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Healing of fractures or bone defects is significantly hindered by overactivated osteoclasts and inhibited osteogenesis in patients with abnormal bone metabolism. Current clinical approaches using titanium alloys or stainless steel provide mechanical support but have no biological effects on bone regeneration. Therefore, designing and fabricating degradable metal materials with sufficient mechanical strength and bidirectional regulation of both osteoblasts and osteoclasts is a substantial challenge. Here, this study first reported an adaptive biodegradable Zn-0.8 Mg alloy with bidirectional regulation of bone homeostasis, which promotes osteogenic differentiation by activating the Pi3k/Akt pathway and inhibits osteoclast differentiation by inhibiting the GRB2/ERK pathway. The anti-osteolytic ability of the Zn-0.8 Mg alloy was verified in a mouse calvarial osteolysis model and its suitability for internal fracture fixation with high-strength screws was confirmed in the rabbit femoral condyle fracture model. Furthermore, in an aged postmenopausal rat femoral condyle defect model, 3D printed Zn-0.8 Mg scaffolds promoted excellent bone regeneration through adaptive structures with good mechanical properties and bidirectionally regulated bone metabolism, enabling personalized bone defect repair. These findings demonstrate the substantial potential of the Zn-0.8 Mg alloy for treating fractures or bone defects in patients with aberrant bone metabolism.

Abstract Background Depression and sleep disturbances are associated with increased risks of various diseases and mortality, but their impacts on mortality in cancer survivors remain unclear. The objective of this study was to characterize the independent and joint associations of depressive symptoms and sleep disturbances with mortality outcomes in cancer survivors. Methods This population-based prospective cohort study included cancer survivors aged ≥ 20 years (n = 2947; weighted population, 21,003,811) from the National Health and Nutrition Examination Survey (NHANES) 2007–2018 cycles. Depressive symptoms and sleep disturbances were self-reported. Depressive symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9). Death outcomes were determined by correlation with National Death Index records through December 31, 2019. Primary outcomes included all-cause, cancer-specific, and noncancer mortality. Results During the median follow-up of 69 months (interquartile range, 37–109 months), 686 deaths occurred: 240 participants died from cancer, 146 from heart disease, and 300 from other causes. Separate analyses revealed that compared with a PHQ-9 score (0–4), a PHQ-9 score (5–9) was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.28; 95% CI, 1.03–1.59), and a PHQ-9 score (≥ 10) was associated with greater risk of all-cause mortality (HR, 1.37; 95% CI, 1.04–1.80) and noncancer mortality (HR, 1.45; 95% CI, 1.01–2.10). Single sleep disturbances were not associated with mortality risk. In joint analyses, the combination of a PHQ-9 score ≥ 5 and no sleep disturbances, but not sleep disturbances, was associated with increased risks of all-cause mortality, cancer-specific mortality, and noncancer mortality. Specifically, compared with individuals with a PHQ-9 score of 0–4 and no sleep disturbances, HRs for all-cause mortality and noncancer mortality in individuals with a PHQ-9 score of 5–9 and no sleep disturbances were 1.72 (1.21–2.44) and 1.69 (1.10–2.61), respectively, and 2.61 (1.43–4.78) and 2.77 (1.27–6.07), respectively, in individuals with a PHQ-9 score ≥ 10 and no sleep disturbances; HRs for cancer-specific mortality in individuals with a PHQ-9 score ≥ 5 and no sleep disturbances were 1.95 (1.16–3.27). Conclusions Depressive symptoms were linked to a high risk of mortality in cancer survivors. The combination of a PHQ-9 score (≥ 5) and an absence of self-perceived sleep disturbances was associated with greater all-cause mortality, cancer-specific mortality, and noncancer mortality risks, particularly in individuals with a PHQ-9 score (≥ 10).

