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Abstract Excessive production of reactive oxygen species (ROS) and inflammation are the key problems that impede diabetic wound healing. In particular, dressings with ROS scavenging capacity play a crucial role in the process of chronic wound healing. Herein, Zr-based large-pore mesoporous metal–organic frameworks (mesoMOFs) were successfully developed for the construction of spatially organized cascade bioreactors. Natural superoxide dismutase (SOD) and an artificial enzyme were spatially organized in these hierarchical mesoMOFs, forming a cascade antioxidant defense system, and presenting efficient intracellular and extracellular ROS scavenging performance. In vivo experiments demonstrated that the SOD@HMUiO-MnTCPP nanoparticles (S@M@H NPs) significantly accelerated diabetic wound healing. Transcriptomic and western blot results further indicated that the nanocomposite could inhibit fibroblast senescence and ferroptosis as well as the stimulator of interferon genes (STING) signaling pathway activation in macrophages mediated by mitochondrial oxidative stress through ROS elimination. Thus, the biomimetic multi-enzyme cascade catalytic system with spatial ordering demonstrated a high potential for diabetic wound healing, where senescence, ferroptosis, and STING signaling pathways may be potential targets. Graphical Abstract Schematic diagram showing the proposed mechanism that S@M@H NPs promoted diabetic wound healing

With the main advantages of simple shape, smart structural and wind direction independence, Straight-bladed vertical axis wind turbines has been increasingly used in rural and marine environments. However, due to its complex aerodynamic characteristics, it is still challenging to improve the performance of straight-bladed vertical axis wind turbines. CFD technology is a useful tool for the study on wind turbine aerodynamics for its low cost and high visualization effect. To provide guidance for the study on SB-VAWTs using numerical simulation by CFD technology, this study reviews the existing methods of CFD technology in the study on straight-bladed vertical axis wind turbines in terms of calculation domain size selection, meshing strategy, time step determination, numerical solution of N–S equation, turbulence model selection, Y+value determination etc. Furthermore, some solutions to some 18 problems of CFD technology in the study on straight-bladed vertical axis wind turbines are proposed. This study can provide a guidance for the study of SB-VAWTs using CFD methods.

Background: Pure magnesium-based ortho-implants have a number of advantages. However, vital parameters like degradation rate and biocompatibility still call for significant improvement. Methods: In this study, poly (1,3-trimethylene carbonate) (PTMC) and polydopamine (PDA) bilayer and micro arc oxidation composite coatings were prepared successively on magnesium surface by immersion method and microarc oxidation. Its corrosion resistance and biocompatibility were evaluated by in vitro corrosion tests, cellular compatibility experiments, and in vivo animal experiments. Results: In vitro experiments demonstrated that the composite coating provides excellent corrosion protection and biocompatibility. Animal studies demonstrated that the composite coating slowed the degradation of the implant and was not toxic to animal viscera. Conclusion: In conclusion, the inorganic-organic composite coating proposed in this study provided good corrosion resistance and enhanced biocompatibility for pure magnesium implants. The translational potential of this article: The translational potential of this article is to develop an anti-corrosion composite coating on a pure magnesium surface and to verify the viability of its use in animal models. It is hoped to open up a new approach to the design of new degradable orthopedic magnesium-based implants.

Abstract Background Although biomedical implants have been widely used in orthopedic treatments, two major clinical challenges remain to be solved, one is the bacterial infection resulting in biofilm formation, and the other is aseptic loosening during implantation due to over-activated osteoclastogenesis. These factors can cause many clinical issues and even lead to implant failure. Thus, it is necessary to endow implants with antibiofilm and aseptic loosening-prevention properties, to facilitate the integration between implants and bone tissues for successful implantation. To achieve this goal, this study aimed to develop a biocompatible titanium alloy with antibiofilm and anti-aseptic loosening dual function by utilizing gallium (Ga) as a component. Methods A series of Ti-Ga alloys were prepared. We examined the Ga content, Ga distribution, hardness, tensile strength, biocompatibility, and anti-biofilm performance in vitro and in vivo. We also explored how Ga3+ ions inhibited the biofilm formation of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) and osteoclast differentiation. Results The alloy exhibited outstanding antibiofilm properties against both S. aureus and E. coli in vitro and decent antibiofilm performance against S. aureus in vivo. The proteomics results demonstrated that Ga3+ ions could disturb the bacterial Fe metabolism of both S. aureus and E. coli, inhibiting bacterial biofilm formation. In addition, Ti-Ga alloys could inhibit receptor activator of nuclear factor-κB ligand (RANKL)-dependent osteoclast differentiation and function by targeting iron metabolism, then suppressing the activation of the NF-κB signaling pathway, thus, showing their potential to prevent aseptic loosening. Conclusion This study provides an advanced Ti-Ga alloy that can be used as a promising orthopedic implant raw material for various clinical scenarios. This work also revealed that iron metabolism is the common target of Ga3+ ions to inhibit biofilm formation and osteoclast differentiation.

