Effects and mechanotransduction pathways of therapeutic ultrasound on healthy and osteoarthritic chondrocytes: a systematic review of in vitro studies.

OBJECTIVE: To investigate the effects and mechanotransduction pathways of therapeutic ultrasound on chondrocytes. METHOD: PubMed, EMBASE and Web of Science databases were searched up to 19th September 2021 to identify in vitro studies exploring ultrasound to stimulate chondrocytes for osteoarthritis (OA) treatment. Study characteristics, ultrasound parameters, in vitro setup, and mechanotransduction pathways were collected. Risk of bias was judged using the Risk of Bias Assessment for Non-randomized Studies (RoBANS) tool. RESULTS: Thirty-one studies were included comprising healthy and OA chondrocytes and explants. Most studies had high risk of performance, detection and pseudoreplication bias due to lack of temperature control, setup calibration, inadequate semi-quantitatively analyzes and independent experiments. Ultrasound was applied to the culture plate via acoustic gel, water bath or culture media. Regardless of the setup used, ultrasound stimulated the cartilage production and suppressed its degradation, although the effect size was nonsignificant. Ultrasound inhibited p38, c-Jun N-terminal kinases (JNK) and factor nuclear kappa B (NFκB) pathways in OA chondrocytes to reduce apoptosis, inflammation and matrix degradation, while triggered phosphoinositide-3-kinase/akt (PI3K/Akt), extracellular signal-regulated kinase (ERK), p38 and JNK pathways in healthy chondrocytes to promote matrix synthesis. CONCLUSION: The included studies suggest that ultrasound application induces therapeutic effects on chondrocytes. However, these results should be interpreted with caution because high risk of performance, detection and pseudoreplication bias were identified. Future studies should explore the application of ultrasound on human OA chondrocytes cultures to potentiate the applicability of ultrasound towards cartilage regeneration of knee with OA.

Hyaluronic Acid.

In recent times, the field of tissue engineering and regenerative medicine (TERM) has considerably increased the extent of therapeutic strategies for clinical application in orthopedics. However, TERM approaches have its rules and requirements, in the respect of the biologic response of each tissue and bioactive agents which need to be considered, respected, and subject of ongoing studies. Different medical devices/products have been prematurely available on the market and used in clinics with limited success. However, other therapeutics, when used in a serious and evidence-based approach, have achieved considerable success, considering the respect for solid expectations from doctors and patients (when properly informed).Orthobiologics has appeared as a recent technological trend in orthopedics. This includes the improvement or regeneration of different musculoskeletal tissues by means of using biomaterials (e.g., hyaluronic acid), stem cells, and growth factors (e.g., platelet-rich plasma). The potential symbiotic relationship between biologic therapies and surgery makes these strategies suitable to be used in one single intervention.However, herein, the recent clinical studies using hyaluronic acid (HA) in the treatment of orthopedic conditions will mainly be overviewed (e.g., osteochondral lesions, tendinopathies). The possibilities to combine different orthobiologic agents as TERM clinical strategies for treatment of orthopedic problems will also be briefly discussed.

Tears of popliteomeniscal fascicles, diagnostic and clinical implications. A review of the evidence.

Postero-lateral corner of the knee is composed of several structures including the popliteo-meniscal fascicles (PMFs). These fibrous structures form a stable ligamentous complex around the popliteus tendon, which stabilize the lateral meniscus, increasing the strength of postero-lateral corner. Studies were retrieved through an electronic search of CINAHL, EMBASE, and Pub-Med, until May 2016. Studies in English, Italian, French, and Spanish were considered for inclusion. Randomized controlled trials, prospective and retrospective comparative studies, case series, and case reports were included. Studies eligible for inclusion concerned PMFs anatomy, biomechanics, diagnostic assessment of PMFs tears and clinical options for tears management. Thirteen studies were included in this review. There were: 7 case series, 4 case reports and 3 anatomical studies. Through anatomic dissection, two or three PMFs (antero-inferior fascicle, aiPMF; postero-superior fascicle, psPMF; postero-inferior fascicle, piPMF) can be indentified and isolated. Evaluation through MRI can be a useful diagnostic tool in detecting PMFs tears, especially using proton density (PD) sequences. The biomechanical analysis assessed that lateral meniscus (LM) motion is directly related with PMFs integrity and increased with section of one or both the fascicles. The clinical studies clearly state that a snapping syndrome, associated with lateral knee pain, can develop when one or both PMFs are torn. The three PMFs described are considered as relevant components of the popliteal hiatus, in the posterolateral aspect of the knee. MRI evaluation can detect these fibrous fascicles with good sensitivity. More studies with larger samples would be needed for a clear comprehension of PMFs function and clinical management of PMFs tears, especially with large case series and modern biomechanical testing.

Pain reduction and improvement of function following ultrasound-guided intra-articular injections of triamcinolone hexacetonide and hyaluronic acid in hip osteoarthritis.

