferate or produce cartilaginous or fibrocartilaginous ECM. Agarose and MeHA could be used for the regeneration of the inner region of meniscus, while GelMA for the outer region., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study aimed to analyze the biomechanical response of the knee cartilage and meniscus to a typical Tai Chi (TC) movement, brush-knee and twist-step (BKTS). Kinematic and kinetic data was recorded while an experienced TC practitioner performed normal walking, jogging and BKTS. The kinetic data were then imported into a validated finite element model of the knee joint to examine the biomechanical response of the articular cartilage and meniscus. Compared with walking and jogging, the BKTS movement showed a greater increase in the range of motion (ROM) of the knee. The ROM in the sagittal plane was 56° (walking), 38° (jogging) and 93° (BKTS). In coronal plane, the knee ROM was 8° (walking), 11° (jogging) and 28° (BKTS). And in horizontal plane the ROM was 17° (walking), 15° (jogging) and 29° (BKTS). The finite element simulation demonstrated that the pressure contact stress is much more concentrated during walking and jogging than BKTS, which is consistent with the lower peak contact stresses recorded on the cartilage and meniscus. In conclusion, the TC movement produced a gentler stress state on the meniscus and cartilage, while also requiring a greater knee ROM. Practicing TC may have a lower risk of knee joint injury compared to walking and jogging.

Impact Statement: Meniscus injury remains the most common indication for orthopedic surgery, but loss of functioning meniscus tissue is strongly correlated with development of early osteoarthritis. However, current clinical options for tissue engineering of the meniscus are limited. This study demonstrates the feasibility of combining human meniscus cells with mesenchymal stromal cells to enhance a meniscus scaffold for meniscus regeneration in a one-stage solution for partial meniscal deficiency.

Aim: The anterior cruciate ligament (ACL) and meniscus injuries often cause post-traumatic knee osteoarthritis (PTOA), which can place great limitations on patients. But to date there is no effective therapy to delay the progression of cartilage destruction in PTOA. This study aimed to compare the effects of early versus delayed swimming exercise on the chondroprotective effects in a rat PTOA model with ACL and meniscus injuries., Main Methods: Thirty-two adult male Sprague-Dawley rats received unilateral ACL transection and medial meniscectomy (ACLMT). These were randomly allocated to four groups: early swimming (eSW), delayed swimming (dSW), sham-operated early swimming (sham-eSW) and sham-operated delayed swimming (sham-dSW). Swimming (30 min per session) continuing for 28 days was started three days and three months after ACLMT surgery as a protocol for eSW and dSW intervention. Cartilage quality was assessed by Mankin HHGS examination (H&E, Safranin-O stain) and collagen type II (CoII) and matrix metalloproteases-13 (MMP13) immunohistochemistry., Key Findings: ACLMT induced the PTOA histopathological changes, inhibited CoII and enhanced MMP13 expressions in cartilage for both sham-eSW and sham-dSW groups. eSW intervention significantly enhanced CoII expression and suppressed MMP13 overexpression in superficial and transitional zones of cartilage, as well as better Mankin scores, corresponding to sham-swimming controls (P < 0.05). dSW intervention provided less enhancement of CoII expression and improvement of histopathological scoring, but significantly reduced MMP13 overexpression compared to animals in eSW (P < 0.05)., Significance: Early intervention by swimming at very early stages of cartilage damage provides greater benefits than delayed intervention when PTOA has already developed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Meniscal injury is typically treated surgically via partial meniscectomy, which has been shown to cause cartilage degeneration in the long-term. Consequently, research has focused on meniscal prevention and replacement. However, none of the materials or implants developed for meniscal replacement have yet achieved widespread acceptance or demonstrated conclusive chondroprotective efficacy. A redesigned silk fibroin scaffold, which already displayed promising results regarding biocompatibility and cartilage protection in a previous study, was characterised in terms of its biomechanical, structural and biological functionality to serve as a potential material for permanent partial meniscal replacement. Therefore, different quasi-static but also dynamic compression tests were performed. However, the determined compressive stiffness (0.56 ± 0.31 MPa and 0.30 ± 0.12 MPa in relaxation and creep configuration, respectively) was higher in comparison to the native meniscal tissue, which could potentially disturb permanent integration into the host tissue. Nevertheless, µ-CT analysis met the postulated requirements for partial meniscal replacement materials in terms of the microstructural parameters, like mean pore size (215.6 ± 10.9 µm) and total porosity (80.1 ± 4.3%). Additionally, the biocompatibility was reconfirmed during cell culture experiments. The current study provides comprehensive mechanical and biological data for the characterisation of this potential replacement material. Although some further optimisation of the silk fibroin scaffold may be advantageous, the silk fibroin scaffold showed sufficient biomechanical competence to support loads already in the early postoperative phase., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Meniscus injuries are very common in the knee joint. Treating a damaged meniscus continues to be a scientific challenge in sport medicine because of its poor self-healing potential and few clinical therapeutic options. Tissue engineering strategies are very promising solutions for repairing and regenerating a damaged meniscus. Meniscus is exposed to a complex biomechanical microenvironment, and it plays a crucial role in meniscal development, growth, and repairing. Over the past decades, increasing attention has been focused on the use of biomechanical stimulus to enhance biomechanical properties of the engineered meniscus. Further understanding the influence of mechanical stimulation on cell proliferation and differentiation, metabolism, relevant gene expression, and pro/anti-inflammatory responses may be beneficial to enhance meniscal repair and regeneration. On the one hand, this review describes some basic information about meniscus; on the other hand, we sum up the various biomechanical stimulus based strategies applied in meniscus tissue engineering and how these factors affect meniscal regeneration. We hope this review will provide researchers with inspiration on tissue engineering strategies for meniscus regeneration in the future.