Current in vitro models for osteosarcoma investigation and drug screening, including two-dimensional (2D) cell culture and tumour spheroids (i.e. cancer stem-like cells), lack extracellular matrix (ECM). Therefore, results from traditional models may not reflect real pathological processes in genuine osteosarcoma histological structures. Here, we report a three-dimensional (3D) bioprinted osteosarcoma model (3DBPO) that contains osteosarcoma cells and shrouding ECM analogue in a 3D frame. Photo-crosslinkable bioinks composed of gelatine methacrylamide and hyaluronic acid methacrylate mimicked tumour ECM. We performed multi-omics analysis, including transcriptomics and DNA methylomics, to determine differences between the 3DBPO model and traditional models. Compared with 2D models and tumour spheroids, our 3DBPO model showed significant changes in cell cycle, metabolism, adherens junctions, and other pathways associated with epigenetic regulation. The 3DBPO model was more sensitive to therapies targeted to the autophagy pathway. We showed that simulating ECM yielded different osteosarcoma cell metabolic characteristics and drug sensitivity in the 3DBPO model compared with classical models. We suggest 3D printed osteosarcoma models can be used in osteosarcoma fundamental and translational research, which may contribute to novel therapeutic strategy discovery.

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Abstract Diabetic osteoporosis (DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1 (HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

Nanomedicine delivery systems combined with photodynamic therapy, improve targeted cancer enrichment, reduce side effects, and enhance anticancer efficacy. Additionally, ferroptosis has emerged as a novel cancer-killing mechanism, with great potential in cancer treatment. The study aimed to treat head and neck cancers by manufacturing ZIF-8@ssPDA as a drug carrier for the chlorin e6 (Ce6) photosensitizer in response to dual stimuli of the tumor microenvironment. The ZIF-8 structure can efficiently load Ce6, and polydopamine modified with a disulfide bond (ssPDA) is evenly and densely distributed on the ZIF-8 surface. In tumor microenvironments where glutathione (GSH) concentrations are high, the ssPDA structure ruptures, directly consuming GSH and further inactivating GPX4, thereby establishing a specific anticancer effect through the ferroptosis pathway. Furthermore, the Ce6@ZIF-8 structure responsively collapses in the acidic tumor microenvironment, releasing loaded Ce6. Under the excitation of a 660-nm near-infrared laser, large singlet oxygen can be generated from released Ce6 within a short period, exerting a strong photodynamic anticancer effect. Depending on the characteristic tumor microenvironment with high GSH level and acidic environment, this dual-responsive strategy combines a photodynamic and ferroptotic effect; it might improve the treatment efficacy of head and neck cancers.