The scientific literature has shown positive results regarding intra-articular injections of hyaluronic acid in osteoarthritic joints. When injecting in the hip joint, the guidance of ultrasound can provide higher injection accuracy and repeatability. However, due to the methodological limitations in the current available literature, its recommendation in the current practice is still controversial. This study shows that ultrasound-guided intra-articular injections of triamcinolone hexacetonide and hyaluronic acid can improve pain, function and quality of life in patients with symptomatic and radiographic hip osteoarthritis. In addition, the administration of triamcinolone hexacetonide and hyaluronic acid to the hip joint in these patients can delay the need for interventional surgery.

Sport and early osteoarthritis: the role of sport in aetiology, progression and treatment of knee osteoarthritis.

Sports activities are considered favourable for general health; nevertheless, a possible influence of sports practice on the development of early osteoarthritis (OA) is a cause for concern. A higher incidence of OA in knees and ankles of former high-impact sports players than in those of the normal population has been shown and it is still debatable whether the cause is either to be recognized generically in the higher number of injuries or in a joint overload. The possibility to address knee OA in its early phases may be strictly connected to the modification of specific extrinsic or intrinsic factors, related to the patient in order to save the joint from further disease progression; these include sport practice, equipment and load. Non-surgical therapies such as continuative muscles reinforce and training play a strong role in the care of athletes with early OA, particularly if professional. There is an overall agreement on the need of an early restoring of a proper meniscal, ligament and cartilage integrity in order to protect the knee and resume sports safely, whereas alignment is a point still strongly debatable especially for professional athletes. Remaining questions still to be answered are the risks of different sports in relation to one another, although an actual protective effect of low-impact sports, such as walking, swimming or cycling, has been recognized on the appearance or worsening of OA, the effect of continuing or ceasing to practice a sport on the natural history of early OA, and even following appropriate treatment is still unknown.

Animal model for chronic massive rotator cuff tear: behavioural and histologic analysis.

PURPOSE: Massive rotator cuff tears (MRCT) are usually chronic lesions that present associated degenerative changes of the myotendinous unit that have been implicated in limitations for surgical repair. In order to develop effective therapies, it is important to establish animal models that mimic the hallmarks of the injury itself. Therefore, in the present work, we aimed to (1) optimize a rodent animal model of MRCT that closely reproduces the fatty infiltration of the cuff muscles seen in humans and (2) describe the effects of unilateral or bilateral lesion in terms of histology and behaviour. METHODS: Massive tear was defined as two rotator cuff tendons-supraspinatus and infraspinatus-section. Twenty-one Wistar rats were randomly assigned to four groups: bilateral lesion (five animals), right-sided unilateral lesion (five animals), left-sided unilateral lesion (five animals) and control (six animals). Behaviour was analyzed with open field and staircase test, 16 weeks after lesion. After that, animals were killed, and the supraspinatus and infraspinatus muscles were processed. RESULTS: Histologic analysis revealed adipocytes, fatty infiltration and atrophy in the injured side with a greater consistency of these degenerative changes in the bilateral lesion group. Behaviour analysis revealed a significant functional impairment of the fine motor control of the forepaw analyzed in staircase test where the number of eaten pellets was significantly higher in sham animals (sham = 7 ± 5.0; left unilateral = 2.6 ± 3.0; right unilateral = 0 ± 0; and bilateral = 0 ± 0, p < 0.05). A trend to reach a lower level of steps, in more injured animals, was also observed (sham animals = 3 ± 1.6 > left unilateral = 2 ± 2.1 > right unilateral = 0.8 ± 1.3 > bilateral = 0.8 ± 1.1). CONCLUSIONS: The present study has been able to establish an animal model that disclosed the hallmarks of MRCT. This can now be used as a valuable, cost-effective, pre-clinical instrument to assist in the development of advanced tissue engineered strategies. Moreover, this animal model overcomes some of the limitations of those that have been reported so far and thus represents a more reliable source for the assessment of future therapeutic strategies with potential clinical relevance.

Biomechanical and cellular segmental characterization of human meniscus: building the basis for Tissue Engineering therapies.

OBJECTIVE: To overcome current limitations of Tissue Engineering (TE) strategies, deeper comprehension on meniscus biology is required. This study aims to combine biomechanical segmental analysis of fresh human meniscus tissues and its correlation with architectural and cellular characterization. METHOD: Morphologically intact menisci, from 44 live donors were studied after division into three radial segments. Dynamic mechanical analysis (DMA) was performed at physiological-like conditions. Micro-computed tomography (CT) analysis of freeze-dried samples assessed micro-structure. Flow cytometry, histology and histomorphometry were used for cellular study and quantification. RESULTS: Anterior segments present significantly higher damping properties. Mid body fresh medial meniscus presents higher values of E' compared to lateral. Cyclic loads influence the viscoelastic behavior of menisci. By increasing the frequency leads to an increase in stiffness. Conversely, with increasing frequencies, the capacity to dissipate energy and damping properties initially decrease and then rise again. Age and gender directly correlate with higher E' and tan δ. Micro-CT analysis revealed that mean porosity was 55.5 (21.2-89.8)% and 64.7 (47.7-81.8)% for freeze-dried lateral and medial meniscus, respectively. Predominant cells are positive for CD44, CD73, CD90 and CD105, and lack CD31, CD34 and CD45 (present in smaller populations). Histomorphometry revealed that cellularity decreases from vascular zone 1 to zone 3. Anterior segments of lateral and medial meniscus have inferior cellularity as compared to mid body and posterior ones. CONCLUSION: Menisci are not uniform structures. Anterior segments have lower cellularity and higher damping. Cyclic loads influence viscoelastic characteristics. Future TE therapies should consider segmental architecture, cellularity and biomechanics of fresh tissue.