We developed customizable biomolecule functionalized 3D poly-ε-caprolactone (PCL) scaffolds reinforced with carbon nanofibers (CNF) for human meniscal tissue engineering. 3D nanocomposite scaffolds exhibited commendable mechanical integrity and electrical properties with augmented cytocompatibility. Especially, the functionalized 3D (10wt% CNF) scaffolds showed ~363% increase in compressive moduli compared to the pristine PCL. In dynamic mechanical analysis, these scaffolds achieved highest value (~42 MPa at 10 Hz) among all tested scaffolds including pristine PCL and human menisci (33, 41, 56 years). In vitro results were well supported by the outcomes of cell proliferation analysis, microscopic images, Hoechst staining and extracellular-matrix estimation. Further, in vivo rabbit bio toxicity studies revealed scaffold's non-toxicity and its future potential as a meniscus scaffold. This study also indicates that the incorporation of CNF in polymer matrix may be optimized based on mechanical properties of patient meniscus and it may help in developing the customized patient specific 3D constructs with improved multifunctional properties., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Menisci in the knee joint are thought to provide stability, increased contact area, decreased contact pressures, and offer protection to the underlying articular cartilage and bone during joint loading. Meniscal loss or injury is typically accompanied by degenerative changes in the knee, leading to an increased risk for osteoarthritis in animals including humans. However, the detailed mechanisms underlying joint degeneration and the development of osteoarthritis remain largely unknown, and the acute effects of meniscal loss have not been studied systematically. We developed a microscopy-based system to study microscale joint mechanics in living mice loaded by controlled muscular contractions. Here, we show how meniscal loss is associated with rapid chondrocyte death (necrosis) in articular cartilage within hours of injury, and how intact menisci protect chondrocytes in vivo in the presence of intense muscle-based joint loading and/or injury to the articular cartilage. Our findings suggest that loading the knee after meniscal loss is associated with extensive cell death in intact and injured knees, and that early treatment interventions should be aimed at preventing chondrocyte death.