Background: Clinic treatment of diabetic foot ulcers (DFUs) is considerably challenging. Impaired wound healing may be caused by poor vascularization and dysfunction of the extracellular matrix, which leads to poor re-epithelialization and increased risk of infection. In this study, we evaluated the treatment potential of a functional dressing comprising quaternized chitosan (hydroxypropyltrimethyl ammonium chloride chitosan) and magnesium (Mg) on DFUs. Methods: Dressings were prepared by vacuum freeze-drying. The cellular proliferation, migration, and angiogenesis potential of the functional dressings were determined in vitro. Methicillin-resistant Staphylococcus aureus (MRSA, ATCC43300) and methicillin-resistant Staphylococcus epidermidis 287 (MRSE287) were used to evaluate the antibacterial efficiency of the dressings. Finally, a diabetic rat model with infected wounds was used to further evaluate the effects of functional dressings on the healing of DFUs. Results: Functional dressings facilitated the migration of human dermal fibroblasts and human umbilical vein endothelial cells (HUVECs), while also stimulating angiogenesis in HUVECs. Additionally, the functional dressing could effectively eradicate MRSA and MRSE, exhibiting excellent antibacterial ability against drug-resistant bacteria. The results of in vivo microbiological and histological tests demonstrated effective anti-infection ability and wound-healing potential of this functional dressing. Conclusions: The dual-functional dressing exhibited wound-healing ability and anti-infection efficiency, demonstrating potential application prospects in DFU treatment. Translational potential of this article: As one of the common and serious complications of diabetes, DFUs do not heal easily, causing great suffering to patients. Therefore, improvement in the prognosis of DFUs is a crucial clinical need. The dual-functional dressing prepared in this study was proven to improve the treatment of DFUs, both in vitro and in vivo. Considering its urgent clinical necessity and good biocompatibility of its raw materials, such as alginate, Mg, and chitosan derivatives, this dual-functional dressing presents good prospects for clinical translation.

Large bone defects face a high risk of pathogen exposure due to open wounds, which leads to high infection rates and delayed bone union. To promote successful repair of infectious bone defects, fabrication of a scaffold with dual functions of osteo-induction and bacterial inhibition is required. This study describes creation of an engineered progenitor cell line (C3H10T1/2) capable of doxycycline (DOX)-mediated release of bone morphogenetic protein-2 (BMP2). Three-dimensional bioprinting technology enabled creation of scaffolds, comprising polycaprolactone/mesoporous bioactive glass/DOX and bioink, containing these engineered cells. In vivo and in vitro experiments confirmed that the scaffold could actively secrete BMP2 to significantly promote osteoblast differentiation and induce ectopic bone formation. Additionally, the scaffold exhibited broad-spectrum antibacterial capacity, thereby ensuring the survival of embedded engineered cells when facing high risk of infection. These findings demonstrated the efficacy of this bioprinted scaffold to release BMP2 in a controlled manner and prevent the occurrence of infection; thus, showing its potential for repairing infectious bone defects.

This study investigates whether the intensity of human activities conducted by urban populations and carried by urban land follows a wave-shaped diffusion rule using a harmonized DMSP-like NTL dataset during 1992–2018 in 234 cities of China. The results show that variations in the intensity of human activities are diffused in a wave-shaped manner from the urban center to the periphery in cities of different sizes and structures. The results demonstrate that variations in the intensity of human activity also exhibit a wave-shaped diffusion pattern, which is best modeled by a Gaussian function with an average R2 of 0.79 and standard deviation of 0.36 across all fitted functions. The outward movement of these waves in monocentric cities with an urban population

With the abuse and misuse of antibiotics, antimicrobial resistance has become a challenging issue in the medical system. Iatrogenic and non-iatrogenic infections caused by multidrug-resistant (MDR) pathogens pose serious threats to global human life and health because the efficacy of traditional antibiotics has been greatly reduced and the resulting socio-economic burden has increased. It is important to find and develop non-antibiotic-dependent antibacterial strategies because the development of new antibiotics can hardly keep pace with the emergence of resistant bacteria. Gallium (III) is a multi-target antibacterial agent that has an excellent antibacterial activity, especially against MDR pathogens; thus, a gallium (III)-based treatment is expected to become a new antibacterial strategy. However, some limitations of gallium ions as antimicrobials still exist, including low bioavailability and explosive release. In recent years, with the development of nanomaterials and clathrates, the progress of manufacturing technology, and the emergence of synergistic antibacterial strategies, the antibacterial activities of gallium have greatly improved, and the scope of application in medical systems has expanded. This review summarizes the advancement of current optimization for these key factors. This review will enrich the knowledge about the efficiency and mechanism of various gallium-based antibacterial agents and provide strategies for the improvement of the antibacterial activity of gallium-based compounds.