Abstract Background Excessive oxidative stress at the wound sites always leads to a prolonged healing and even causes chronic inflammatory wounds. Therefore, antioxidative dressings with multiple features are desired to improve wound healing performance. Herein, we fabricated a ROS-scavenging hybrid hydrogel by incorporating mussel-inspired fullerene nanocomposites (C60@PDA) into gelatin methacryloyl (GelMA) hydrogel. Results The developed C60@PDA/GelMA hydrogel showed a sustainable free radical scavenging ability, and eliminated ROS to protect cells against external oxidative stress damage. Besides, the hydrogel presented favorable cytocompatibility, hemocompatibility, and antibacterial ability in vitro. Furthermore, in a mouse full-thickness wound defect model, the in situ forming hybrid hydrogel accelerated wound closure by 38.5% and 42.9% on day 3 and day 7 over the control. Histological results demonstrated that hybrid hydrogels effectively enhanced wound healing on re-epithelialization, collagen deposition and angiogenesis. Conclusion Collectively, the C60@PDA/GelMA hydrogel could be a promising dressing for promoting cutaneous wound repair.

Objective The current diagnostic criteria for periprosthetic joint infection (PJI) are diverse and controversial, leading to delayed diagnosis. This study aimed to evaluate and unify their diagnostic accuracy and the threshold selection of serum and synovial routine tests for PJI at an early stage. Methods We searched the MEDLINE and Embase databases for retrospective or prospective studies which reported preoperative‐available assays (serum, synovial, or culture tests) for the diagnosis of chronic PJI among inflammatory arthritis (IA) or non‐IA populations from January 1, 2000 to June 30, 2022. Threshold effective analysis was performed on synovial polymorphonuclear neutrophils (PMN%), synovial white blood cell (WBC), serum C‐reactive protein (CRP), and erythrocyte sedimentation rate (ESR) to find the relevant cut‐offs. Results Two hundred and sixteen studies and information from 45,316 individuals were included in the final analysis. Synovial laboratory‐based α‐defensin and calprotectin had the best comprehensive sensitivity (0.91 [0.86–0.94], 0.95 [0.88–0.98]) and specificity (0.96 [0.94‐0.97], 0.95 [0.89–0.98]) values. According to the threshold effect analysis, the recommended cut‐offs are 70% (sensitivity 0.89 [0.85–0.92], specificity 0.90 [0.87–0.93]), 4100/μL (sensitivity 0.90 [0.87–0.93], specificity 0.97 [0.93–0.98]), 13.5 mg/L (sensitivity 0.84 [0.78–0.89], specificity 0.83 [0.73–0.89]), and 30 mm/h (sensitivity 0.79 [0.74–0.83], specificity 0.78 [0.72–0.83]) for synovial PMN%, synovial WBC, serum CRP, and ESR, respectively, and tests seem to be more reliable among non‐IA patients. Conclusions The laboratory‐based synovial α‐defensin and synovial calprotectin are the two best independent preoperative diagnostic tests for PJI. A cut off of 70% for synovial PMN% and tighter cut‐offs for synovial WBC and serum CRP could have a better diagnostic accuracy for non‐IA patients with chronic PJI.

Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters.

Porous tantalum implants are a class of materials commonly used in clinical practice to repair bone defects. However, the cumbersome and problematic preparation procedure have limited their widespread application. Additive manufacturing has revolutionized the design and process of orthopedic implants, but the pore architecture feature of porous tantalum scaffolds prepared from additive materials for optimal osseointegration are unclear, particularly the influence of porosity. We prepared trabecular bone-mimicking tantalum scaffolds with three different porosities (60%, 70% and 80%) using the laser powder bed fusing technique to examine and compare the effects of adhesion, proliferation and osteogenic differentiation capacity of rat mesenchymal stem cells on the scaffolds in vitro. The in vivo bone ingrowth and osseointegration effects of each scaffold were analyzed in a rat femoral bone defect model. Three porous tantalum scaffolds were successfully prepared and characterized. In vitro studies showed that scaffolds with 70% and 80% porosity had a better ability to osteogenic proliferation and differentiation than scaffolds with 60% porosity. In vivo studies further confirmed that tantalum scaffolds with the 70% and 80% porosity had a better ability for bone ingrowh than the scaffold with 60% porosity. As for osseointegration, more bone was bound to the material in the scaffold with 70% porosity, suggesting that the 3D printed trabecular tantalum scaffold with 70% porosity could be the optimal choice for subsequent implant design, which we will further confirm in a large animal preclinical model for better clinical use.

