Background/Objectives: Tenosynovitis is a common feature of psoriatic arthritis (PsA) and is typically assessed using semi-quantitative magnetic resonance imaging (MRI) scoring. However, visual scoring s variability. This study evaluates a fully automated, deep-learning approach for ankle tenosynovitis segmentation and volume-based quantification from MRI in psoriatic arthritis (PsA) patients. Methods: We analyzed 364 ankle 3T MRI scans from 71 PsA patients. Four tenosynovitis pathologies were manually scored and used to create ground truth segmentations through a human–machine workflow. For each pathology, 30 annotated scans were used to train a deep-learning segmentation model based on the nnUNet framework, and 20 scans were used for testing, ensuring patient-level disjoint sets. Model performance was evaluated using Dice scores. Volumetric pathology measurements from test scans were compared to radiologist scores using Spearman correlation. Additionally, 218 serial MRI pairs were assessed to analyze the relationship between changes in pathology volume and changes in visual scores. Results: The segmentation model achieved promising performance on the test set, with mean Dice scores ranging from 0.84 to 0.92. Pathology volumes correlated with visual scores across all test MRIs (Spearman ρ = 0.52–0.62). Volume-based quantification captured changes in inflammation over time and identified subtle progression not reflected in semi-quantitative scores. Conclusions: Our automated segmentation tool enables fast and accurate quantification of ankle tenosynovitis in PsA patients. It may enhance sensitivity to disease progression and complement visual scoring through continuous, volume-based metrics.

Recent evidence indicates the potential of gamma-irradiated (γi) Staphylococcus aureus to be used as an osteo-immunomodulator for bone regeneration. This study aims at characterizing the inflammatory milieu caused by the stimulation of γi S. aureus in immune cells and investigates its effects on MSC osteogenic differentiation. Furthermore, we aimed to recreate the immune-modulatory response exhibited by γi S. aureus by using a mixture of various synthetic pathogen recognition receptor (PRR) ligands consisting of TLR2, TLR8, TLR9, and NOD2 agonists. Human peripheral blood mononuclear cells (hPBMCs), isolated from healthy human donors, were exposed to γi S. aureus or seven different ligand mixtures. After 24 h, the conditioned medium (CM) from the hPBMCs was collected and its effects on hMSC osteogenic differentiation were investigated by assessing alkaline phosphatase (ALP) activity and matrix mineralization. The hPBMCs and their CM were also analyzed by bulk RNA sequencing and for cytokine secretion. CM from the γi S. aureus and the mixture consisting of Pam3CSK4, C-class CpG oligodeoxynucleotide (CpG ODN C), and murabutide targeting TLR2, TLR9, and NOD2 showed a fivefold increase in ALP and matrix mineralization in a donor-dependent manner. These effects were due to the upregulation of inflammatory signaling pathways, which led to an increase in cytokines and chemokines TNF, interleukin (IL)-6, IFN-γ, IL-1α, CXCL10, CCL18, CCL17, CXCL1, and CCL5. Upregulation of genes like BMP2R, BMP6R, BGLAP, and others contributed to the upregulation of osteogenic pathways in the hPBMCs stimulated with γi S. aureus and the aforementioned mix. Thus, formulations with mixtures of PRR ligands may serve as immune-modulatory osteogenesis-enhancing agents.