Background: The anatomical properties of the enthesis of the rotator cuff are hardly regained during the process of healing. The tendon-to-bone interface is normally replaced by fibrovascular tissue instead of interposition fibrocartilage, which impairs biomechanics in the shoulder and causes dysfunction. Tissue engineering offers a promising strategy to regenerate a biomimetic interface. Here, we report heterogeneous tendon-to-bone interface engineering based on a 3D-printed multiphasic scaffold. Methods: A multiphasic poly(ε-caprolactone) (PCL)–PCL/tricalcium phosphate (TCP)–PCL/TCP porous scaffold was manufactured using 3D printing technology. The three phases of the scaffold were designed to mimic the graded tissue regions in the tendon-to-bone interface—tendon, fibrocartilage, and bone. Fibroblasts, bone marrow–derived mesenchymal stem cells, and osteoblasts were separately encapsulated in gelatin methacrylate (GelMA) and loaded seriatim on the relevant phases of the scaffold, by which a cells/GelMA-multiphasic scaffold (C/G-MS) construct, replicating the native interface, was fabricated. Cell proliferation, viability, and chondrogenic differentiation were evaluated in vitro. The C/G-MS constructs were further examined to determine the potential of regenerating a continuous interface with gradual transition of teno-, fibrocartilage- and osteo-like tissues in vivo. Results: In vitro tests confirmed the good cytocompatibility of the constructs. After seven days in culture, cellular microfilament staining indicated that not only could cells well proliferate in GelMA hydrogels ​but also efficiently attach to and grow on scaffold fibres. Moreover, by immunolocalizing collagen type II, chondrogenesis was identified in the intermediate phase of the C/G-MS construct that had been treated with transforming growth factor β3 for 21 days. After subcutaneous implantation in mice, the C/G-MS construct exhibited a heterogeneous and graded structure up to eight weeks, with distinguished matrix distribution observed at one week. Overall, gene expression of tenogenic, chondrogenic, and osteogenic markers showed increasing patterns for eight weeks. Among them, expression of collagen type X gene was found drastically increasing during eight weeks, indicating progressive formation of calcifying cartilage within the constructs. Conclusion: Our findings demonstrate that the stratified manner of fabrication based on the 3D-printed multiphasic scaffold is an effective strategy for tendon-to-bone interface engineering in terms of efficient cell seeding, chondrogenic potential, and distinct matrix deposition in varying phases. The translational potential of this article: We fabricated a biomimetic tendon-to-bone interface by using a 3D-printed multiphasic scaffold and adopting a stratified cell-seeding manner with GelMA. The biomimetic interface might have applications in tendon-to-bone repair in the rotator cuff. It can not only be an alternative to a biological fixation device ​but also offer an ex vivo living graft to replace the damaged enthesis.

The objective was to investigate the effect of kinsenoside (Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis (OA) progression. RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium (CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection (ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB (NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases (MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages, promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment. KEY WORDS: Kinsenoside, Osteoarthritis, Macrophages, Polarization, Chondrocytes

Joint replacement is essential for the treatment of serious joint disease. However, prosthetic failure remains an important clinical issue, with periprosthesis osteolysis (PO), caused by osteoclastic bone resorption induced by wear particles, being the leading cause of failure. Nuclear factor of activated T cells c1 (NFATc1) appears to play an important role in wear particle-induced osteoclastogenesis, with bicarbonate/chloride exchanger, solute carrier family 4, anion exchanger, member 2, (SLC4A2) being upregulated during osteoclastogenesis in an NFATc1-dependent manner. Anion exchange mediated by SLC4A2 in osteoclasts could affect the bone resorption activity by regulating pHi. This study investigated the role and mechanism of SLC4A2 in wear particle-induced osteoclast differentiation and function in vitro. The use of 4, 4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS), an anion exchange inhibitor, suppressed wear particle-induced PO in vivo. Furthermore, controlled release of DIDS from chitosan microspheres can strengthen the PO therapy effect. Therefore, anion exchange mediated by osteoclastic SLC4A2 may be a potential therapeutic target for the treatment of aseptic loosening of artificial joints.

