NIR-responsive electrospun nanofiber dressing promotes diabetic-infected wound healing with programmed combined temperature-coordinated photothermal therapy.

BACKGROUND: Diabetic wounds present significant challenges, specifically in terms of bacterial infection and delayed healing. Therefore, it is crucial to address local bacterial issues and promote accelerated wound healing. In this investigation, we utilized electrospinning to fabricate microgel/nanofiber membranes encapsulating MXene-encapsulated microgels and chitosan/gelatin polymers. RESULTS: The film dressing facilitates programmed photothermal therapy (PPT) and mild photothermal therapy (MPTT) under near-infrared (NIR), showcasing swift and extensive antibacterial and biofilm-disrupting capabilities. The PPT effect achieves prompt sterilization within 5 min at 52 °C and disperses mature biofilm within 10 min. Concurrently, by adjusting the NIR power to induce local mild heating (42 °C), the dressing stimulates fibroblast proliferation and migration, significantly enhancing vascularization. Moreover, in vivo experimentation successfully validates the film dressing, underscoring its immense potential in addressing the intricacies of diabetic wounds. CONCLUSIONS: The MXene microgel-loaded nanofiber dressing employs temperature-coordinated photothermal therapy, effectively amalgamating the advantageous features of high-temperature sterilization and low-temperature promotion of wound healing. It exhibits rapid, broad-spectrum antibacterial and biofilm-disrupting capabilities, exceptional biocompatibility, and noteworthy effects on promoting cell proliferation and vascularization. These results affirm the efficacy of our nanofiber dressing, highlighting its significant potential in addressing the challenge of diabetic wounds struggling to heal due to infection.

Unraveling the mechanism of ceftaroline-induced allosteric regulation in penicillin-binding protein 2a: insights for novel antibiotic development against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) acquires high-level resistance against ß-lactam antibiotics by expressing penicillin-binding protein 2a (PBP2a). PBP2a is a cell wall-synthesizing protein whose closed active site exhibits a reduced binding affinity toward ß-lactam antibiotics. Ceftaroline (CFT), a fifth-generation cephalosporin, can effectively inhibit the PBP2a activity by binding to an allosteric site to trigger the active site opening, allowing a second CFT to access the active site. However, the essential mechanism behind the allosteric behavior of PBP2a remains unclear. Herein, computational simulations are employed to elucidate how CFT allosterically regulates the conformation and dynamics of the active site of PBP2a. While CFT stabilizes the allosteric domain surrounding it, it simultaneously enhances the dynamics of the catalytic domain. Specifically, the study successfully captured the opening process of the active pocket in the allosteric CFT-bound systems and discovered that CFT alters the potential signal-propagating pathways from the allosteric site to the active site. These findings reveal the implied mechanism of the CFT-mediated allostery in PBP2a and provide new insights into dual-site drug design or combination therapy against MRSA targeting PBP2a.

Synergistic inhibition mechanism of quinazolinone and piperacillin on penicillin-binding protein 2a: a promising approach for combating methicillin-resistant Staphylococcus aureus.

The production of penicillin-binding protein 2a (PBP2a), a cell wall synthesis protein, is primarily responsible for the high-level resistance observed in methicillin-resistant Staphylococcus aureus (MRSA). PBP2a exhibits a significantly reduced affinity for most ß-lactam antibiotics owing to its tightly closed active site. Quinazolinones (QNE), a novel class of non-ß-lactam antibiotics, could initiate the allosteric regulation of PBP2a, resulting in the opening of the initially closed active pocket. Based on our previous study, we have a basic understanding of the dual-site inhibitor ceftaroline (CFT) induced allosteric regulation of PBP2a. However, there are still limitations in the knowledge of how combining medicines, QNE and piperacillin (PIP), induce the allosteric response of PBP2a and inhibit its function. Herein, molecular dynamics (MD) simulations were performed to elucidate the intricate mechanisms underlying the combination mode of QNE and PIP. Our study successfully captured the opening process of the active pocket upon the binding of the QNE at the allosteric site, which alters the signaling pathways with a favorable transmission to the active site. Subsequent docking experiments with different conformational states of the active pocket indicated that all three inhibitors, PIP, QNE, and CFT, exhibited higher docking scores and more favorable docking poses to the open active pocket. These findings reveal the implied mechanism of QNE-mediated allostery underlying combination therapy and provide novel insights into developing innovative therapeutic modalities against MRSA.Communicated by Ramaswamy H. Sarma.

