Osteomyelitis is associated with increased anti-inflammatory response and immune exhaustion.

Introduction: Osteomyelitis (OMS) is a bone infection causing bone pain and severe complications. A balanced immune response is critical to eradicate infection without harming the host, yet pathogens manipulate immunity to establish a chronic infection. Understanding OMS-driven inflammation is essential for disease management, but comprehensive data on immune profiles and immune cell activation during OMS are lacking. Methods: Using high-dimensional flow cytometry, we investigated the detailed innate and adaptive systemic immune cell populations in OMS and age- and sex-matched controls. Results: Our study revealed that OMS is associated with increased levels of immune regulatory cells, namely T regulatory cells, B regulatory cells, and T follicular regulatory cells. In addition, the expression of immune activation markers HLA-DR and CD86 was decreased in OMS, while the expression of immune exhaustion markers TIM-3, PD-1, PD-L1, and VISTA was increased. Members of the T follicular helper (Tfh) cell family as well as classical and typical memory B cells were significantly increased in OMS individuals. We also found a strong correlation between memory B cells and Tfh cells. Discussion: We conclude that OMS skews the host immune system towards the immunomodulatory arm and that the Tfh memory B cell axis is evident in OMS. Therefore, immune-directed therapies may be a promising alternative for eradication and recurrence of infection in OMS, particularly in individuals and areas where antibiotic resistance is a major concern.

An Updated Overview of Risk Factors for Shoulder Stiffness. / Risikofaktoren für die Entstehung der primären Schultersteife: ein aktueller Überblick.

A painful reduction in shoulder mobility, known as "shoulder stiffness", can occur both as a primary idiopathic condition and as a secondary condition, for example, following surgical procedures. Various factors can contribute to the development of primary shoulder stiffness. In this review we summarize the pathophysiological mechanisms, genetic influences, endocrine disorders, metabolic conditions, as well as other diseases and medical-therapeutic approaches that might have an impact on the development of primary shoulder stiffness.

Comparison of Minced Cartilage Implantation with Autologous Chondrocyte Transplantation in an In Vitro Inflammation Model.

The current gold standard to treat large cartilage defects is autologous chondrocyte transplantation (ACT). As a new surgical method of cartilage regeneration, minced cartilage implantation (MCI) is increasingly coming into focus. The aim of this study is to investigate the influence of chondrogenesis between isolated and cultured chondrocytes compared to cartilage chips in a standardized inflammation model with the proinflammatory cytokine TNFα. Articular chondrocytes from bovine cartilage were cultured according to the ACT method to passage 3 and transferred to spheroid culture. At the same time, cartilage was fragmented (<1 mm3) to produce cartilage chips. TNFα (20 ng/mL) was supplemented to simulate an inflammatory process. TNFα had a stronger influence on the passaged chondrocytes compared to the non-passaged ones, affecting gene expression profiles differently between isolated chondrocytes and cartilage chips. MCI showed less susceptibility to TNFα, with reduced IL-6 release and less impact on inflammation markers. Biochemical and histological analyses supported these findings, showing a greater negative influence of TNFα on the passaged pellet cultures compared to the unpassaged cells and MCI constructs. This study demonstrated the negative influence of TNFα on chondrogenesis in a chondrocyte spheroid culture and cartilage fragment model. Passaged chondrocytes are more sensitive to cytokine influences compared to non-passaged cells and chondrons. This suggests that MCI may have superior regeneration potential in osteoarthritic conditions compared to ACT. Further investigations are necessary for the translation of these findings into clinical practice.

In Vitro Biocompatibility of the Novel Ceramic Composite Baghdadite for Defect Augmentation in Revision Total Hip Arthroplasty.

