Osteoarthritis (OA) is the most common degenerative disease of the joints, causing significant disability and socio-economic burden in the aging population. Simultaneously, however, it is a common occurrence in younger individuals, initiated by joint injuries or obesity alongside other factors. Intravenous and oral pharmaceutical OA management have both been associated with systemic adverse effects, thereby resulting in a growing interest in intra-articular (IA) treatment. IA-administered drugs circumvent the requirement for high dosage, offering immediate access to the site of interest while minimizing any unfavorable effects. Nonetheless, IA-injected drugs, administered in their free form, present low retention time in the knee joint raising the need for multiple injection dosage regimens, while their capability to target the cartilage or specific cell populations is limited. Liposomes, due to their unique characteristics and tunable nature, have proven to be excellent candidates for the management of knee OA. This review explores the last decade's research on the efficacy of various IA liposomal formulations, investigating their multifaceted properties as pharmaceutical carriers, lubricating agents, and a basis for combinatorial approaches paving the way to novel treatment solutions for OA.

New technologies are required to support a radical shift towards preventive healthcare. Here we focus on evaluating the possibility of finite element (FE) analysis-aided prevention of knee osteoarthritis (OA), a disease that affects 100 million citizens in the US and EU and this number is estimated to increase drastically. Current clinical methods to diagnose or predict joint health status relies on symptoms and tissue failures obtained from clinical imaging. In a joint with no detectable injuries, the diagnosis of the future health of the knee can be assumed to be very subjective. Quantitative approaches are therefore needed to assess the personalized risk for the onset and development of knee OA. FE analysis utilizing an atlas-based modeling approach has shown a preliminary capability for simulating subject-specific cartilage mechanical responses. However, it has been verified with a very limited subject number. Thus, the aim of this study is to verify the real capability of the atlas-based approach to simulate cartilage degeneration utilizing different material descriptions for cartilage. A fibril reinforced poroviscoelastic (FRPVE) material formulation was considered as state-of-the-art material behavior, since it has been preliminary validated against real clinical follow-up data. Simulated mechanical tissue responses and predicted cartilage degenerations within knee joint with FRPVE material were compared against simpler constitutive models for cartilage. The capability of the atlas-based modeling to offer a feasible approach with quantitative evaluation for the risk for the OA development (healthy vs osteoarthritic knee, p < 0.01, AUC ~ 0.7) was verified with 214 knees. Furthermore, the results suggest that accuracy for simulation of cartilage degeneration with simpler material models is similar to models using FPRVE materials if the material parameters are chosen properly.

As a serious global problem, knee osteoarthritis (KOA) often leads to pain and disability. Manual therapy is widely used as a kind of physical treatment for KOA.

To explore further the efficacy of Maitland and Mulligan mobilization methods for adults with KOA.

We searched PubMed, the Cochrane Library, EMbase, Web of Science and Google Scholar from inception to September 20, 2020 to collect studies comparing Maitland and Mulligan mobilization methods in adults with KOA. The quality of the studies was assessed using the Physiotherapy Evidence Database Scale for randomized controlled trials. Data analyses were performed using Review Manager 5.0 software.

A total of 341 articles were screened from five electronic databases (PubMed, the Cochrane Library, EMbase, Web of Science and Google Scholar) after excluding duplicates. Ultimately, eight trials involving 471 subjects were included in present systematic review and meta-analysis. The mean PEDro scale score was 6.6. Mulligan mobilization was more effective in alleviating pain [standardized mean difference (SMD) = 0.60; 95% confidence interval (CI): 0.17 to 1.03, P = 0.007; I 2 = 60%, P = 0.020) and improving Western Ontario and McMaster Universities function score (SMD = 7.41; 95%CI: 2.36 to 12.47, P = 0.004; I 2 = 92%, P = 0.000). There was no difference in the effect of the two kinds of mobilization on improving the range of motion (SMD = 9.63; 95%CI: -1.23 to 20.48, P = 0.080; I 2 = 97%, P = 0.000).

Mulligan mobilization technique is a promising intervention in alleviating pain and improving function score in KOA patients.