Abstract Background Increasing total knee arthroplasty (TKA) surgeries are being performed on working-age patients with prominent manifestations of pain and dysfunction. But few studies have explored the risk factors for pain and dysfunction in working-age patients with knee osteoarthritis (KOA) being considered for TKA. Therefore, this study sought to explore the relationship between mental health/physical activity and pain/dysfunction in working-age patients with KOA being considered for TKA. Methods This study was a secondary analysis of data derived from a public database, the Work participation In Patients with Osteoarthritis cohort study, which included 152 working-age patients (65 men and 87 women) with KOA planning for TKA. We analyzed preoperative data comprising age, educational level, body mass index (BMI), mental factors (Patient Health Questionnaire-9 [PHQ-9] and the 36-Item Short Form Survey Instrument [SF-36 mental health]), physical activity level, and clinical outcomes (the Western Ontario and McMaster Universities Osteoarthritis Index and SF-36 sub-item score). Multivariate regression analysis was performed to determine risk factors for pain and dysfunction in working-age patients with KOA being considered for TKA. Results Women had lower pain, worse function, and higher PHQ-9 scores than men (p

Due to the vasculature defects and/or the avascular nature of cartilage, as well as the complex gradients for bone-cartilage interface regeneration and the layered zonal architecture, self-repair of cartilage and subchondral bone is challenging. Currently, the primary osteochondral defect treatment strategies, including artificial joint replacement and autologous and allogeneic bone graft, are limited by their ability to simply repair, rather than induce regeneration of tissues. Meanwhile, over the past two decades, three-dimension (3D) printing technology has achieved admirable advancements in bone and cartilage reconstruction, providing a new strategy for restoring joint function. The advantages of 3D printing hybrid materials include rapid and accurate molding, as well as personalized therapy. However, certain challenges also exist. For instance, 3D printing technology for osteochondral reconstruction must simulate the histological structure of cartilage and subchondral bone, thus, it is necessary to determine the optimal bioink concentrations to maintain mechanical strength and cell viability, while also identifying biomaterials with dual bioactivities capable of simultaneously regenerating cartilage. The study showed that the regeneration of bone-cartilage interface is crucial for the repair of osteochondral defect. In this review, we focus on the significant progress and application of 3D printing technology for bone-cartilage interface regeneration, while also expounding the potential prospects for 3D printing technology and highlighting some of the most significant challenges currently facing this field.

