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There has been considerable advancement over the last few years in the treatment of osteoarthritis, common chronic disease and a major cause of disability in older adults. In this pathology, the entire joint is involved and the regeneration of articular cartilage still remains one of the main challenges, particularly in an actively inflammatory environment. The recent strategies for osteoarthritis treatment are based on the use of different therapeutic solutions such as cell and gene therapies and tissue engineering. In this review, we provide an overview of current regenerative strategies highlighting the pros and cons, challenges and opportunities, and we try to identify areas where future work should be focused in order to advance this field.

Articular cartilage injuries are common in the population. The increment in the elderly people and active life results in an increasing demand for new technologies and good outcomes to satisfy longer and healthier life expectancies. However, because of cartilage's low regenerative capacity, finding an efficacious treatment is still challenging for orthopedics. Since the pioneering studies based on autologous cell transplantation, regenerative medicine has opened new approaches for cartilage lesion treatment. Tissue engineering combines cells, biomaterials, and biological factors to regenerate damaged tissues, overcoming conventional therapeutic strategies. Cells synthesize matrix structural components, maintain tissue homeostasis by modulating metabolic, inflammatory, and immunologic pathways. Scaffolds are well acknowledged by clinicians in regenerative applications since they provide the appropriate environment for cells, can be easily implanted, reduce surgical morbidity, allow enhanced cell proliferation, maturation, and an efficient and complete integration with surrounding articular cartilage. Growth factors are molecules that facilitate tissue healing and regeneration by stimulating cell signal pathways. To date, different cell sources and a wide range of natural and synthetic scaffolds have been used both in pre-clinical and clinical studies with the aim to find the suitable solution for recapitulating cartilage microenvironment and inducing the formation of a new tissue with the biochemical and mechanical properties of the native one. Here, we describe the current concepts for articular cartilage regeneration, highlighting the key actors of this process trying to identify the best perspectives.

Joint pain and arthralgia can be manifestations of COVID-19, and studies evaluating long COVID symptoms identified the persistence of these disorders. Moreover, some case reports highlighted the development of new inflammatory arthritis in patients with COVID-19, suggesting a possible relation. Viral infections and rheumatic diseases share a documented relationship; they have been associated with genetic and environmental risk factors responsible for some of them. There is crosstalk between viruses and the immune system during the development of several rheumatic diseases. Moreover, infections may participate in the pathogenesis of autoimmune rheumatic diseases and contribute to patient mortality. Therefore, it is crucial to provide a clearer insight into the interaction between viral infections and rheumatic diseases. Here, we provide a mini-review of the current literature with the aim of shedding light on the relationship between COVID-19 and rheumatic or musculoskeletal diseases, which is still unclear. Specifically, we examined several aspects: risk for the rheumatic population of acquiring the virus or developing severe symptoms, similarities of COVID-19 and arthritis, the possible rheumatic consequence of COVID-19, of rheumatic drugs and vaccines, and COVID-19 prevention in rheumatic patients through vaccination.

Osteoarthritis is a significant global problem, causing pain and limitations, and contributing to socioeconomic expenses. The etiopathogenesis of this disease encloses genetic, biological, and mechanical aspects. Regenerative medicine, utilizing tissue engineering, has opened the way to new therapeutic approaches employing various orthobiologics. Combined with hydrogels, these compounds may represent a notable option for treating degenerative and inflammatory lesions in OA. The review reports on the main orthobiologics used in preclinical and clinical studies, as well as their association with various types of natural and synthetic hydrogels. Research may increasingly focus on tailored therapies adjusted to suit the joint involved and the severity of the pathology encountered in each patient.

Background: The treatment of articular cartilage damage has always represented a problem of considerable practical interest for orthopedics. Over the years, many surgical techniques have been proposed to induce the growth of repairing tissue and limit degeneration. In 1994, the turning point occurred: implanted autologous cells paved the way for a new treatment option based more on regeneration than repair. Objectives: This review aims to outline biological and clinical advances, from the use of mature adult chondrocytes to cell-derived products, going through progenitor cells derived from bone marrow or adipose tissue and their concentrates for articular cartilage repair. Moreover, it highlights the relevance of gene therapy as a valuable tool for successfully implementing current regenerative treatments, and overcoming the limitations of the local delivery of growth factors. Conclusions: Finally, this review concludes with an outlook on the importance of understanding the role and mechanisms of action of the different cell compounds with a view to implementing personalized treatments.

Adipose-derived cell therapies are one of the most common regenerative therapeutic options to alleviate the multi-component damage of osteoarthritis (OA). Adipose stromal vascular fraction (SVF) has gained scientific consensus for its ability to interact protectively with the joint microenvironment. Recently, the wide range of enzyme-free tissue processing systems has outperformed classical treatments, because of their ability to produce connective micrografts enriched with the SVF (mctSVF). This preclinical study evaluates the chondroprotective potential of a newly generated mctSVF compared with expanded adipose stromal cells (ASC) in OA. A mild grade of OA was induced through bilateral anterior cruciate ligament transection (ACLT) surgery in 32 Specific Pathogen Free (SPF) Crl: KBL (NZW) male rabbits followed by the surgical excision of inguinal adipose tissue. After 2 months, OA joints were treated with an intra-articular (IA) injection of mctSVF or ASC. Local biodistribution analysis was used to determine migration patterns of PKH26-labelled cells in the knee joint after 1 month. Efficacy was assessed by gross analysis, histology and immunohistochemistry on the osteochondral unit, synovial membrane and meniscus. We elucidate the effectiveness of a one-step approach based on mechanical isolation of mctSVF. Through epifluorescence analysis, we found a similar pattern of cell distribution between cell treatments, mainly towards articular cartilage. Similar regenerative responses were observed in all experimental groups. These effects included: (i) osteochondral repair (promotion of typical anabolic markers and reduction of catabolic ones); (ii) reduction of synovial reactions (reduced synovial hypertrophy and inflammation, and change of macrophage phenotype to a more regenerative one); and (iii) reduction of degenerative changes in the meniscus (reduction of tears). Our study demonstrates the validity of a novel mechanical system for the generation of the mctSVF micrograft with chondroprotective potential in a preclinical model of moderate OA. The resulting final product can counteract inflammatory processes beyond the OA microenvironment and protect cartilage through the colonization of its structure. The intact and active microanatomy of mctSVF makes it a suitable candidate for translational medicine to treat OA without the need for cell manipulation as with ASC.

