Xinhua Qu

Treatment of septic patients is confronted with complex immune dysregulation: excessive pro‐inflammatory responses trigger cytokine storm leading to organ damage and high mortality, while concurrent and persistent immune dysfunction manifesting as T cell exhaustion, monocyte and macrophage functional suppression, and impaired antigen presentation significantly increases the risk of secondary infections. Current clinical therapeutic strategies can effectively control infection and cytokine storm, but fail to resolve persistent T cell exhaustion, which is a critical determinant of poor long‐term survival in sepsis patients. This study reported a multifunctional engineered macrophage therapeutic strategy based on in situ LNP delivery of IL‐6/4 fusion protein and LL37 antimicrobial peptide mRNA. The IL‐6/4 fusion blocks IL‐6 mediated pro‐inflammatory signaling and activates IL‐4 mediated anti‐inflammatory pathways, reducing inflammatory injury and promoting tissue repair. LL37 antimicrobial peptide disrupts bacterial membranes to reduce bacterial burden while modulating immune responses. In sepsis mouse models, engineered macrophages significantly improved survival rates, reduced histopathological damage and organ bacterial burden, and effectively restored T cell and macrophage functions, achieving infection control, inflammation modulation, and immune reconstitution. These findings demonstrate the substantial clinical translational potential of this engineered macrophage approach for precision sepsis treatment.

Achieving high strength and robust osteogenesis simultaneously remains a challenge for biodegradable orthopedic materials. Here we show that incorporating trace rare-earth (RE) elements into a Zn-Li-Mn system bridges this gap. By forming REZn_11-13 intermetallic phases, we engineer a bimodal grain structure that elevates tensile strength to 772 MPa and bending strength to 1207 MPa, approaching the level of medical-grade titanium alloy (Ti-6Al-4V) while retaining biodegradability. Crucially, these phases act as "potential-buffering" electrodes, ensuring uniform degradation and controlled zinc ion release. This optimized ion concentration activates the Rap1 signaling pathway, resulting in twofold greater bone regeneration compared to titanium alloy implants. By integrating ultrahigh mechanical strength with potent bioactivity, this Zn-Li-Mn-Y alloy provides a superior platform for next-generation load-bearing implants, offering a degradable alternative to permanent metallic fixations.

The localized immunosuppressive microenvironment is a primary driver of treatment failure and high recurrence in periprosthetic joint infection (PJI). Although this state of immune paralysis is critical to the persistence of infection, clinically applicable immunomodulatory strategies to reverse it remain lacking. Here, utilizing single‐cell RNA sequencing to delineate the immunosuppressive landscape of a murine PJI model, we identified a pivotal subset of polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSCs) characterized by high CXCR4 expression. Mechanistically, we reveal that these CXCR4 ⁺ PMN‐MDSCs interact with AHR ⁺ and TIM1 ⁺ regulatory B cells (Bregs) to sustain a robust immunosuppressive axis. Modulation of CXCR4 signaling reduced the secretion of immunosuppressive mediators, such as ARG1, and decreased Breg abundance, effectively disrupting this suppressive network. To translate these immunological insights into clinical practice, we employed drug screening and identified alendronate as a specific inhibitor of CXCR4 ⁺ PMN‐MDSCs that acts directly via the signal transducer and activator of transcription 3 (STAT3). In vivo evidence from multiple infection models, combining alendronate with vancomycin significantly enhanced bacterial clearance, reversed local immune paralysis, and profoundly promoted structural bone repair. These findings uncover a druggable CXCR4 ⁺ PMN‐MDSC‐Breg immune tolerance network, offering a highly translational immunomodulatory paradigm for overcoming persistent skeletal infections.

Ion release‐driven inflammation and bone loss underlie metallic implant failure. Here, micro‐galvanic coupling design of alloys electrochemically programs essential element releasing dose to modulate immune responses and promote regenerative healing. Using model alloys, finely dispersed Mg ₂ Zn ₁₁ particles in Zn‐0.8Mg act as sacrificial anodes, suppressing Zn matrix dissolution. In contrast, coarse FeZn ₁₃ phases in Zn‐0.8Fe establish a “large cathode‐small anode” galvanic regime, elevating anodic current densities by two orders of magnitude. Consequently, Zn‐0.8Fe implants in bone marrow release excessive Zn ²⁺ , drive massive neutrophil recruitment and proinflammatory polarization (Day 3), and induce M1‐dominant macrophage responses (Day 14), culminating in poor bone formation at Day 90. Conversely, Zn‐0.8Mg releases a moderate Zn ²⁺ flux, promotes pro‐regenerative neutrophil polarization, and guides an M2‐dominant macrophage milieu that fosters osteogenesis rich in type I collagen. Findings here provide the composition design rationale for the development and translational application of a biodegradable Zn alloy cranio‐maxillofacial internal fixation system.