Electrospun polyvinyl alcohol-chitosan dressing stimulates infected diabetic wound healing with combined reactive oxygen species scavenging and antibacterial abilities.

Diabetic wounds (DW) are constantly challenged by excessive reactive oxygen species (ROS) accumulation and susceptibility to bacterial contamination. Therefore, the elimination of ROS in the immediate vicinity and the eradication of local bacteria are critical to stimulating the efficient healing of diabetic wounds. In the current study, we encapsulated mupirocin (MP) and cerium oxide nanoparticles (CeNPs) into a polyvinyl alcohol/chitosan (PVA/CS) polymer, and then a PVA/chitosan nanofiber membrane wound dressing was fabricated using electrostatic spinning, which is a simple and efficient method for fabricating membrane materials. The PVA/chitosan nanofiber dressing provided a controlled release of MP, which produced rapid and long-lasting bactericidal activity against both methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains. Simultaneously, the CeNPs embedded in the membrane exhibited the desired ROS scavenging capacity to maintain the local ROS at a normal physiological level. Moreover, the biocompatibility of the multifunctional dressing was evaluated both in vitro and in vivo. Taken together, PVA-CS-CeNPs-MP integrated the desirable features of a wound dressing, including rapid and broad-spectrum antimicrobial and ROS scavenging activities, easy application, and good biocompatibility. The results validated the effectiveness of our PVA/chitosan nanofiber dressing, highlighting its promising translational potential in the treatment of diabetic wounds.

Using a degradable three-layer sandwich-type coating to prevent titanium implant infection with the combined efficient bactericidal ability and fast immune remodeling property.

Titanium (Ti) implant-associated infections are a challenge in orthopedic surgery, for which a series of antibacterial coatings have been designed and fabricated to reduce the risk of bacterial contamination. Herein, we created a degradable three-layer sandwich-type coating to achieve long-term antibacterial effects while simultaneously reconstructing the local immune microenvironment. The vancomycin (Van)-loaded vaterite coating constitutes the outer and inner layers, whereas Interleukin-12 (IL-12)-containing liposomes embedded in sodium alginate constitutes the middle layer. Van, released from the vaterite, demonstrated a favorable and rapid bactericidal ability against the representative methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) strains. The released IL-12 exhibited the desired immune reconstitution abilities, actively facilitating defenses against subsequent bacterial invasions. Furthermore, the biocompatibility and cell-binding feature of the multifunctional coating was beneficial for achieving solid interface intergradation. Overall, the benefits of the three-layer sandwich-type coating, including the convenient fabrication process, efficient antimicrobial activity, fast immune remodeling property, fine cell-binding feature, and biodegradability, highlight its promising translational potential in preventing implant infection. STATEMENT OF SIGNIFICANCE: To prevent titanium implant infections, researchers have designed various antibacterial coatings. However, most of these coatings focused only on killing the invading bacteria over a limited postoperative period. However, the local immune microenvironment is compromised during surgery. Local immune deflection impedes the ability of the local immune defenses to clear bacteria and limits immune memory building from active defense against long-term subsequent bacterial invasions. Furthermore, these coatings are usually nondegradable and differ substantially from bone components, thereby impairing the integration of the coating and bone interface and generating concerns about implant stability and bacterial contamination. In this work, we synthesized a degradable coating that provides sustained antibacterial activity, promotes immune reconstitution, and simultaneously achieves solid bone integration.

Incidence and Risk Factors of In-Hospital Prosthesis-Related Complications Following Total Knee Arthroplasty: A Retrospective Nationwide Inpatient Sample Database Study.