Advancements in biomaterials design increasingly focus on material-host immune interactions as one of the strategies to promote new bone formation, referred to as osteoimmunomodulation. Recent studies indicate that inflammatory stimuli can synergize with growth factors such as bone morphogenetic protein 2 (BMP-2) to promote bone formation. Pathogen-associated molecular patterns (PAMPs) are motifs expressed by microbes that are recognized by immune cells and induce an immune-stimulatory response. In this study, we combined PAMPs with low-dose BMP-2 on a biphasic calcium phosphate (BCP) scaffold and evaluated its effect on ectopic bone formation in a subcutaneous implantation model. The PAMPs tested include gamma-irradiated whole microbes (γi-Staphylococcus aureus and γi-Candida albicans), a vaccine (Bacillus Calmette-Guérin containing Mycobacterium bovis), bacterial cell wall components (peptidoglycan [PGN], lipopolysaccharide [LPS], lipoteichoic acid, and Pam3CysSerLys4), an exopolysaccharide (Curdlan), and nucleic acid analogues (polyinosinic:polycytidylic acid [Poly(I:C)] and Cytidine-phosphate-guanosine [CpG]-containing oligonucleotides type C). Implants consisting of BCP, PAMPs, and BMP-2 were placed subcutaneously in rabbits and evaluated for ectopic bone formation after 5 weeks. Implants with only BMP-2 served as controls. Of the PAMPs tested, only PGN and BMP-2 showed a positive bone volume compared with the control, with borderline significance (+4.4%, p = 0.08). Decreased bone volume was seen for LPS (−7.4%, p = 0.03) and Poly(I:C) (−6.3%, p = 0.04). Fluorochrome labeling at weeks 2 and 3 assessed mineralization onset, revealing no mineralization in the first 2 weeks and some implants showing onset at week 3. We observed variability in ectopic bone formation across animals, associated with higher osteoclast numbers in those where ectopic bone occurred versus those that did not (p = 0.004). PAMPs can modulate bone formation, but their effects are variable, requiring further refinement to harness their osteoimmunomodulatory properties effectively. Additionally, we highlight osteoclasts’ important role in stimulating ectopic bone formation.

Osteoimmunomodulation is a strategy to promote bone regeneration in implants by modifying the immune environment. CpG-containing oligonucleotides type C (CpG ODN C) and Polyinosinic:polycytidylic acid (Poly[I:C]) are analogs of microbial nucleic acids that have been studied for various immunotherapeutic applications. This research investigates the potential of CpG ODN C and Poly(I:C) as an osteoimmunomodulatory agent for bone regenerative purposes. We encapsulated each nucleic acid in a lipid-based nanoparticle to facilitate the delivery into intracellular pathogen recognition receptors in immune cells. The lipid-based nanoparticles were ±250 nm in size with a negative charge (−36 to −40 mV) and an encapsulation efficiency of ±60 %. Lipid-based nanoparticles containing nucleic acids, Lip/CpG ODN C and Lip/Poly(I:C), increased the production of TNF, IL-6, and IL-10 by primary human macrophages compared to free-form nucleic acids. Conditioned medium from macrophages treated with CpG ODN C (10 µg/ml) and Lip/CpG ODN C (0.1, 1, and 10 µg/ml) promoted osteoblast differentiation of human mesenchymal stromal cells by 2.6-fold and 3-fold, respectively; no effect was seen for Lip/Poly(I:C). Bone implants were prepared, consisting of a biphasic calcium phosphate scaffold, bone morphogenetic protein (BMP) 2, and lipid-based nanoparticles suspended in gelatin methacryloyl (GelMA) hydrogel. Implants were evaluated for de novo bone formation in an extra-skeletal implantation model in rabbits for 5 weeks. Based on the particles suspended in GelMA, six groups of implants were prepared: Lip/CpG ODN C, Lip/Poly(I:C), Lip (empty), CpG ODN C, Poly(I:C), and a control group consisting of empty GelMA. After 5 weeks, healthy bone tissue formed in all of the implants with active osteoblast and osteoclast activity, however, the amount of new bone volume and scaffold degradation were similar for all implants. We suggest that the working concentrations of the nucleic acids employed were inadequate to induce a relevant inflammatory response. Additionally, the dosage of BMP-2 used may potentially mask the immune-stimulatory effect. Lip/CpG ODN C holds potential as a bioactive agent for osteoimmunomodulation, although further in vivo demonstration should corroborate the current in vitro findings.

Osteoarthritis (OA) is a common degenerative inflammatory joint disease with progressive loss of articular cartilage that undermines patients’ quality of life. There are no regulatory-approved, disease-modifying OA medications, despite a great deal of studies done to elucidate OA pathogenesis. Until now, OA pharmacological treatment focused mainly on generalized inhibition of inflammation and pain. Currently, monoclonal antibodies and nucleic-acid aptamers emerge as targeted therapies offering potential alternatives by addressing the complex challenges posed by OA, such as specifically reducing inflammation and pain in the joint targeting specific molecular key players, instead of a systemic and generalized approach like with non-steroidal anti-inflammatory drugs. Aptamers’ properties, including structure versatility, reduced immunogenicity, and flexible administration methods, position them as high-potential candidates for OA treatment. This review summarizes results from clinical trials applying monoclonal antibodies to treat OA, preclinical research, and the development of aptamers as a new generation of targeting agents. Meanwhile, it provides a comprehensive comparison of the characteristics, advantages, and limitations of aptamers versus monoclonal antibodies. Notably, the promising applications of aptamers, demonstrated in other inflammatory and degenerative conditions, underscore their potential for OA therapy. We anticipate that the application of aptamer could offer a new way of OA pharmacological intervention.