Healthy articular cartilage, covering the ends of bones in major joints such as hips and knees, presents the most efficiently-lubricated surface known in nature, with friction coefficients as low as 0.001 up to physiologically high pressures. Such low friction is indeed essential for its well-being. It minimizes wear-and-tear and hence the cartilage degradation associated with osteoarthritis, the most common joint disease, and, by reducing shear stress on the mechanotransductive, cartilage-embedded chondrocytes (the only cell type in the cartilage), it regulates their function to maintain homeostasis. Understanding the origins of such low friction of the articular cartilage, therefore, is of major importance in order to alleviate disease symptoms, and slow or even reverse its breakdown. This progress report considers the relation between frictional behavior and the cellular mechanical environment in the cartilage, then reviews the mechanism of lubrication in the joints, in particular focusing on boundary lubrication. Following recent advances based on hydration lubrication, a proposed synergy between different molecular components of the synovial joints, acting together in enabling the low friction, has been proposed. Additionally, recent development of natural and bio-inspired lubricants is reviewed.

Knee osteoarthritis (OA) is one of the most prevalent disorders in elderly population. Among various therapeutic alternatives, we employed stromal vascular fraction (SVF), a heterogeneous cell population, to regenerate damaged knee cartilage. OA patients were classified on the basis of age, gender, body mass index (BMI), and x-ray-derived Kellgren-Lawrence (KL) grade. They were treated with SVF and followed-up for 24 months. Visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index were used to determine treatment efficacy. Cartilage healing was assessed using the MRI-based Outerbridge score (OS) and evaluation of bone marrow edema (BME) lesions, while a placebo group was used as a control. Time- and KL-dependent changes were also monitored. We observed a decreasing trend in VAS score and WOMAC index in the SVF-treated group up to 24 months, as compared with the placebo group. Besides, a significant increase and decrease in Lysholm and OS, respectively, were observed in the treatment group. Compared with the values before treatment, the greatly reduced WOMAC scores of KL3 than KL2 groups at 24 months, indicate more improvement in the KL3 group. Highly decreased BME in the treated group was also noted. In conclusion, the SVF therapy is effective in the recovery of OA patients of KL3 grade in 24 months.

Articular cartilage is commonly described as a tissue that is made of up to 80% water, is devoid of blood vessels, nerves, and lymphatics, and is populated by only one cell type, the chondrocyte. At first glance, an easy tissue for clinicians to repair and for scientists to reproduce in a laboratory. Yet, chondral and osteochondral defects currently remain an open challenge in orthopedics and tissue engineering of the musculoskeletal system, without considering osteoarthritis. Why do we fail in repairing and regenerating articular cartilage? Behind its simple and homogenous appearance, articular cartilage hides a heterogeneous composition, a high level of organisation and specific biomechanical properties that, taken together, make articular cartilage a unique material that we are not yet able to repair or reproduce with high fidelity. This review highlights the available therapies for cartilage repair and retraces the research on different biomaterials developed for tissue engineering strategies. Their potential to recreate the structure, including composition and organisation, as well as the function of articular cartilage, intended as cell microenvironment and mechanically competent replacement, is described. A perspective of the limitations of the current research is given in the light of the emerging technologies supporting tissue engineering of articular cartilage.

The mechanical properties of articular tissue reflect its functionally organised composition and the recreation of its structure challenges the success of in vitro and in vivo reproduction of the native cartilage. Tissue engineering and biomaterials science have revolutionised the way scientists approach the challenge of articular cartilage repair and regeneration by introducing the concept of the interdisciplinary approach. The clinical translation of the current approaches are not yet fully successful, but promising results are expected from the emerging and developing new generation technologies.

Traumatic impacts on the articular joint surface in vitro are known to lead to degeneration of the cartilage. The main objective of this study was to develop a spring-loaded impact device that can be used to deliver traumatic impacts of consistent magnitude and rate and to find whether impacts cause catabolic activities in articular cartilage consistent with other previously reported impact models and correlated with the development of osteoarthritic lesions. In developing the spring-loaded impactor, the operating hypothesis is that a single supraphysiologic impact to articular cartilage in vitro can affect cartilage integrity, cell viability, sulfated glycosaminoglycan and inflammatory mediator release in a dose-dependent manner.