OBJECTIVE: To examine the incidence and risk factors of in-hospital prosthesis-related complications (PRCs) following total knee arthroplasty (TKA) using a large-scale national database. METHODS: A retrospective database analysis was performed based on Nationwide Inpatient Sample (NIS) from 2005-2014. Patients who underwent TKA were included. The recruited cases were divided into two groups according to the occurrence of PRCs. Patient demographics (age, sex, and race), hospital characteristics (type of admission and payer, and bedsize, teaching status, location, and region of hospital), length of stay (LOS), total charges during hospitalization, in-hospital mortality, comorbidities, and perioperative complications were analyzed. RESULTS: A total of 1,227,244 TKAs were captured from the NIS database. There were 8484 cases of in-hospital PRCs after TKA and the overall incidence was 0.69%, with a slight downward trend annually. Periprosthetic joint infection (PJI) was the main category among PRCs (0.20%), followed by mechanical loosening (0.04%), dislocation (0.02%), and periprosthetic fracture (PPF) (0.01%). Patients suffered from in-hospital PRCs were 3 years younger (64 years vs 67 years) and 6.51% more likely to be male (43.60% vs 37.09%) compared to the nonaffected population (P < 0.0001). Additionally, patients experiencing in-hospital PRCs after TKA were 2.11% less likely through elective admission (92.07% vs 94.18%) while 2.34% more likely in teaching hospital (45.53% vs 43.19%) than those without these complications (P < 0.0001). Furthermore, the occurrence of in-hospital PRCs was associated with longer LOS (4 days vs 3 days; P < 0.0001), more total charges ($53,418 vs $41,204, P < 0.0001), and higher in-hospital mortality (0.30% vs 0.07%; P < 0.0001). Multivariate logistic regression was performed to identify independent risk factors of in-hospital PRCs after TKA which included younger age, male, non-elective admission, teaching hospital, deficiency and chronic blood loss anemia, coagulopathy, congestive heart failure, depression, diabetes with chronic complications, fluid and electrolyte disorders, pulmonary circulation disorders, metastatic cancer, and weight loss. Besides, in-hospital PRCs after TKA were associated with secondary osteoarthritis, inflammatory arthritis, prior knee arthroscopy, acute renal failure, acute myocardial infarction, deep vein thrombosis, sepsis, transfusion, and wound dehiscence. CONCLUSION: It is beneficial to study the risk factors of in-hospital PRCs after TKA to ensure the appropriate management and optimize consequences although a relatively low incidence was identified.

Nanohydroxyapatite, Nanosilicate-Reinforced Injectable, and Biomimetic Gelatin-Methacryloyl Hydrogel for Bone Tissue Engineering.

PURPOSE: Given that autologous bone graft for bone defects is limited by insufficient supply and morbidity at the donor site, developing biomimetic graft materials as an alternative has gained consistent attention. However, obstacles in designing bone-mimetic materials that could integrate the biomimetic nature of the bone extracellular matrix, osteogenic cells, and osteoinductive ingredients with a fast and convenient strategy still exist. METHODS: This study designed and fabricated a mesenchymal stem cell (MSC)-laden, nanohydroxyapatite (HAP), and nanosilicate (SN)-loaded bone mimetic and injectable gelatin-methacryloyl hydrogel (GelMA-HAP-SN) system for bone tissue engineering, and systemically investigated the osteogenic capacity of GelMA-HAP-SN in vitro and in vivo. RESULTS: Introducing HAP enhanced the compositional similarity to the natural bone extracellular matrix, and SN loading endowed the hydrogel with injectable and osteogenic ability. As a result, the GelMA-HAP-SN hydrogel demonstrated an increase in cellular viability, proliferation, and spreading behavior. The GelMA-HAP-SN hydrogel also amplified the embedded MSCs' osteogenic biomarkers' expression and matrix mineralization. Furthermore, the MSC-encapsulated GelMA-HAP-SN hydrogel was injected into rats' critical-sized calvaria defect, and micro-CT and histomorphometry staining results further confirmed its excellent bone regeneration ability. CONCLUSION: These MSC-loaded GelMA-HAP-SN hydrogels are potential graft materials for bone defect treatment.