The meniscus is the most commonly injured structure in the human knee. Meniscus deficiency has been shown to lead to advanced osteoarthritis (OA) due to abnormal mechanical forces, and replacement strategies for this structure have lagged behind other tissue engineering endeavors. The challenges include the complex 3D structure with individualized size parameters, the significant compressive, tensile and shear loads encountered, and the poor blood supply. In this progress report, a review of the current clinical treatments for different types of meniscal injury is provided. The state-of-the-art research in cellular therapies and novel cell sources for these therapies is discussed. The clinically available cell-free biomaterial implants and the current progress on cell-free biomaterial implants are reviewed. Cell-based tissue engineering strategies for the repair and replacement of meniscus are presented, and the current challenges are identified. Tissue-engineered meniscal biocomposite implants may provide an alternative solution for the treatment of meniscal injury to prevent OA in the long run, because of the limitations of the existing therapies., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hydraulic permeability is an important material property of cartilaginous tissues, governing the rate of fluid flow, which is crucial to tissue biomechanics and cellular nutrition. The effects of strain, anisotropy, and region on the hydraulic permeability in meniscus tissue have not been fully elucidated. Using a one-dimensional direct permeation test, we measured the hydraulic permeability within statically compressed porcine meniscus specimens, prepared such that the explants were in either the axial or circumferential direction of either the central or horn (axial direction only) region of the medial and lateral menisci. A constant flow was applied and the pressure difference was measured using pressure transducers. Specimens were tested under 10-20% compressive strain. Permeability values were in the range of 1.53-1.87 × 10 -15  m 4 /Ns, which is comparable to values found in the literature. Permeability was significantly anisotropic, being higher in the circumferential direction than in the axial direction. Additionally, there was a significant negative correlation between strain level and permeability for all groups. Lastly, no statistically significant difference was found between permeability coefficients from different regional locations. This study provides important information regarding structure-function relationships in meniscal tissues that helps to elucidate biomechanics and transport in the tissue, and can aid in the understanding of the tissue's role in the function of the knee joint and onset of osteoarthritis., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

To elucidate how maturation impacts the structure and mechanics of meniscus extracellular matrix (ECM) at the length scale of collagen fibrils and fibers, we tested the micromechanical properties of fetal and adult bovine menisci via atomic force microscopy (AFM)-nanoindentation. For circumferential fibers, we detected significant increase in the effective indentation modulus, E ind , with age. Such impact is in agreement with the increase in collagen fibril diameter and alignment during maturation, and is more pronounced in the outer zone, where collagen fibrils are more aligned and packed. Meanwhile, maturation also markedly increases the E ind of radial tie fibers, but not those of intact surface or superficial layer. These results provide new insights into the effect of maturation on the assembly of meniscus ECM, and enable the design of new meniscus repair strategies by modulating local ECM structure and mechanical behaviors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This study aimed to investigate the biomechanical properties of anterior cruciate ligament (ACL); tibial, femoral articular cartilage; and meniscus in knee joints receiving computer-aided or conventional ACL reconstruction. Three-dimensional (3D) knee joint finite element models were established for healthy volunteers (normal group) and patients receiving computer-aided surgery (CAS) or conventional (traditional surgery [TS]) ACL reconstruction. The stress and stress distribution on the ACL, tibial, femoral articular cartilage, and meniscus were examined after force was applied on the 3D knee joint finite element models. No significant differences were observed in the stress on ACL among normal group, CAS group, and TS group when a femoral backward force was loaded. However, when a vertical force of 350 N was loaded on the knee joints, TS group had significant higher stress on the articular cartilage and meniscus than the other two groups at any flexion angle of 0, 30, 60, and 90 degrees. However, no significant differences were observed between CAS group and normal group. In conclusion, computer-aided ACL reconstruction has advantages over conventional surgery approach in restoring the biomechanical properties of knee joints, thus reducing the risk of damage to the knee joint cartilage and meniscus after ACL reconstruction., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Meniscal pathologies are among the most common injuries of the femorotibial joint in both human and equine patients. Pathological forces and ensuing injuries of the cranial horn of the equine medial meniscus are considered analogous to those observed in the human posterior medial horn. Biomechanical properties of human menisci are site- and depth- specific. However, the influence of equine meniscus topography and composition on its biomechanical properties is yet unknown. A better understanding of equine meniscus composition and biomechanics could advance not only veterinary therapies for meniscus degeneration or injuries, but also further substantiate the horse as suitable translational animal model for (human) meniscus tissue engineering. Therefore, the aim of this study was to investigate the composition and structure of the equine knee meniscus in a site- and age-specific manner and their relationship with potential site-specific biomechanical properties. The meniscus architecture was investigated histologically. Biomechanical testing included evaluation of the shore hardness (SH), stiffness and energy loss of the menisci. The SH was found to be subjected to both age and site-specific changes, with an overall higher SH of the tibial meniscus surface and increase in SH with age. Stiffness and energy loss showed neither site nor age related significant differences. The macroscopic and histologic similarities between equine and human menisci described in this study, support continued research in this field.