Background/objective: Orthopaedic implants are important devices aimed at relieving pain and improving mobility. Staphylococcal infection and aseptic loosening are two common events associated with inflammatory osteolysis that lead to implant failures. Bone mass and biomechanical properties are important indicators that could influence patient outcomes after revision surgery. However, the dynamics of bacterial infections and their influence on bone mass and biomechanical properties remain unclear. Hence, in this study, we developed rabbit aseptic inflammation and staphylococcal infection models to determine the effects of coagulase-positive and coagulase-negative bacterial infection, as well as aseptic inflammation, on the mass and biomechanical properties of the bone. Methods: Sixty New Zealand white rabbits were randomly assigned to 6 groups, and each group had 10 rabbits. The medullary cavities in rabbits of each group were injected with phosphate-buffered saline (100 ​μL), titanium (Ti)-wear particles (300 μg/100 ​μL), a low concentration of Staphylococcus epidermidis (105/100 ​μL), a high concentration of S. epidermidis (108/100 ​μL), a low concentration of Staphylococcus aureus (105/100 ​μL), and a high concentration of S. aureus (108/100 ​μL), respectively. At four and eight weeks after surgery, the rabbits were sacrificed, and the tibias on the surgical side were analysed via histopathology, microcomputed tomography, and nanoindentation testing. Results: Histopathological analysis demonstrated that inflammatory responses and bacterial loads caused by high concentrations of staphylococcal infections, particularly coagulase-positive staphylococci, are more detrimental than low concentrations of bacterial infection and Ti-wear particles. Meanwhile, microcomputed tomography and nanoindentation testing showed that high concentrations of S. aureus caused the highest loss in bone mass and most biomechanical function impairment in rabbits experiencing aseptic inflammation and staphylococcal infections. Conclusions: Inflammatory osteolysis caused by a high concentration of coagulase-positive staphylococci is significantly associated with low bone mass and impaired biomechanical properties. The translational potential of this article: It is necessary to obtain an overall assessment of the bone mass and biomechanical properties before revision surgery, especially when S. aureus infection is involved. In addition, a better understanding of these two parameters might help develop a reasonable treatment regimen and reduce the risk of adverse events after revision surgery. Keywords: Biomechanical phenomena, Bone density, Bone resorption, Osteolysis, Staphylococcal infections

Biofilms refer to complex bacterial communities that are attached to the surface of animate or inanimate objects, which highly resist the antibiotics or the host immune defense mechanisms. Pathogenic biofilms in medicine are general, chronic, and even costly, especially on medical devices and orthopedic implants. Bacteria within biofilms are the cause of many persistent infections, which are almost impossible to eradicate. Though some progress has been made in comprehending the mechanisms of biofilm formation and persistence, novel alternative compounds or strategies and effective anti-biofilm antibiotics are still lacking. Smart materials of nano size which are able to respond to an external stimulus or internal environment have a great range of applications in clinic. Recently, smart nanomaterials with or without carriage of antibiotics, targeting specific bacteria and biofilm under some stimuli, have shown great potential for pathogenic biofilm and resident bacteria eradication. First, this review briefly summarizes and describes the significance of biofilms and the process of biofilm formation. Then, we focus on some of the latest research studies involving biofilm elimination, which probably could be applied in orthopedic implants. Finally, some outstanding challenges and limitations that need to be settled urgently in order to make smart nanomaterials effectively target and treat implant biofilms are also discussed. It is hoped that there will be more novel anti-biofilm strategies for biofilm infection in the prospective future.

Abstract Implant infections caused by methicillin‐resistant Staphylococcus aureus (MRSA) can cause major complications during the perioperative period. Diclofenac, one of the most widely used nonsteroidal anti‐inflammatory drugs, is often used to relieve pain and inflammation. In this study, it is found that high‐dose diclofenac can inhibit the growth of MRSA, and does not easily induce drug‐resistant mutations after continuous passage. However, low‐doses diclofenac can resensitize bacteria to β‐lactams, which help to circumvent drug resistance and improve the antibacterial efficacy of conventional antibiotics. Further, low‐dose diclofenac in combination with β‐lactams inhibit MRSA associated biofilm formation in implants. Transcriptomic and proteomic analyses indicate that diclofenac can reduce the expression of genes and proteins associated with β‐lactam resistance: mecA, mecR, and blaZ; peptidoglycan biosynthesis: murA, murC, femA, and femB; and biofilm formation: altE and fnbP. Murine implant infection models indicate that diclofenac combined with β‐lactams, can substantially alleviate MRSA infections in vivo. In addition, it is investigated that low dose diclofenac can inhibit MRSA antibiotic resistance via the mecA/blaZ pathway and related biofilms in implants. The synergistic effect of diclofenac and β‐lactams might have promising applications for preventing perioperative infection, considering its multitarget effects against MRSA.