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Background. Development of pre-clinical models of long-lasting inflammation is needed for the study of inflammatory diseases. Osteoarthritis (OA), the most common inflammatory joint pathology, is characterized by an abundance of M1-like macrophages producing several pro-inflammatory cytokines and proteolytic enzymes damaging the local tissues. Here we developed a novel in vitro model of long-lasting inflammation using primary human monocyte-derived macrophages continuously cultured for 15 days. Results. We first screened synovial fluids from 11 OA patients using multiplex Ella® and we found measurable levels of IL-6, CCL2, CCL5, CXCL8, CXCL10, TNFa, IL-1b, using them as read-outs of the following experiments. We then found an increased survival of macrophages differentiated with both M-CSF and GM-CSF (M-/GM-Mf) compared either with macrophages differentiated with M-CSF alone (M-Mf) or macrophages differentiated with GM-CSF alone (GM-Mf) and, consequently, decided to use them to set up the in vitro model of long-lasting inflammation. Consistently with the increased survival, the repeated stimulation of M-/GM-Mfs either with lipopolysaccharide + interferon-g (LPS+IFN-g) or Pam3CysSerLys4 (Pam3CSK4) led to the sustained production of IL-6, CCL2 and CXCL8 over time. Finally, to investigate the usefulness of our model for OA research, we repeatedly exposed stimulated macrophages to dexamethasone (DEX) and/or celecoxib (CEL), two anti-inflammatory drugs commonly used for OA therapy. We found an excellent anti-inflammatory activity but significant toxicity of DEX for concentrations over 10 nM, while CEL was not toxic and efficiently inhibited PGE2 secretion. Of interest, the inflammatory profile of macrophages differentiated with M-CSF or GM-CSF and activated with the two pro-inflammatory stimuli (LPS+IFN-g vs Pam3CSK4) was not identical, overall showing production of more inflammatory mediators with GM-CSF-macrophages stimulated with Pam3CSK4. Conclusions. We introduce here a novel easy-to-use in vitro culture model of long-lasting inflammation using primary human macrophages, that could be useful for the screening of new compounds and drug delivery systems, to improve the therapy of inflammatory disorders.

The study investigated the existing guidelines on the quality and frequency of the follow-up visits after total hip replacement surgery and assessed the level of evidence of these recommendations. The review process was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Additional works were retrieved by direct investigation of the available guidelines of the most important orthopedic societies and regulatory agencies. The current systematic review of the literature resulted in zero original papers, four guidelines for routine follow-up and three guidelines for special cases. Concerning the quality of evidence behind them, these guidelines were not evidence based but drafted from expert consensus. The most important finding of this review is the large variation of recommendations in the follow-up schedule after total hip arthroplasty and the lack of evidence-based indications. Indeed, all the above-reported guidelines are the result of a consensus among experts in the field (level of recommendation class D ‘very low’) and not based on clinical studies.

The aims of the present study were: (1) to characterize the bone-marrow aspirate (BMA) obtained with a centrifuge-free process, employing a dedicated aspiration device; (2) to test the in vitro efficacy of BMA in a model of cartilage inflammation; and (3) to report the preliminary clinical results in a small cohort of patients affected by knee OA. Ten patients (4 M, 6 W; mean age: 51.9 ± 9.2 yy) affected by mild to moderate unicompartmental knee OA (KL grade 2–3) were treated by intra-articular and subchondral injections of BMA obtained by a centrifuge-free process. To evaluate the effectiveness of the device in harvesting mesenchymal stem cells (MSCs), samples of the obtained BMA were tested by flow cytometry before and after subculture; BMA ability to counteract inflammation was also tested in an in vitro model of cartilage cell inflammation, evaluating the expression of MMP1, MMP3, TGFβ and TIMP-1 by real-time PCR. Patients were also evaluated up to two years’ follow-up by using: VAS for pain, IKDC-subjective and KOOS scores. The laboratory analysis showed that BMSCs accounted for 0.011% of BMA cells, similar to what had been expected in native bone marrow. The paracrine activity of BMA was able to reduce in vitro the catabolic response of human chondrocyte, as shown by the decrease in metalloproteases concentration and increase in anti-inflammatory mediators. Moreover, the clinical evaluation showed significant improvements in all scores adopted, with stable results up to two years. The present data showed the effectiveness of the study device to harvest pure bone marrow with minimal peripheral blood contamination. The relevant content of MSCs resulted in the ability to counteract the catabolic cascade through a paracrine action. The clinical outcomes in patients affected by unicompartmental knee OA were encouraging in terms of pain reduction and functional improvement up to mid-term evaluation.