Biological augmentation of bony defects in weight-bearing areas of both the acetabulum and the femur remains challenging. The calcium-silicate-based ceramic Baghdadite is a very interesting material to be used in the field of revision total hip arthroplasty for the treatment of bony defects in weight-bearing and non-weight-bearing areas alike. The aim of this study was to investigate the biocompatibility of Baghdadite utilizing an osteoblast-like, human osteosarcoma cell line (MG-63) and the human monocytic leukemia-derived cell line (THP-1). THP-1-derived macrophages and MG-63 were indirectly exposed to Baghdadite for 7 days using a transwell system. Viability was assessed with MTT assay and pH analysis. To investigate proliferation rate, both cell lines were labelled using CFSE and flow cytometrically analyzed. ELISA was used to measure the secretion of IL-1ß, IL-6 and TNFα. The investigation of viability, while showing a slight difference in optical density for the MTT assays in MG-63 cells, did not present a meaningful difference between groups for both cell lines. The comparison of pH and the proportion of living cells between groups did not present with a significant difference for both THP-1 and MG-63. Baghdadite did not have a relevant impact on the proliferation rate of the investigated cell lines. Mean fluorescence intensity was calculated between groups with no significant difference. Baghdadite exerted a proinflammatory effect, which could be seen in an upregulated production of TNFα in macrophages. Production of IL-1ß and IL-6 was not statistically significant, but the IL-6 ELISA showed a trend to an upregulated production as well. A similar effect on MG-63 was not observed. No relevant cytotoxicity of Baghdadite ceramics was encountered. Baghdadite ceramics exhibit a proinflammatory potential by significantly increasing the secretion of TNFα in THP-1-derived macrophages. Whether this proinflammatory potential results in a clinically relevant effect on osteointegration is unclear and requires further investigation. Baghdadite ceramics provide an interesting alternative to conventional bone substitutes and should be further investigated in a biomechanical and in vivo setting.

Poor midterm clinical outcomes and a high percentage of unsatisfying results are reported after seizure-related shoulder injuries, especially after posterior proximal humerus fracture-dislocations.

BACKGROUND: Treating seizure-related shoulder injuries is challenging, and an evidence-based consensus to guide clinicians is lacking. The aim of this prospective single-center observational clinical trial was to evaluate the clinical results of a cohort of patients undergoing treatment of seizure-related shoulder injuries, to categorize them according to the lesion's characteristics, with special focus on patients with proximal humerus fracture-dislocations (PHFDs), and to define groups at risk of obtaining unsatisfactory results. We hypothesized that patients with a PHFD, considered the worst-case scenario among these injuries, would report worse clinical results in terms of the quick Disabilities of the Arm, Shoulder, and Hand questionnaire (qDASH) as compared to the other patients. METHODS: Patients referred to a tertiary epilepsy center who have seizure-related shoulder injuries and with a minimum follow-up of 1 year were included. A quality-of-life assessment instrument (EQ-5D-5L), a district-specific patient-reported outcome measure (qDASH), and a pain assessment tool (visual analog scale [VAS]) were used for the clinical outcome evaluation. Subjective satisfaction and fear of new shoulder injuries was also documented. Categorization and subgroup analysis according to the presence and features of selected specific lesions were performed. RESULTS: A total of 111 patients were deemed eligible and 83 were available for follow-up (median age 38 years, 30% females), accounting for a total of 107 injured shoulders. After a median follow-up of 3.9 (1.6-8.2) years, overall moderate clinical results were reported. In addition, 34.1% of the patients reported a VAS score ≥35 mm, indicating moderate to severe pain, and 34.1% a qDASH score ≥40 points, indicating severe disability of an upper limb. These percentages rose to, respectively, 45.5% and 48.5% in the subgroup of patients with PHFDs and to 68.8% and 68.8% in patients experiencing posterior PHFD. Overall, 46.9% of the patients considered themselves unsatisfied with the treatment and 62.5% reported a persistent fear of a new shoulder injury. CONCLUSIONS: Patients with seizure-related shoulder injuries reported only moderate clinical results at their midterm follow-up. Older age, male sex, and absence or discontinuation of antiepileptic drug (AED) treatment were identified as characterizing features of patients with posterior dislocation episodes. In patients with PHFD, a tendency to worse clinical results was observed, with posterior PHFD patients emerging as a definite subgroup at risk of reporting unsatisfying results after treatment.