Background: Lateral atlantoaxial (LAA) joints are established sources of nociceptive input in chronic whiplash associated disorder (WAD). These joints contain intra-articular meniscoids that may be damaged in whiplash trauma. LAA joint meniscoid morphology has not been investigated comprehensively in a chronic WAD population, and it is unclear whether morphological differences exist compared to a pain-free population., Objectives: This study examined LAA joint meniscoid volume in individuals with chronic WAD who report pain in a distribution consistent with LAA joint pain., Design: Case-control study., Method: Fourteen individuals with chronic WAD with pain in an LAA joint distribution (mean [SD] age 38.1 [10.8] years; six female) and 14 age- and sex-matched pain-free controls (38.0 [10.5] years) underwent cervical spine magnetic resonance imaging. LAA joint images were inspected for meniscoids; meniscoid volume was calculated in mm 3 and as a percentage of articular cavity volume. Symptom duration, location and intensity were recorded. Data were analysed using paired t-tests, Wilcoxon signed-rank testing, Spearman's rank testing, linear and logistic regression (α < 0.05)., Results: Ventral and dorsal meniscoids (n = 112) were found in each LAA joint. Greater dorsal meniscoid volume as a percentage of articular cavity volume was associated with higher pain intensity (odds ratio 1.48, p = 0.03; likelihood ratio test chi-square 2  = 6.64, p = 0.04), however no significant differences existed between meniscoid volumes of WAD and control participants., Conclusions: Findings indicate a potential link between dorsal LAA joint meniscoid volume and pain, suggesting larger meniscoid size may have pathoanatomical significance in WAD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Meniscus injuries represent one of the most-common intra-articular knee injuries. The current treatment options include meniscectomy and allograft transplantation, both with poor long-term outcomes. Therefore, there is a need for regenerative techniques to restore meniscal function. To preclinically test scaffolds for meniscus replacement, large animal models need to be established and standardized. This review establishes the anatomical and compositional similarities between human and sheep menisci and provides guidance for implantation and evaluation of such devices. The ovine meniscus represents a scaled-down version of the human meniscus, with only slight structural differences that can be addressed during device fabrication. Implantation protocols in sheep remain a challenge, as the meniscus cannot be visualized with the arthroscopic-assisted procedures commonly performed in human patients. Thus, we recommend the appropriate implantation protocols for meniscus visualization, ligamentous restoration, and surgical fixation of both total and partial meniscus replacement devices. Last, due to the lack of standardization in evaluation techniques, we recommend a comprehensive battery of tests to evaluate the efficacy of meniscus replacement implants. We recommend other investigators utilize these surgical and testing techniques to establish the ovine model as the gold standard for preclinical evaluation of meniscus replacement devices.

The kangaroo knee is, as in other species, a complex diarthrodial joint dependent on interacting osseous, cartilaginous and ligamentous components for its stability. While principal load bearing occurs through the femorotibial articulation, additional lateral articulations involving the fibula and lateral fabella also contribute to the functional arrangement. Several fibrocartilage and ligamentous structures in this joint remain unexplained or have been misunderstood in previous studies. In this study, we review the existing literature on the structure of the kangaroo 'knee' before providing a new description of the gross anatomical and histological structures. In particular, we present strong evidence that the previously described 'femorofibular disc' is best described as a fibular meniscus on the basis of its gross and histological anatomy. Further, we found it to be joined by a distinct tendinous tract connecting one belly of the m. gastrocnemius with the lateral meniscus, via a hyaline cartilage cornu of the enlarged lateral fabella. The complex of ligaments connecting the fibular meniscus to the surrounding connective tissues and muscles appears to provide a strong resistance to external rotation of the tibia, via the restriction of independent movement of the proximal fibula. We suggest this may be an adaptation to resist the rotational torque applied across the joint during bipedal saltatory locomotion in kangaroos., (© 2017 Anatomical Society.)