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Millions of people worldwide suffer from trauma- or age-related orthopedic diseases such as osteoarthritis, osteoporosis, or cancer. Tissue Engineering (TE) and Regenerative Medicine are multidisciplinary fields focusing on the development of artificial organs, biomimetic engineered tissues, and cells to restore or maintain tissue and organ function. While allogenic and future autologous transplantations are nowadays the gold standards for both cartilage and bone defect repair, they are both subject to important limitations such as availability of healthy tissue, donor site morbidity, and graft rejection. Tissue engineered bone and cartilage products represent a promising and alternative approach with the potential to overcome these limitations. Since the development of Advanced Therapy Medicinal Products (ATMPs) such as TE products requires the knowledge of diverse regulation and an extensive communication with the national/international authorities, the aim of this review is therefore to summarize the state of the art on the clinical applications of human bone marrow-derived stromal cells for cartilage and bone TE. In addition, this review provides an overview of the European legislation to facilitate the development and commercialization of new ATMPs.

Calcification of articular tissues is commonly observed in later osteoarthritis (OA) stages and can be caused by basic calcium phosphate (BCP) or calcium pyrophosphate (CPP) crystals. Calcification, particularly CPP deposition, has recently been associated with inflammation and cellular senescence. Investigating this association, we analyzed the concentration of various inflammatory mediators in synovial fluid and synovial membrane of OA patients in relation to calcification and the different crystal types. Synovial fluid was collected from OA patients during joint replacement surgery. Cytokine concentrations were measured using magnetic bead-based multiplex assay using Luminex® technology. Radiographs were used to determine and grade calcification of the knee joint and involved calcium crystal types were identified via Raman spectroscopy. Synovial fluid of patients with radiological calcification showed elevated levels of multiple cytokines (IL-10, IL-15, IL-1ra, GM-CSF), chemokines (IL-8, MCP-1, MIP-1b) and growth factors (PDGF-AB/BB, VEGF). Crystal differentiation revealed higher synovial fluid concentrations of IL-15, IL-1ra, IL-10, GM-CSF, PDGF-AB/BB and MIP-1b in patients with CPP- compared to BCP-calcified cartilage. We show an elevated cytokine profile in synovial fluid of patients with radiological calcification that may be linked to CPP depositison in cartilage.

Tissue engineering is rapidly progressing toward clinical application. In the musculoskeletal field, there has been an increasing necessity for bone and cartilage replacement. Despite the promising translational potential of tissue engineering approaches, careful attention should be given to the quality of developed constructs to increase the real applicability to patients. After a general introduction to musculoskeletal tissue engineering, this narrative review aims to offer an overview of methods, starting from classical techniques, such as gene expression analysis and histology, to less common methods, such as Raman spectroscopy, microcomputed tomography, and biosensors, that can be employed to assess the quality of constructs in terms of viability, morphology, or matrix deposition. A particular emphasis is given to standards and good practices (GXP), which can be applicable in different sectors. Moreover, a classification of the methods into destructive, noninvasive, or conservative based on the possible further development of a preimplant quality monitoring system is proposed. Biosensors in musculoskeletal tissue engineering have not yet been used but have been proposed as a novel technology that can be exploited with numerous advantages, including minimal invasiveness, making them suitable for the development of preimplant quality control systems.

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Raman spectroscopy allows for analyzing local molecular matrix components while preserving spatial resolution in tissue samples. The aim of this study was to use Raman line scans to discriminate between healthy and diseased cartilage tissue based on the depth-dependent sulfated glycosaminoglycans (sGAG) and total GAGs distribution. Full-thickness articular cartilage tissue was harvested from human individuals at different maturation stages (skeletally immature, skeletally mature) and from patients with diagnosed osteoarthritis. Raman spectroscopic line scans (30 µm step size) were utilized to analyze the sub-zonal sGAG (1062 cm−1) and total GAG (1370–1380 cm−1) distribution relative to the organic matrix (CH2 band 1430–1480 cm−1). We found a linear trend of the sGAG/CH2 ratio over the tissue depth in all samples (p < 0.0001). The total GAG/CH2 ratio of the skeletally immature and mature cartilage showed a characteristic non-linear behavior over the tissue distance. The elderly osteoarthritic cartilage exhibited lower total GAG/CH2 ratios compared to the ratios of the skeletally immature and mature samples, without a pronounced increase in the superficial area. Raman spectroscopic line scans are a fast and representative method allowing us to identify the local and tissue depth-dependent distribution of GAGs at higher specificity and resolution compared to histological staining.

Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach. A total of 23 patients with IgAN were treated with sparsentan via the Managed Access Programme between December 2023 and August 2024. The patients were stable on maximum tolerated doses of renin-angiotensin system (RAS) and SGLT2 inhibitors, with an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m² and a urine protein/creatinine ratio (UPCR) >0.75 g/g. In the 23 patients, median (IQR) baseline eGFR (CKD-EPI) was 42 mL/min/1.73 m (32-63) and median baseline UPCR was 1.5 g/g (0.9-1.8). After initiation of sparsentan, UPCR significantly decreased (  < 0.0001) to a median of 0.85 g/g (0.42-1.15) in the 2-week follow-up and further declined (  = 0.001) to a median of 0.60 g/g (0.32-0.82) after 14 weeks, equivalent to a relative reduction in proteinuria up to 62% (45-74). A similar significant reduction was observed for the urine albumin/creatinine ratio. No drug-related serious adverse events were reported. In this real-world setting, sparsentan shows a significant impact on proteinuria, leading to a relative reduction of 62% in UPCR after 14 weeks and beyond, even in patients already receiving SGLT2 inhibitors.

This project examines the modern perception of ancient women, specifically through the creative (and often anachronistic) lens of film. All three women examined, Cleopatra VII, Livia Augusta, and Servilia Caepionis, all exemplify the modern influence on interpreting historical sources, resulting in all three becoming agents of feminism in their own times. Each woman did not culminate the probable influence they had in Roman society, but they are instead reflective of the patriarchal paradigms understood by 20th and 21 st century audiences. The burgeoning feminist ideologies of the 20 th century would influence the depictions of each character in an anachronistic fashion, distorting the actual control such figures had in history. While Elizabeth Taylor’s Cleopatra capitalized on youth and sexuality as tools of powers, Siân Phillips’ Livia emphasized age and experience to advance in patriarchal Rome. Servilia, however, was an older matron who had both the experience and the sexuality to control those around her. While each figure approached it in very distinct methods, their common goal of changing Roman politics was reflective of the continued (and relatively unchanged) perception of ancient Roman women: as intelligent, yet dangerous, figures that served to derail patriarchal Roman politics.

Cartilage defect treatment strategies are dependent on the lesion size and severity. Osteochondral explants models are a platform to test cartilage repair strategies ex vivo. Current models lack in mimicking the variety of clinically relevant defect scenarios. In this controlled laboratory study, an automated device (artificial tissue cutter, ARTcut®) was implemented to reproducible create cartilage defects with controlled depth. In a pilot study, the effect of cartilage defect depth and oxygen tension on cartilage repair was investigated. Osteochondral explants were isolated from porcine condyles. 4 mm chondral and full thickness defects were treated with either porcine chondrocytes (CHON) or co-culture of 20 % CHON and 80 % MSC (MIX) embedded in collagen hydrogel. Explants were cultured with tissue specific media (without TGF-β) under normoxia (20 % O2) and physiological hypoxia (2 % O2). After 28 days, immune-histological stainings (Collagen II and X, Aggrecan) were scored (modified Bern-score, 3 independent scorer) to quantitatively compare treatments outcome. ARTcut® represents a software-controlled device for creation of uniform cartilage defects. Comparing the scoring results of the MIX and the CHON treatment, a positive relation between oxygen tension and defect depth was observed. Low oxygen tension stimulated cartilaginous matrix deposition in MIX group in chondral defects and CHON treatment in full thickness defects. ARTcut® has proved a powerful tool to create cartilage defects and thus opens a wide range of novel applications of the osteochondral model, including the relation between oxygen tension and defect depth on cartilage repair.