Effects of single and repeated shock wave application on the osteogenic differentiation potential of human primary mesenchymal stromal cells and the osteoblastic cell line MG63 in vitro.

Introduction: Extracorporeal shock wave therapy is a non-invasive and effective option for treating various musculoskeletal disorders. Recent literature indicates that the parameters for extracorporeal shock wave therapy, such as the optimal intensity, treatment frequency, and localization, are yet to be determined. Studies reporting on the effects of shock wave application on primary mesenchymal stromal cells (MSCs) as well as osteoblastic cell lines in vitro are barely available and not standardized. Methods: In this study, we designed a special setup to precisely expose primary MSCs and the osteoblastic cell line MG63 to shock waves and subsequently analyzed the resulting cellular responses using standardized protocols to investigate their viability, proliferation behavior, cytokine secretion, and osteogenic differentiation potential in vitro. The shock wave transducer was coupled to a specifically designed water bath containing a 5 mL tube holder. Primary human MSCs and MG63 cells were trypsinated and centrifuged in a 5 mL tube and exposed to single and repeated shock wave application using different intensities and numbers of pulses. Results: Single treatment of MSCs using intensities 5, 10, 15, and 20 and pulse numbers 100, 250, 500, 750, and 1,000 at a constant pulse repetition frequency of 1 Hz resulted in a decreased viability and proliferation of both cell types with an increase in the intensity and number of pulses compared to controls. No significant difference in the osteogenic differentiation was observed at different time intervals in both cell types when a single shock wave application was performed. However, repeated shock wave sessions over three consecutive days of primary MSCs using low intensity levels 0.1 and 1 showed significant osteogenic differentiation 4-fold higher than that of the extracted Alizarin Red S at day 14, whereas MG63 cells showed no significant osteogenic differentiation compared to their corresponding controls. More specifically, repeated shock wave application triggered a significant downregulation of COL1A1, upregulation of RUNX2, and sustained increase of OCN in primary MSCs but not in the cell line MG63 when induced toward the osteogenic differentiation. Discussion: The effects of shock wave application on MSCs make it an effective therapy in regenerative medicine. We established a protocol to analyze a standardized shock wave application on MSCs and were able to determine conditions that enhance the osteogenic differentiation of MSCs in vitro.

Socioeconomic differences in the utilization of diagnostic imaging and non-pharmaceutical conservative therapies for spinal diseases.

BACKGROUND: A different utilization of health care services due to socioeconomic status on the same health plan contradicts the principle of equal treatment. We investigated the presence and magnitude of socioeconomic differences in utilization of diagnostic imaging and non-pharmaceutical conservative therapies for patients with spinal diseases. METHODS: The cohort study based on routine healthcare data from Germany with 11.7 million patient-years between 2012 and 2016 for patients with physician-confirmed spinal diseases (ICD-10: M40-M54), occupation and age 20 to 64 years. A Poisson model estimated the effects of the socioeconomic status (school education, professional education and occupational position) for the risk ratio of receiving diagnostic imaging (radiography, computed tomography, magnetic resonance imaging) and non-pharmaceutical conservative therapies (physical therapy including exercise therapy, manual therapy and massage, spinal manipulative therapy, acupuncture). RESULTS: Patients received diagnostic imaging in 26%, physical therapy in 32%, spinal manipulative therapy in 25%, and acupuncture in 4% of all patient-years. Similar to previous survey-based studies higher rates of utilization were associated with higher socioeconomic status. These differences were most pronounced for manual therapy, exercise therapy, and magnetic resonance imaging. CONCLUSIONS: The observed differences in health care utilization were highly related to socioeconomic status. Socioeconomic differences were higher for more expensive health services. Further research is necessary to identify barriers to equitable access to health services and to take appropriate action to decrease existing social disparities.

[The third-generation modern cementing technique in hip and knee arthroplasty]. / Moderne Zementiertechnik der dritten Generation in der Knie- und Hüftendoprothetik.