Metallic biomaterials have transformed modern medicine, with copper (Cu), zinc (Zn), and selenium (Se) emerging as critical components in medical applications. The study of the single and synergistic effects of serum metal concentrations on human health can provide valuable insights for future clinical transformation of biodegradable alloys. We evaluated 2381 NHANES 2011–2016 participants to study individual and combined effects of these metals on health outcomes. Multivariable logistic regression, restricted cubic splines, and piecewise linear regression were used to examine linear, nonlinear, and threshold relationships. Overall metal mixture effects were assessed using weighted quantile sum (WQS) and Bayesian kernel-machine regression (BKMR). Elevated serum Cu levels were significantly associated with an increased risk of osteoarthritis. When Serum Cu ≥ 99.48 μg/dL, each 1-unit increase in Ln Cu raised diabetes risk 4.55-fold. For Se ≥ 122.74 μg/L, each 1-unit increase in Ln Se led to a 29.96-fold rise in diabetes prevalence, for Se < 157.56 μg/L it increased heart attack risk 165.19-fold. Furthermore, mixtures of Cu, Se, and Zn were positively associated with diabetes, hypertension, and heart attack risks; each unit increase in the mixture corresponded to a 23 % rise in diabetes and a 15 % rise in hypertension prevalence. Serum Cu levels ≥99.48 μg/dL are significantly linked to diabetes risk, while serum Se levels ≥122.74 μg/L are associated with diabetes risk and levels <157.56 μg/L with elevated heart attack risk. Serum metal mixtures containing Cu, Se and Zn were significantly and positively associated with risk of diabetes, hypertension and heart attack.

Background: Early knee effusion is a common phenomenon after total knee arthroplasty (TKA), with potential clinical implications. Unlike traditional alloy knee prostheses, the polyetheretherketone (PEEK) knee system has radiographic transparency on magnetic resonance (MR) scans, which allows analysis of prosthetic knee effusion. We aimed to identify the distribution and volume of knee effusion after TKA with the PEEK prosthesis with use of MR imaging and to analyze whether dynamic changes in effusion were correlated with serum inflammatory marker changes and knee function recovery. Methods: Nine patients with osteoarthritis who were 59 to 74 years old underwent unilateral TKA with the PEEK prosthesis between June 2021 and August 2021. Dynamic early postoperative changes in the volume and distribution of knee effusion were evaluated with use of 3D MR stereoscopic images. Serum inflammatory markers were measured via blood tests, and joint function was evaluated with use of the subjective functional score of the Knee Society Score (KSS) and knee range of motion (ROM). Linear regression analyses were performed to assess for correlations between knee effusion volume and inflammatory markers and between knee effusion volume and joint function. Results: The mean serum inflammatory marker levels increased significantly at 1 week after TKA with the PEEK prosthesis and then gradually decreased with time from 1 to 6 months. The mean total knee effusion volume gradually decreased over time. Concurrently, the mean KSS subjective functional score and mean knee ROM improved with time. Total knee effusion volume was positively correlated with C-reactive protein level (R² = 0.16; p = 0.007) and negatively correlated with the change in KSS score between the preoperative and postoperative time points (R² = 0.19; p = 0.003). Using the 1-week total knee effusion volume as a reference, a positive correlation was observed between the reduction in total knee effusion volume and the actual value of the ROM (R² = 0.36; p = 0.0001) from 3 to 24 months postoperatively. Conclusions: Through 3D MR imaging, the precise distribution and volume of, and dynamic changes in, knee effusion after TKA with the PEEK prosthesis were confirmed and were found to be correlated with inflammation and joint function in the early postoperative period. The results demonstrate the potential clinical benefit of the PEEK-based knee system for future use. Level of Evidence: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

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.

Background: The posterior cruciate ligament (PCL) attachment may be damaged in cruciate-retaining total knee arthroplasty (CR-TKA) using the complete resection for tibial preparation, and resection amount varies greatly among individuals. Discoid lateral meniscus (DLM) is one of the most common anatomic knee variants. This study aimed to evaluate the difference in PCL attachment sacrifice in CR-TKA between patients with and without DLM. Methods: Fifty-one knees in the study group (DLM group) were matched 1:1 to 51 control knees (non-DLM group) by age, sex, and maximum width of the tibial plateau. The percentage of the sacrificed PCL attachment and the morphological parameters of the tibial plateau were evaluated using magnetic resonance imaging (MRI) in a blind manner. Results: With a tibial cut simulated at a 0°, 3°, and 7° osteotomy slope, the mean PCL attachment resection percentages in the non-DLM group were 40.5%, 53.6%, and 72.6%, respectively. The corresponding resection percentages in the DLM group were 61.0% (P < 0.001), 73.3% (P < 0.001), and 85.7% (P < 0.001), respectively. The percentage of the minimum meniscus width to the maximum tibia width showed a weak positive correlation with the percentage of PCL attachment sacrifice. Conclusions: A significantly greater portion of PCL attachment was sacrificed in DLM patients undergoing CR-TKA using the complete proximal tibia resection. Attention should be paid to PCL attachment resection during CR-TKA in patients with DLM, and alternative techniques or prosthesis types should be considered. Graphical