Impacts of increasing force are delivered to adult bovine articular cartilage explants in confined compression. Impact parameters are correlated with tissue damage, cell viability, matrix and inflammatory mediator release, and gene expression 24 hours postimpact.

Nitric oxide release is first detected after 7.7 MPa impacts, whereas cell death, glycosaminoglycan release, and prostaglandin E2 release are first detected at 17 MPa. Catabolic markers increase linearly to maximal levels after ≥36 MPa impacts.

A single supraphysiologic impact negatively affects cartilage integrity, cell viability, and GAG release in a dose-dependent manner. Our findings showed that 7 to 17 MPa impacts can induce cell death and catabolism without compromising the articular surface, whereas a 17 MPa impact is sufficient to induce increases in most common catabolic markers of osteoarthritic degeneration.

In this study, we applied a spring-loaded impactor to deliver traumatic forces to articular cartilage in vivo. Based on our recent finding that a 0.28-J impact induces maximal catabolic response in adult bovine articular cartilage in vitro using this device, we hypothesize that this impact will induce the formation of a focal osteoarthritic defect in vivo.

The femoral condyle of New Zealand White rabbits was exposed and one of the following procedures performed: 0.28 J impact, anterior cruciate ligament transection, articular surface grooving, or no joint or cartilage destruction (control). After 24 hours, 4 weeks, or 12 weeks (n = 3 for each time point), wounds were localized with India ink, and tissue samples were collected and characterized histomorphometrically with Safranin O/Fast green staining and Hoechst 33342 nuclear staining for cell vitality.

The spring-loaded device delivered reproducible impacts with the following characteristics: impact area of 1.39 ± 0.11 mm(2), calculated load of 326 ± 47.3 MPa, time-to-peak of 0.32 ± 0.03 ms, and an estimated maximal displacement of 25.1% ± 4.5% at the tip apex. The impact resulted in immediate cartilage fissuring and cell loss in the surface and intermediate zones, and it induced the formation of a focal lesion at 12 weeks. The degeneration was defined and appeared more slowly than after anterior cruciate ligament transection, and more pronounced and characteristic than after grooving.

A single traumatic 0.28 J impact delivered with this spring-loaded impactor induces focal cartilage degeneration characteristic of osteoarthritis.

Because of the implications for prevention and treatment, how a clinician views osteoarthritis (OA) matters. We view OA as an attempt to contain a mechanical problem in the joint and as failed repair of damage caused by excessive mechanical stress on the joint. OA is organ failure of the synovial joint. Because of insufficient focus on reduction of the habitually loaded contact area of the joint and on aberrant loading, we believe that therapeutic efforts aimed at pathogenetic mechanisms in OA have been misdirected: neither the large role that a reduction of excessive levels of mechanical stress plays in promoting the healing response in OA nor the evidence that relief of joint pain and improvement in function, rather than the appearance of the articular surface, are the most important outcomes of the healing process have been sufficiently emphasized. Various mechanical abnormalities can trigger the processes involved in repair and attempts by the joint to contain the mechanical insult, but without a return to mechanical normality, attempts at healing will fail. In our view, drugs may be helpful symptomatically, but cannot accomplish this. In our view, as long as the joint remains in the same adverse mechanical environment that got it into trouble in the first place, it is unlikely that a drug that inhibits a specific enzyme or cytokine in the pathways of cartilage breakdown, or further stimulates the already increased synthesis of cartilage matrix molecules will solve the problem of OA. Also, because the subchondral bone is critically important in containing the mechanical abnormalities that damage the cartilage, emphasis on cartilage repair alone is likely to be futile. On the other hand, if the abnormal stresses on the joint are corrected, intervention with a structure-modifying drug may be superfluous.

Mechanical signals are key determinants in tissue morphogenesis, maintenance, and restoration strategies in regenerative medicine, although molecular mechanisms of mechanotransduction remain to be elucidated. This study was undertaken to investigate the mechanotransduction process of expression of superficial zone protein (SZP), a critical joint lubricant.