BACKGROUND: Implant loosening is the most common reason for revision surgery. OBJECTIVES: Contribution of modern cementing technique to the long-term stability of an implant. METHODS: Evaluation of the available evidence on modern cementing technique. RESULTS: Modern cementing technique in hip arthroplasty is considered established and leads to better cementing results. In knee arthroplasty, there are also specific recommendations, including intensive cleaning of the bone bed, mixing of bone cement under vacuum and application of bone cement to the implant and the bone. CONCLUSIONS: The use of modern cementing technique in hip and knee arthroplasty facilitates cementing, increases safety, and minimizes the risk of mechanical loosening.

[Customized partial pelvis replacement: three-dimensional planning and management concepts]. / Individuelle Beckenteilersatz-Implantate: 3-D-Planung und Versorgungskonzepte.

The planning and implantation of a customized partial pelvis replacement places high demands on both the surgeon and the entire team (engineer, assistants, surgical team). Thanks to careful preoperative planning and meticulous perioperative execution, customized partial pelvic replacement represents a complex but reliable procedure for defect reconstruction even with highly complex acetabular bone defects or after multiple previous surgeries.

Smartphone Use-Influence on Posture and Gait during Standing and Walking.

Prolonged gaze at a smartphone is characterized by pronounced flexion of the cervical spine and is associated with health risks. In addition, it is suspected that smartphone distraction could lead to gait changes. Therefore, the aim of this study was to detect smartphone-associated postural changes at thoracic and lumbar levels as well as gait changes. Spinal analysis was performed prospectively in 21 healthy men using the DIERS 4Dmotion®Lab in a controlled crossover design to evaluate posture-associated parameters while standing and walking. The examination sequence provided three randomized gaze directions: GN = Gaze Neutral; S1H = Smartphone one-handed; S2H = Smartphone two-handed. Results reveal a higher vertebra prominens (VP)-flexion in S1H (23.8° ± 6.9°; p ≤ 0.001) and S2H (22.4° ± 4.7°; p ≤ 0.001) compared to GN (17.6° ± 3.8°). Kyphosis angles were also different with higher values observed in S1H (58.8° ± 5.8°; p ≤ 0.001) and S2H (61.6° ± 4.9°; p ≤ 0.001) compared to GN (49.1° ± 4.6°). During walking, similar results were observed in kyphosis angles. No differences were observed in gait during smartphone use (p = 0.180-0.883). The study revealed a significantly increased inclination of the lower cervical and thoracic spine during smartphone use. However, the inclination was larger during S2H. Standing or walking conditions did not affect the measurement outcomes. Long-term smartphone use associated with a larger inclination of the cervical and thoracic spine might result in increased pressure and shear forces acting on vertebral bodies, intervertebral discs, and muscles, which potentially increases the risk of spinal pain and disease.

Immunomodulatory potential of mesenchymal stromal cell-derived extracellular vesicles in chondrocyte inflammation.

Introduction: Osteoarthritis (OA) affects a large percentage of the population worldwide. Current surgical and nonsurgical concepts for treating OA only result in symptom-modifying effects. However, there is no disease-modifying therapy available. Extracellular vesicles released by mesenchymal stem/stromal cells (MSC-EV) are promising agents to positively influence joint homeostasis in the osteoarthritic surroundings. This pilot study aimed to investigate the effect of characterized MSC-EVs on chondrogenesis in a 3D chondrocyte inflammation model with the pro-inflammatory cytokine TNFα. Methods: Bovine articular chondrocytes were expanded and transferred into pellet culture at passage 3. TNFα, human MSC-EV preparations (MSC-EV batches 41.5-EVi1 and 84-EVi), EVs from human platelet lysate (hPL4-EV), or the combination of TNFα and EVs were supplemented. To assess the effect of MSC-EVs in the chondrocyte inflammation model after 14 days, DNA, glycosaminoglycan (GAG), total collagen, IL-6, and NO release were quantified, and gene expression of anabolic (COL-II, aggrecan, COMP, and PRG-4), catabolic (MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5), dedifferentiation (COL-I), hypertrophy (COL-X, VEGF), and inflammatory (IL-8) markers were analyzed; histological evaluation was performed using safranin O/Fast Green staining and immunohistochemistry of COL I and II. For statistical evaluation, nonparametric tests were chosen with a significance level of p < 0.05. Results: TNFα supplementation resulted in catabolic stimulation with increased levels of NO and IL-6, upregulation of catabolic gene expression, and downregulation of anabolic markers. These findings were supported by a decrease in matrix differentiation (COL-II). Supplementation of EVs resulted in an upregulation of the chondrogenic marker PRG-4. All MSC-EV preparations significantly increased GAG retention per pellet. In contrast, catabolic markers and IL-8 expression were upregulated by 41.5-EVi1. Regarding protein levels, IL-6 and NO release were increased by 41.5-EVi1. Histologic and immunohistochemical evaluations indicated a higher differentiation potential of chondrocytes treated with 84-EVi. Discussion: MSC-EVs can positively influence chondrocyte matrix production in pro-inflammatory surroundings, but can also stimulate inflammation. In this study MSC-EV 41.5-EVi1 supplementation increased chondrocyte inflammation, whereas MSC-84-EVi supplementation resulted a higher chondrogenic potential of chondrocytes in 3D pellet culture. In summary, the selected MSC-EVs exhibited promising chondrogenic effects indicating their significant potential for the treatment of OA; however, the functional heterogeneity in MSC-EV preparations has to be solved.