Objective
To study the association between various radiographic definitions of acetabular dysplasia (AD) and incident radiographic hip osteoarthritis (RHOA), and to analyze in subgroups.

Methods
Hips free of RHOA at baseline and with follow-up within 4–8 years were drawn from the World COACH consortium. The Wiberg center edge angle (WCEA), acetabular depth width ratio (ADR), and the modified acetabular index (mAI) were calculated. AD was defined as WCEA≤25°, and for secondary analyses as WCEA≤20°, ADR ≤250, mAI ≥ 13°, and a combination. A logistic regression model with generalized mixed effects with 3 levels adjusted for age, biological sex, and body mass index (BMI) was used. Descriptive statistics stratified by age, biological sex and BMI were reported.

Results
A total of 18,807 hips from 9 studies were included. Baseline characteristics: age 61.84 (± 8.32) years, BMI 27.40 (± 4.49) kg/m², 70.1% women. 4766 hips (25.3%) had WCEA≤25°. Within 4–8 years (mean 5.8 ±1.6) follow-up, 378 hips (2.0%) developed incident RHOA. We found an association between AD and RHOA (adjusted OR [aOR] 1.80 95% confidence interval [CI] 1.40–2.34). In secondary analyses, all other definitions of AD were also associated with incident RHOA (aOR ranging from 1.52 95% CI 1.19–1.94 to 1.96 95% CI 1.26–3.02). Descriptive statistics showed that the relative risk (RR) in AD hips to develop RHOA was higher compared to non-AD hips in age group 61–70 (RR 1.70), BMI<25 (RR 1.66), and in female hips (RR 1.73).

Conclusion
AD was consistently associated with incident RHOA. Explorative analyses show that AD hips in women and age group 61–70 years seem to be more at risk of developing RHOA compared to non-AD hips.

Objective: To analyze and synthesize the information available from five pivotal, large-scale, multicenter, observational studies (CHECK, OAI, FNIH Biomarkers Consortium, IMI-APPROACH, and MOST) focusing on knee osteoarthritis (OA), which can be used to elucidate disease progression, risk factors, and the effectiveness of potential interventions. Design: For this narrative review, a comprehensive literature search and data extraction from official web pages and scientific databases were conducted to compare methodologies, in- and exclusion criteria, outcomes, and cohort characteristics across the studies. Thematic, comparative, and qualitative analyses were employed to identify trends, commonalities, and disparities among the findings. Results: The studies collectively enhanced understanding of the onset and progression of knee OA, and in several of the studies, hip OA, emphasizing the importance of both systemic and local risk factors. Advanced imaging and biomarkers are important components in all the cohorts, with the goal of aiding early diagnosis and tracking disease progression. All cohorts evaluated unique markers generally not available in the other cohorts, while other factors overlap, suggesting possibilities for combining or cross-validating between cohorts. Conclusions: The collaborative efforts of major OA research significantly advance our understanding of knee OA. These studies highlight the importance of a multifaceted approach, integrating advanced imaging, biomarkers, and longitudinal data to tackle the complexities of OA. By synthesizing findings and addressing knowledge gaps such as heterogeneity of patients and used measurements, and use of novel pain measures, future research can develop more effective diagnostic tools and treatments, ultimately enhancing the quality of life for OA patients.