Regional expression of SZP was first quantified in cartilage obtained from the femoral condyles of immature bovines, using immunoblotting, and visualized by immunohistochemistry. Contact pressure mapping in whole joints was accomplished using pressure-sensitive film and a load application system for joint testing. Friction measurements on cartilage plugs were acquired under boundary lubrication conditions using a pin-on-disk tribometer modified for reciprocating sliding. Direct mechanical stimulation by shear loading of articular cartilage explants was performed with and without inhibition of transforming growth factor beta (TGFbeta) signaling, and SZP content in media was quantified by enzyme-linked immunosorbent assay.

An unexpected pattern of SZP localization in knee cartilage was initially identified, with anterior regions exhibiting high levels of SZP expression. Regional SZP patterns were regulated by mechanical signals and correlated with tribological behavior. Direct relationships were demonstrated between high levels of SZP expression, maximum contact pressures, and low friction coefficients. Levels of SZP expression and accumulation were increased by applying shear stress, depending on location within the knee, and were decreased to control levels with the use of a specific inhibitor of TGFbeta receptor type I kinase and subsequent phospho-Smad2/3 activity.

These findings indicate a new role for TGFbeta signaling in the mechanism of cellular mechanotransduction that is especially significant for joint lubrication.

The cyclic impacts induced by heel strike when walking were studied using both a high-resonance-frequency force plate and a low-mass skin-mounted accelerometer. The data were computer analyzed. The results showed that during normal human walking, the locomotor system is subjected to repetitive impact loads at heel strike, lasting about 5 ms and consisting of frequency spectra up to and above 100 Hz. The natural shock-absorbing structures in the musculoskeletal system have viscoelastic time-dependent mechanical behavior, which is relatively ineffective in withstanding sudden impulsive loads. Degenerative joint diseases may thus be seen as a late clinical result of fatigue failure of the natural shock absorbers, submitted to deleterious impacts over a period of time.

Friction measurements were performed on fractions prepared from bovine synovial fluid by using a cartilage on glass apparatus. A fraction containing lubricating glycoprotein-I (LGP-I) as the only detectable component at concentrations of 30-50 microgram/ml was able to lubricate in an identical manner to whole synovial fluid. These data indicate that LGP-I is th molecule responsible for the lubricating ability of synovial fluid. 125Iodine-labeled LGP-I also lubricated in a manner similar to synovial fluid, whereas when this sample was reduced and alkylated or treated with neuraminidase, the lubricating activity was greatly decreased. In tests to measure binding of 125I LGP-I to cartilage, an initial linear increase in binding was observed, followed by a decrease in binding at higher concentrations. In contrast, both the reduced and alkylated and the neuraminidase treated samples did not show the same concentration-dependent binding to the cartilage. It is suggested, therefore, that at least part of the lubricating ability of LGP-I is dependent upon its ability to bind to articular cartilage.

A mechanochemical method was developed for studying the enzymatic degradation of insoluble collagen fibers. The method involves stretching the collagen fiber to a fixed extension in the presence of a solution of collagenase and measuring the rate of relaxation of the force induced in the fiber. In this work, bacterial collagenase was used for reasons of availability. We observed invariably an exponential decrease in force with respect to ttime. The slope of the linear plot of logarithm of the force versus time was taken as a measure of the rate of enzymatic degradation. This rate was found a) to vary linearly with collagenase concentration; b) to be maximal at pH 7-8; c) to vary with temperature according to the Arrhenius relationship in the range 10-56 degrees C; d) to be reduced to varying extent by addition of EDTA omicron-phenanthroline, 2,3-dimercaptopropanolol, and D,L-cysteine; e) to be minimal when the strain on the fiber was ca. 4%; f) to be increased dramatically by denaturation of the collagen fiber; and g) to be reduced by an increase in the crosslink density of the collagen fiber. Except for the effect of strain, which can not be conveniently studied by existing methods these results are consistent with those observed by other methods for the study of the enzymatic degradation of collagen. The mechanochemical method is, however, uniquely suited to monitor continuously the enzymatically induced decay in the stress-bearing ability of collagen fibers. It has also been found useful in the design of collagenous implants with specified resistance to enzymatic degradation in vivo.