Implant-related infection is a devastating complication in clinical trauma and orthopedics. The aim of this study is to use a bifunctional biomaterial surface in order to investigate the competitive colonization between osteoblasts and bacteria, which is the cause of implant-related infection. A bone-engineering material capable of simultaneously facilitating osteoblast adhesion and inhibiting the growth of Staphylococcus aureus (S. aureus) was prepared. Then, three different co-cultured systems were developed in order to investigate the competitive colonization between the two cohorts on the surface. The results suggested that while the pre-culturing of either cohort compromised the subsequent adhesion of the other according to the ‘race for the surface’ theory, the synergistic effect of preferential cell adhesion and antibacterial activity of the bifunctional surface led to the predominant colonization and survival of osteoblasts, effectively inhibiting the bacterial adhesion and biofilm formation of S. aureus in the co-culture systems with both cohorts. This research offers new insight into the investigation of competitive surface-colonization between osteoblasts and bacteria for implant-related infection.

A novel poly(lactic-co-glycolic acid) (PLGA)-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) composite nanofiber wound dressing was prepared through electrospinning and the entrapment-graft technique as an antibacterial dressing for cutaneous wound healing. HACC with 30% degrees of substitution (DS) was immobilized onto the surface of PLGA membranes via the reaction between carboxyl groups in PLGA after alkali treatment and the reactive groups (–NH2) in HACC molecules. The naked PLGA and chitosan graft PLGA (PLGA-CS) membranes served as controls. The surface immobilization was characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier transform infrared (FTIR), thermogravimetric analysis (TGA) and energy dispersive X-ray spectrometry (EDX). The morphology studies showed that the membranes remain uniform after the immobilization process. The effects of the surface modification by HACC and CS on the biological properties of the membranes were also investigated. Compared with PLGA and PLGA-CS, PLGA-HACC exhibited more effective antibacterial activity towards both Gram-positive (S. aureus) and Gram-negative (P. aeruginosa) bacteria. The newly developed fibrous membranes were evaluated in vitro for their cytotoxicity using human dermal fibroblasts (HDFs) and human keratinocytes (HaCaTs) and in vivo using a wound healing mice model. It was revealed that PLGA-HACC fibrous membranes exhibited favorable cytocompatibility and significantly stimulated adhesion, spreading and proliferation of HDFs and HaCaTs. PLGA-HACC exhibited excellent wound healing efficacy, which was confirmed using a full thickness excision wound model in S. aureus-infected mice. The experimental results in this work suggest that PLGA-HACC is a strong candidate for use as a therapeutic biomaterial in the treatment of infected wounds.

Senile osteoporosis is characterized by age-related bone loss and bone microarchitecture deterioration. However, little is known to date about the mechanism that maintains bone homeostasis during aging. In this study, we identify adenosine monophosphate-activated protein kinase alpha 1 (AMPKα1) as a critical factor regulating the senescence and lineage commitment of mesenchymal stem cells (MSCs). A phospho-mutant mouse model shows that constitutive AMPKα1 activation prevents age-related bone loss and promoted MSC osteogenic commitment with increased bone-derived insulin-like growth factor 1 (IGF-1) secretion. Mechanistically, upregulation of IGF-1 signalling by AMPKα1 depends on cAMP-response element binding protein (CREB)-mediated transcriptional regulation. Furthermore, the essential role of the AMPKα1/IGF-1/CREB axis in promoting aged MSC osteogenic potential is confirmed using three-dimensional (3D) culture systems. Taken together, these results can provide mechanistic insight into the protective effect of AMPKα1 against skeletal aging by promoting bone-derived IGF-1 secretion. [ABSTRACT FROM AUTHOR]

Antibiotics are among the most used weapons in fighting microbial infections and have greatly improved the quality of human life. However, bacteria can eventually evolve to exhibit antibiotic resistance to almost all prescribed antibiotic drugs. Photodynamic therapy (PDT) develops little antibiotic resistance and has become a promising strategy in fighting bacterial infection. To augment the killing effect of PDT, the conventional strategy is introducing excess ROS in various ways, such as applying high light doses, high photosensitizer concentrations, and exogenous oxygen. In this study, we report a metallacage-based PDT strategy that minimizes the use of ROS by jointly using gallium-metal organic framework rods to inhibit the production of bacterial endogenous NO, amplify ROS stress, and enhance the killing effect. The augmented bactericidal effect was demonstrated both in vitro and in vivo. This proposed enhanced PDT strategy will provide a new option for bacterial ablation. [ABSTRACT FROM AUTHOR]