Background: Addressing prosthetic joint infections poses a significant challenge within orthopedic surgery, marked by elevated morbidity and mortality rates. The presence of biofilms and infections attributed to Staphylococcus aureus (S. aureus) further complicates the scenario. Objective: To investigate the potential of radioimmunotherapy as an innovative intervention to tackle biofilm-associated infections. Methods: Our methodology involved employing specific monoclonal antibodies 4497-IgG1, designed for targeting wall teichoic acids found on S. aureus and its biofilm. These antibodies were linked with radionuclides actinium-225 (²²⁵Ac) and lutetium-177 (¹⁷⁷Lu) using DOTA as a chelator. Following this, we evaluated the susceptibility of S. aureus and its biofilm to radioimmunotherapy in vitro, assessing bacterial viability and metabolic activity via colony-forming unit enumeration and xylenol tetrazolium assays. Results: Both [²²⁵Ac]4497-IgG1 and [¹⁷⁷Lu]4497-IgG1 exhibited a noteworthy dose-dependent reduction in S. aureus in planktonic cultures and biofilms over a 96-h exposure period, compared to non-specific antibody control groups. Specifically, doses of 7.4 kBq and 7.4 MBq of [²²⁵Ac]4497-IgG1 and [¹⁷⁷Lu]4497-IgG1 resulted in a four-log reduction in planktonic bacterial counts. Within biofilms, 14.8 kBq of [²²⁵Ac]4497-IgG1 and 14.8 Mbq [¹⁷⁷Lu]4497-IgG1 led to reductions of two and four logs, respectively. Conclusion: Our findings underscore the effectiveness of [²²⁵Ac]4497-IgG1 and [¹⁷⁷Lu]4497-IgG1 antibodies in exerting dose-dependent bactericidal effects against planktonic S. aureus and biofilms in vitro. This suggests that radioimmunotherapy might serve as a promising targeted treatment approach for combating S. aureus and its biofilm.

Introduction Implant infections caused by Staphylococcus aureus are responsible for high mortality and morbidity worldwide. Treatment of these infections can be difficult especially when bacterial biofilms are involved. In this study we investigate the potential of infrared photoimmunotherapy to eradicate staphylococcal infection in a mouse model. Methods A monoclonal antibody that targets Wall Teichoic Acid surface components of both S. aureus and its biofilm (4497-IgG1) was conjugated to a photosensitizer (IRDye700DX) and used as photoimmunotherapy in vitro and in vivo in mice with a subcutaneous implant pre-colonized with biofilm of Staphylococcus aureus. A dose of 400 μg and 200 μg of antibody-photosensitizer conjugate 4497-IgG–IRDye700DXwas administered intravenously to two groups of 5 mice. In addition, multiple control groups (vancomycin treated, unconjugated IRDye700DX and IRDye700DX conjugated to a non-specific antibody) were used to verify anti-microbial effects. Results In vitro results of 4497-IgG-IRDye700DX on pre-colonized (biofilm) implants showed significant (p<0.01) colony-forming units (CFU) reduction at a concentration of 5 μg of the antibody-photosensitizer conjugate. In vivo, treatment with 4497-IgG-IRDye700DX showed no significant CFU reduction at the implant infection. However, tissue around the implant did show a significant CFU reduction with 400 μg 4497-IgG-IRDye700DX compared to control groups (p = 0.037). Conclusion This study demonstrated the antimicrobial potential of photoimmunotherapy for selectively eliminating S. aureus in vivo. However, using a solid implant instead of a catheter could result in an increased bactericidal effect of 4497-IgG-IRDye700DX and administration locally around an implant (per operative) could become valuable applications in patients that are difficult to treat with conventional methods. We conclude that photoimmunotherapy could be a potential additional therapy in the treatment of implant related infections, but requires further improvement.

Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific immune training of macrophages that affect their functional state, resulting in heightened (trained) or reduced (tolerant) responses upon exposure to a second stimulus. This is known as innate immune memory. Here, we study the impact of macrophages’ memory trait on osteoblast differentiation of human mesenchymal stromal cells (hMSCs) and osteoclast differentiation. An in vitro trained immunity protocol of monocyte-derived macrophages was employed using inactivated Candida albicans and Bacillus Calmette–Guérin (BCG) to induce a ‘trained’ state and Pam3CSK4 (PAM) and Lipopolysaccharides (LPS) to induce a ‘tolerance’ state. Macrophages were subsequently cocultured with hMSCs undergoing osteogenic differentiation during either resting (unstimulated) or inflammatory conditions (restimulated with LPS). Alkaline phosphatase activity, mineralization, and cytokine levels (TNF, IL-6, oncostatin M and SDF-1α) were measured. In addition, macrophages underwent osteoclast differentiation. Our findings show that trained and tolerized macrophages induced opposing results. Under resting conditions, BCG-trained macrophages enhanced ALP levels (threefold), while under inflammatory conditions this was found in the LPS-tolerized macrophages (fourfold). Coculture of hMSCs with trained macrophages showed mineralization while tolerized macrophages inhibited the process under both resting and inflammatory conditions. While osteoclast differentiation was not affected in trained-macrophages, this ability was significantly loss in tolerized ones. This study further confirms the intricate cross talk between immune cells and bone cells, highlighting the need to consider this interaction in the development of personalized approaches for bone regenerative medicine. Graphical Abstract: (Figure presented.).