Objective: Cemented total knee arthroplasty still represents the reference standard in the field of prothesis knee replacement; but since cementless total knee arthroplasties were introduced there have been strong discussions over the years among cemented and non-cemented total knee arthroplasties to establish which gives the best benefits for the patient and for the surgeon. The purpose of this meta-analysis is to systematically analyze the use of cemented and cementless total knee arthroplasties by investigating clinical and radiological outcomes and rate of complications, in order to assess which techniques confers more benefits to the patient and the surgeon. Materials and Methods: The current systematic review has been written in accordance to the Cochrane handbook and the PRISMA statement for reporting of systematic reviews incorporating network. Results: Six randomized controlled trials were finally included in this systematic review. The statistical analysis revealed no significant differences in all clinical scores of interest (Knee Society Score, clinical and functional, Oxford Knee Score, Visual Analogue Score) and a similar revision rate. Conclusion: the results of the current metanalysis suggest the non-inferiority of cementless fixation with respect to cemented total knee arthroplasties in terms of clinical outcomes and survival rates of the implants.

Knee osteoarthritis is a degenerative condition characterized by progressive cartilage degradation, subchondral damage, and bone remodelling. Among the approaches implemented to achieve symptomatic and functional improvements, injection treatments have gained increasing attention due to the possibility of intra-articular delivery with reduced side effects compared to systemic therapies. In addition to well-established treatment options such as hyaluronic acid (HA), cortico-steroids (CS) and oxygen-ozone therapy, many other promising products have been employed in the last decades such as polydeoxyribonucleotide (PDRN) and biologic agents such as platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs). Moreover, ultrasound-guided intra-meniscal injection and X-ray-guided subchondral injection techniques have been introduced into clinical practice. Even when not supported by high evidence consensus, intra-articular CS and HA injections have gained precise indications for symptomatic relief and clinical improvement in OA. Biological products are strongly supported by in vitro evidence but there is still a lack of robust clinical evidence. PRP and MSCs seem to relieve OA symptoms through a regulation of the joint homeostasis, even if their capability to restore articular cartilage is still to be proved in vivo. Due to increasing interest in the subchondral bone pathology, subchondral injections have been developed with promising results in delaying joint replacement. Nevertheless, due to their recent development and the heterogeneity of the injected products (biologic agents or calcium phosphate), this approach still lacks strong enough evidence to be fully endorsed. Combined biological treatments, nano-molecular approaches, monoclonal antibodies and ‘personalized’ target therapies are currently under development or under investigation with the aim of expanding our armamentarium against knee OA. Cite this article: EFORT Open Rev 2021;6:501-509. DOI: 10.1302/2058-5241.6.210026

Many efforts have been made in the field of nanotechnology to improve the local and sustained release of drugs, which may be helpful to overcome the present limitations in the treatment of knee OA. Nano-/microparticles and/or hydrogels can be now engineered to improve the administration and intra-articular delivery of specific drugs, targeting molecular pathways and pathogenic mechanisms involved in OA progression and remission. In order to summarize the current state of this field, a systematic review of the literature was performed and 45 relevant studies were identified involving both animal models and humans. We found that polymeric nanoparticles loaded with anti-inflammatory drugs (i.e., dexamethasone or celecoxib) are the most frequently investigated drug delivery systems, followed by microparticles and hydrogels. In particular, the nanosystem most frequently used in preclinical research consists of PLGA-nanoparticles loaded with corticosteroids and non-steroidal anti-inflammatory drugs. Overall, improvement in histological features, reduction in joint inflammation, and improvement in clinical scores in patients were observed. The last advances in the field of nanotechnology could offer new opportunities to treat patients affected by knee OA, including those with previous meniscectomy. New smart drug delivery approaches, based on nanoparticles, microparticles, and hydrogels, may enhance the therapeutic potential of intra-articular agents by increasing the permanence of selected drugs inside the joint and better targeting specific receptors and tissues.

Osteoarthritis (OA) is the most common joint pathology causing severe pain and disability. Macrophages play a central role in the pathogenesis of OA. In the joint microenvironment, macrophages with an M1-like pro-inflammatory phenotype induce chronic inflammation and joint destruction, and they have been correlated with the development and progression of the disease, while the M2-like anti-inflammatory macrophages support the recovery of the disease, promoting tissue repair and the resolution of inflammation. Nowadays, the treatment of OA in the clinic relies on systemic and/or intra-articular administration of anti-inflammatory and pain relief drugs, as well as surgical interventions for the severe cases (i.e., meniscectomy). The disadvantages of the pharmacological therapy are related to the chronic nature of the disease, requiring prolonged treatments, and to the particular location of the pathology in joint tissues, which are separated anatomical compartments with difficult access for the drugs. To overcome these challenges, nanotechnological approaches have been investigated to improve the delivery of drugs toward macrophages into the diseased joint. This strategy may offer advantages by reducing off-target toxicities and improving long-term therapeutic efficacy. In this review, we describe the nanomaterial-based approaches designed so far to directly or indirectly manipulate macrophages for the treatment of osteoarthritis.