(1) Background: Synovial tissue plays a fundamental role in inflammatory processes. Therefore, understanding the mechanisms regulating healthy and diseased synovium functions, as in rheumatic diseases, is crucial to discovering more effective therapies to minimize or prevent pathological progress. The present study aimed at developing a bioartificial synovial tissue as an in vitro model for drug screening or personalized medicine applications using 3D bioprinting technology. (2) Methods: The volumetric extrusion technique has been used to fabricate cell-laden scaffolds. Gelatin Methacryloyl (GelMA), widely applied in regenerative medicine and tissue engineering, was selected as a bioink and combined with an immortalized cell line of fibroblast-like synoviocytes (K4IM). (3) Results: Three different GelMA formulations, 7.5–10–12.5% w/v, were tested for the fabrication of the scaffold with the desired morphology and internal architecture. GelMA 10% w/v was chosen and combined with K4IM cells to fabricate scaffolds that showed high cell viability and negligible cytotoxicity for up to 14 days tested by Live & Dead and lactate dehydrogenase assays. (4) Conclusions: We successfully 3D bioprinted synoviocytes-laden scaffolds as a proof-of-concept (PoC) towards the fabrication of a 3D synovial membrane model suitable for in vitro studies. However, further research is needed to reproduce the complexity of the synovial microenvironment to better mimic the physiological condition.

(1) Background: Osteonecrosis (ON) of the femoral head is a disabling disease for which limited treatment options exist. Identifying therapeutic targets of its evolution could provide crucial insights into multi-targeted approaches. The aim of this pilot study was to assess the histopathological features of patients with non-traumatic femoral head (NTFH) and post-traumatic femoral head (PTFH) ON to produce a fresh vision for clinical use. (2) Methods: We got biopsies from patients with different ON stages, according to the ARCO system. Samples from multi-organ donors were used as controls. Histological and immunohistochemical evaluations were performed on the osteochondral unit. (3) Results: The PTFH group displayed several fibrotic reactions, a small stem cell pool and a lower international cartilage repair society (ICRS)-I score than NTFH, which instead presented intact cartilage similar to the controls. Immunostaining for collagen I and autotaxin confirmed these features in the PTFH group, which displayed top levels of MMP-13 involved in cartilage loss and reduced CB-2 in the underlying bone. Both groups manifested a similar pattern of apoptotic and pain mediators. (4) Conclusions: The different histopathological features suggest a multi-disciplinary and multi-targeted approach for ON. Further studies are necessary to measure the effect size to gain clinical evidence.

Background: Research in the fields of musculoskeletal tissue engineering and regenerative medicine may suffer a slowdown during the ongoing COVID-19 pandemic emergency. This is likely to harm the development of new therapeutic strategies and their translation into the clinic in the long term. Recently, the need to maintain continuity in research activities in those fields has assumed even greater importance due to the accumulation of data concerning the effects of SARS-CoV-2 on the musculoskeletal system. This study is aimed at the identification of a series of safe handling practices against COVID-19 diffusion to apply in a research environment, thus allowing the maintenance of research lab activities. Methods: The control measures to apply to mitigate the COVID-19 risk were identified and categorized utilizing the Hierarchy of Controls. We also compared our analysis with that assessed before the pandemic to consider the additional risk of COVID-19. Results: Results highlighted that the most relevant implemented measures to control SARS-CoV-2 were based on protecting people through engineering (e.g., ventilation and social distancing), and administrative (e.g., hand sanitization, work shifts) measures or Personnel Protective Equipment, rather than eliminating hazards at the source (e.g., smart working). Conclusions: Work continuity in research labs during the COVID-19 emergency should be guaranteed by ensuring the protection of researchers in the workplace and considering the physical environment, the type of operators and work activity, and the proven ability of workers to face biological risks. The increased knowledge and awareness on lab’ risks should be useful to prevent and mitigate future viral outbreaks.

Excessive bone resorption by osteoclasts (OCs) covers an essential role in developing bone diseases, such as osteoporosis (OP) and rheumatoid arthritis (RA). Monocytes or macrophages fusion and multinucleation (M-FM) are key processes for generating multinucleated mature cells with essential roles in bone remodelling. Depending on the phenotypic heterogeneity of monocyte/macrophage precursors and the extracellular milieu, two distinct morphological and functional cell types can arise mature OCs and giant cells (GCs). Despite their biological relevance in several physiological and pathological responses, many gaps exist in our understanding of their formation and role in bone, including the molecular determinants of cell fusion and multinucleation. Here, we outline fusogenic molecules during M-FM involved in OCs and GCs formation in healthy conditions and during OP and RA. Moreover, we discuss the impact of the inflammatory milieu on modulating macrophages phenotype and their differentiation towards mature cells. Methodological approach envisaged searches on Scopus, Web of Science Core Collection, and EMBASE databases to select relevant studies on M-FM, osteoclastogenesis, inflammation, OP, and RA. This review intends to give a state-of-the-art description of mechanisms beyond osteoclastogenesis and M-FM, with a focus on OP and RA, and to highlight potential biological therapeutic targets to prevent extreme bone loss.