Purpose Hip osteoarthritis (OA) is a major cause of pain and disability worldwide. Lack of effective therapies may reflect poor knowledge on its aetiology and risk factors, and result in the management of end-stage hip OA with costly joint replacement. The Worldwide Collaboration on OsteoArthritis prediCtion for the Hip (World COACH) consortium was established to pool and harmonise individual participant data from prospective cohort studies. The consortium aims to better understand determinants and risk factors for the development and progression of hip OA, to optimise and automate methods for (imaging) analysis, and to develop a personalised prediction model for hip OA. Participants World COACH aimed to include participants of prospective cohort studies with ≥200 participants, that have hip imaging data available from at least 2 time points at least 4 years apart. All individual participant data, including clinical data, imaging (data), biochemical markers, questionnaires and genetic data, were collected and pooled into a single, individual-level database. Findings to date World COACH currently consists of 9 cohorts, with 38 021 participants aged 18–80 years at baseline. Overall, 71% of the participants were women and mean baseline age was 65.3±8.6 years. Over 34 000 participants had baseline pelvic radiographs available, and over 22 000 had an additional pelvic radiograph after 8–12 years of follow-up. Even longer radiographic follow-up (15–25 years) is available for over 6000 of these participants.

Background and purpose — Hip dysplasia can present challenges for total hip arthroplasty (THA) due to anatomic abnormalities. We aimed to assess the association of age, sex, osteotomies prior to THA, and fixation method on 5-and 10-year revision-free implant survival and patient-reported outcome measures (PROMs) of THAs in patients with hip dysplasia. Methods — Using Dutch Arthroplasty Register data, we studied hip dysplasia patients receiving primary THAs in 2007–2021 (n = 7,465). THAs were categorized by age, pelvic osteotomy prior to THA (yes/no), and fixation (cemented, uncemented, hybrid, reverse hybrid). Kaplan–Meier and multivariable Cox models were used to determine 5-and 10-year revision-free implant survival and adjusted hazard ratios including 95% confidence intervals (CIs). Reasons for revision and PROMs were compared within the categories. Results — We found a 10-year revision-free implant survival of 94.9% (CI 94.3–95.5). Patients younger than 50 years had a 10-year implant survival of 93.3% (CI 91.9– 94.7), Patients with prior pelvic osteotomy had a 10-year implant survival of 92.0% (CI 89.8–94.2). Fixation method and sex were not associated with implant survival. Patients with a prior pelvic osteotomy had more revisions due to cup loosening and reported lower PROM scores than patients without earlier osteotomy. Conclusion — 5-and 10-year revision-free implant survival rates of THA for hip dysplasia are 96.4% and 94.9%. Age and prior osteotomies were associated with decreased implant survival rates in patients with hip dysplasia, while fixation method was not. Prior osteotomies were also associated with reduced PROM scores.

Background: Lumbar interbody fusion (IF) is a common procedure to fuse the anterior spine. However, a lack of consensus on image-based fusion assessment limits the validity and comparison of IF studies. This systematic review aims to (1) report on IF assessment strategies and definitions and (2) summarize available literature on the diagnostic reliability and accuracy of these assessments. Methods: Two searches were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Search 1 identified studies on adult lumbar IF that provided a detailed description of image-based fusion assessment. Search 2 analyzed studies on the reliability of specific fusion criteria/classifications and the accuracy assessed with surgical exploration. Results: A total of 442 studies were included for search 1 and 8 studies for search 2. Fusion assessment throughout the literature was highly variable. Eighteen definitions and more than 250 unique fusion assessment methods were identified. The criteria that showed most consistent use were continuity of bony bridging, radiolucency around the cage, and angular motion <5°. However, reliability and accuracy studies were scarce. Conclusion: This review highlights the challenges in reaching consensus on IF assessment. The variability in IF assessment is very high, which limits the translatability of studies. Accuracy studies are needed to guide innovations of assessment. Future IF assessment strategies should focus on the standardization of computed tomography-based continuity of bony bridging. Knowledge from preclinical and imaging studies can add valuable information to this ongoing discussion.