Surgical treatment for early osteoarthritis. Part I: cartilage repair procedures.

Young patients with early osteoarthritis (OA) represent a challenging population due to a combination of high functional demands and limited treatment options. Conservative measures such as injection and physical therapy can provide short-term pain relief but are only palliative in nature. Joint replacement, a successful procedure in the older population, is controversial in younger patients, who are less satisfied and experience higher failure rates. Therefore, while traditionally not indicated for the treatment of OA, cartilage repair has become a focus of increased interest due to its potential to provide pain relief and alter the progression of degenerative disease, with the hope of delaying or obviating the need for joint replacement. This review of cartilage repair techniques will discuss currently available procedures, specifically pertaining to experiences in the setting of early OA. Level of evidence IV.

Posterior talar process as a suitable cell source for treatment of cartilage and osteochondral defects of the talus.

Osteochondral defects of the ankle are common lesions affecting the talar cartilage and subchondral bone. Current treatments include cell-based therapies but are frequently associated with donor-site morbidity. Our objective is to characterize the posterior process of the talus (SP) and the os trigonum (OT) tissues and investigate their potential as a new source of viable cells for application in tissue engineering and regenerative medicine. SP and OT tissues obtained from six patients were characterized by micro-computed tomography and histological, histomorphometric and immunohistochemical analyses. Proliferation and viability of isolated cells were evaluated by MTS assay, DNA quantification and live/dead staining. The TUNEL assay was performed to evaluate cell death by apoptosis. Moreover, the production of extracellular matrix was evaluated by toluidine blue staining, whereas cells phenotype was investigated by flow cytometry. Characterization of ankle explants showed the presence of a cartilage tissue layer in both SP and OT tissues, which represented at least 20%, on average, of the explant. The presence of type II collagen was detected in the extracellular matrix. Isolated cells presented a round morphology typical of chondrocytes. In in vitro studies, cells were viable and proliferating for up to 21 days of culture. No signs of apoptosis were detected. Flow-cytometry analysis revealed that isolated cells maintained the expression of several chondrocytic markers during culture. The results indicated that the SP and OT tissues were a reliable source of viable chondrocytes, which could find promising applications in ACI/MACI strategies with minimal concerns regarding donor zone complications. Copyright © 2015 John Wiley & Sons, Ltd.

Cartilage Repair Using Hydrogels: A Critical Review of in Vivo Experimental Designs.

This review analyzes the outcomes and technical aspects of in vivo studies published in the past decade using gels and hydrogels for cartilage repair. Using PubMed search engine, original research publications during the period of 2002/01/01 to 2015/04/30 identified 115 published papers. Of these, 3 studies failed to find a statistically significant improvement of treatment group as compared to control and 18 studies did not clearly identify hyaline-like cartilage formation in the treated groups. The most frequent repaired lesion was the rabbit acute full thickness trochlear defect, using a scaffold combining a gel or hydrogel and other material. One third of the scaffolds were cell-free (35%) and the majority of the studies did not use growth factors (71%). The present review may constitute a useful tool in design of future studies, as limitations of study designs are pointed and results in terms of translation to human application is discussed.

Current concepts: tissue engineering and regenerative medicine applications in the ankle joint.

Tissue engineering and regenerative medicine (TERM) has caused a revolution in present and future trends of medicine and surgery. In different tissues, advanced TERM approaches bring new therapeutic possibilities in general population as well as in young patients and high-level athletes, improving restoration of biological functions and rehabilitation. The mainstream components required to obtain a functional regeneration of tissues may include biodegradable scaffolds, drugs or growth factors and different cell types (either autologous or heterologous) that can be cultured in bioreactor systems (in vitro) prior to implantation into the patient. Particularly in the ankle, which is subject to many different injuries (e.g. acute, chronic, traumatic and degenerative), there is still no definitive and feasible answer to 'conventional' methods. This review aims to provide current concepts of TERM applications to ankle injuries under preclinical and/or clinical research applied to skin, tendon, bone and cartilage problems. A particular attention has been given to biomaterial design and scaffold processing with potential use in osteochondral ankle lesions.

Anatomy of the proximal tibiofibular joint.

This paper describes the anatomy and function of the proximal tibiofibular joint (PTFJ). The physical dimensions of the joint and the topology of the articular surfaces are described. It is noted that the inclination of the joint is variable, and that joints with a steeper slope away from the transverse plane are less mobile. The ligamentous and tendinous attachments are described. Finally, the histological features of the articular surfaces are presented. The clinical importance of the anatomical features is discussed.