A Worldwide Analysis of Adipose-Derived Stem Cells and Stromal Vascular Fraction in Orthopedics: Current Evidence and Applications.

The biological enhancement of tissue regeneration and healing is an appealing perspective in orthopedics. We aimed to conduct a systematic review to describe the global distribution of studies investigating the use of adipose tissue derivates in orthopedics and to provide information on their quality and on the products available. The quality of the included studies was assessed using the modified Coleman Methodology Score (mCMS) and the Cochrane risk-of-bias tool for randomized trials. Eighty-two studies were included, with a total of 3594 patients treated. In total, 70% of the studies investigated the treatment of knee disorders, predominantly osteoarthritis; 26% of all studies dealt with expanded adipose-derived stem/stromal cells (ADSCs), 72% of which had stromal vascular fraction (SVF); 70% described the injection of adipose tissue derivates into the affected site; and 24% described arthroscopies with the addition of adipose tissue derivates. The mean mCMS for all studies was 51.7 ± 21.4 points, with a significantly higher score for the studies dealing with expanded ADSCs compared to those dealing with SVF (p = 0.0027). Our analysis shows high heterogeneity in terms of the types of performed procedures as well as the choice and processing of adipose tissue derivates.

Methods of Conservative Intra-Articular Treatment for Osteoarthritis of the Hip and Knee.

BACKGROUND: Osteoarthritis is a degenerative joint disease that is becoming increasingly common as the population ages. Conservative treatment for hip or knee osteoarthritis has been limited to pain control. Intra-articular injections for targeted local treatment have been widely used in clinical practice for many years. METHODS: This review is based on publications retrieved by a selective literature search, including recent meta-analyses, systematic reviews, randomized controlled trials (RCTs), and current guidelines. RESULTS: In Germany, the 12-month prevalence of osteoarthritis in adults is 17.9%. Conservative treatments are intended to alleviate symptoms and do not affect the progression of the disease. Glucocorticoids can be used to relieve otherwise intractable pain in the short term, but their prolonged use increases the risk of cartilage loss and progression of osteoarthritis. According to multiple guidelines, there is only weak evidence for the use of hyaluronic acid. Evidence does exist that high-molecular-weight hyaluronic acid may lead to better outcomes than the low-molecular-weight form. RCTs have revealed no more than short-term clinical efficacy for a variety of specific therapeutic approaches, including the use of cytokine inhibitors. Other treatments, e.g., with platelet-enriched plasma, aspirates from bone marrow or adipose tissue, or expanded mesenchymal stromal cells (MSC), have not been found to have clinically relevant long-term effects. CONCLUSION: In view of the scant available evidence, further standardized RCTs will be needed to give a more comprehensive picture of the efficacy of intra-articular treatments for hip and knee osteoarthritis.