Bacterial infections and antimicrobial resistance are posing substantial difficulties to the worldwide healthcare system. The constraints of conventional diagnostic and therapeutic approaches in dealing with continuously changing infections highlight the necessity for innovative solutions. Aptamers, which are synthetic oligonucleotide ligands with a high degree of specificity and affinity, have demonstrated significant promise in the field of bacterial infection management. This review examines the use of aptamers in the diagnosis and therapy of bacterial infections. The scope of this study includes the utilization of aptasensors and imaging technologies, with a particular focus on their ability to detect conditions at an early stage. Aptamers have shown exceptional effectiveness in suppressing bacterial proliferation and halting the development of biofilms in therapeutic settings. In addition, they possess the capacity to regulate immune responses and serve as carriers in nanomaterial-based techniques, including radiation and photodynamic therapy. We also explore potential solutions to the challenges faced by aptamers, such as nuclease degradation and in vivo instability, to broaden the range of applications for aptamers to combat bacterial infections.

Objective: The objective is to determine the association and absolute risk of femoroacetabular impingement syndrome (FAIS) for the development of radiographic hip osteoarthritis (RHOA). Methods: This is a nationwide, multicentre prospective cohort study (Cohort Hip and Cohort Knee) with 1002 individuals aged between 45 and 65 years. Hips without definitive RHOA (Kellgren-Lawrence (KL) grade≤1) at baseline and with anteroposterior pelvic radiographs at baseline and 10-year follow-up available (n=1386 hips) were included. FAIS was defined by the baseline presence of a painful hip, limited internal hip rotation≤25° and cam morphology defined by an alpha angle>60°. The outcomes were incident RHOA (KL grade≥2 or total hip replacement (THR)) and incident end-stage RHOA (KL≥3 or THR) within 10 years. Results: Of the 1386 included hips (80% women; mean age 55.7±5.2 years), 21 hips fulfilled criteria for FAIS and 563 hips did not fulfil any of the FAIS criteria (reference group; no symptoms, no signs, no cam morphology). Within 10-year follow-up, 221 hips (38%) developed incident RHOA and 15 hips (3%) developed end-stage RHOA (including 9 hips with THR). Adjusted for sex, age and body mass index, FAIS with cam morphology resulted in an OR of 6.85 (95% CI 2.10 to 22.35) for incident RHOA and 47.82 (95% CI 12.51 to 182.76) for incident end-stage RHOA, compared with hips not having any FAIS criteria. The absolute risk of FAIS was 81% for incident RHOA and 33% for incident end-stage RHOA. Conclusion: FAIS was strongly associated with the development of RHOA within 10 years. Although the baseline prevalence of FAIS was low, the high absolute risk of FAIS for RHOA warrants further studies to determine preventive strategies.

Autologous bone grafts are commonly used to repair defects in skeletal tissue, however, due to their limited supply there is a clinical need for alternatives. Synthetic ceramics present a promising option but currently lack biological activity to stimulate bone regeneration. One potential approach to address this limitation is the incorporation of immunomodulatory agents. In this study, we investigate the application of microbial stimuli to stimulate bone formation. Three different microbial stimuli were incorporated in a biphasic calcium phosphate (BCP) ceramic: Bacille Calmette-Guérin (BCG), gamma-irradiated Staphylococcus aureus (γi-S. aureus), or γi-Candida albicans (γi-C. Albicans). The constructs were then implanted in both a rabbit posterolateral spinal fusion (PLF) and an intramuscular implant model for 10 weeks and compared to a nonstimulated control construct. For the PLF model, the formation of a bony bridge was evaluated by manual palpation, micro computed tomography, and histology. While complete fusion was not observed, the BCG condition was most promising with higher manual stiffness and almost twice as much bone volume in the central fusion mass compared to the control (9 ± 4.4% bone area vs. 4.6 ± 2.3%, respectively). Conversely, the γi-S. aureus or γi-C. albicans appeared to inhibit bone formation (1.4 ± 1.4% and 1.2 ± 0.6% bone area). Bone induction was not observed in any of the intramuscular implants. This study indicates that incorporating immunomodulatory agents in ceramic bone substitutes can affect bone formation, which can be positive when selected carefully. The readily available and clinically approved BCG showed promising results, which warrants further research for clinical translation.

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies.

The development of antibacterial coatings is a promising approach to preventing biofilm formation and reducing the overuse of systemic antibiotics. However, widespread antibiotic use has resulted in antibiotic-resistant bacteria, limiting the efficacy of antibiotic-based coatings. Herein, an antibacterial coating is developed by layer-by-layer (LbL) assembly of two polymers namely PDLG (poly (D,L-lactide-co-glycolide)) and gelatin methacryloyl (GelMA) while chicken cathelicidin-2 (CATH-2), a cationic and amphipathic peptide, is loaded between these polymer layers. The electrospray method is used to apply the coatings to achieve efficient peptide loading and durability. The CATH-2 bactericidal concentration ranges are first identified, followed by a study of their cytotoxicity to human mesenchymal stem cells (hMSCs) and macrophage cell lines. Later, different LbL electrospray coating assemblies loaded with the optimal peptide concentration are sought. Various coating strategies are investigated to identify an LbL coating that exhibits prolonged and biocompatible CATH-2 release. The resulting CATH-2-coated titanium surfaces exhibit strong antibacterial activity against both Staphylococcus aureus and Escherichia coli bacteria for 4 days and are biocompatible with hMSCs and macrophage cells. This coating can be considered as a versatile delivery system platform for the delivery of CATH-2 peptides while avoiding cytotoxicity, particularly for the prevention of infections associated with implants.

Background: Despite the extensive use of silver ions or nanoparticles in research related to preventing implant-associated infections (IAI), their use in clinical practice has been debated. This is because the strong antibacterial properties of silver are counterbalanced by adverse effects on host cells. One of the reasons for this may be the lack of comprehensive in vitro models that are capable of analyzing host-bacteria and host-host interactions.

Methods and results: In this study, we tested silver efficacy through multicellular in vitro models involving macrophages (immune system), mesenchymal stem cells (MSCs, bone cells), and S. aureus (pathogen). Our model showed to be capable of identifying each element of culture as well as tracking the intracellular survival of bacteria. Furthermore, the model enabled to find a therapeutic window for silver ions (AgNO3) and silver nanoparticles (AgNPs) where the viability of host cells was not compromised, and the antibacterial properties of silver were maintained. While AgNO3 between 0.00017 and 0.017 µg/mL retained antibacterial properties, host cell viability was not affected. The multicellular model, however, demonstrated that those concentrations had no effect on the survival of S. aureus, inside or outside host cells. Similarly, treatment with 20 nm AgNPs did not influence the phagocytic and killing capacity of macrophages or prevent S. aureus from invading MSCs. Moreover, exposure to 100 nm AgNPs elicited an inflammatory response by host cells as detected by the increased production of TNF-α and IL-6. This was visible only when macrophages and MSCs were cultured together.

Conclusions: Multicellular in vitro models such as the one used here that simulate complex in vivo scenarios can be used to screen other therapeutic compounds or antibacterial biomaterials without the need to use animals.

Background: Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) hold promise as a disease modifying treatment in osteoarthritis (OA). Obesity, and its associated inflammation, contribute to OA development and metabolic OA represents a specific and significant group of the OA patient population. Given their immunomodulatory properties, MSC and MSC-EVs are especially interesting for this group of patients as a therapeutic option. Here, we were the first to compare the therapeutic efficacy of MSCs and MSC-EVs in a mild OA model taking these metabolic aspects into consideration. Methods: Male Wistar-Han rats (Crl:WI(Han) (n = 36) were fed a high fat diet for 24 weeks, with unilateral induction of OA by groove surgery after 12 weeks. Eight days after surgery rats were randomized in three treatment groups receiving MSCs, MSC-EVs or vehicle injection. Pain-associated behavior, joint degeneration, and local and systemic inflammation were measured. Results: We demonstrated that despite not having a significant therapeutic effect, MSC-EV treatment results in lower cartilage degeneration, less pain behaviour, osteophytosis and joint inflammation, than MSC treatment. Suggesting that MSC-EVs could be a more promising therapeutic strategy than MSCs in this mild metabolic OA model. Conclusion: In summary, we find that MSC treatment has negative effects on the joint in metabolic mild OA. This is an essential finding for the significant group of patients with metabolic OA phenotype, and might help to understand why clinical translation of MSC treatment shows varying therapeutic efficacy thus far. Our results also suggest that MSC-EV-based treatment might be a promising option for these patients, however MSC-EV therapeutic efficacy will need improvement.