Targeted Light-Induced Immunomodulatory Strategy for Implant-Associated Infections via Reversing Biofilm-Mediated Immunosuppression.

The clinical treatment efficacy for implant-associated infections (IAIs), particularly those caused by Methicillin-resistant Staphylococcus aureus (MRSA), remains unsatisfactory, primarily due to the formation of biofilm barriers and the resulting immunosuppressive microenvironment, leading to the chronicity and recurrence of IAIs. To address this challenge, we propose a light-induced immune enhancement strategy, synthesizing BSA@MnO2@Ce6@Van (BMCV). The BMCV exhibits precise targeting and adhesion to the S. aureus biofilm-infected region, coupled with its capacity to catalyze oxygen generation from H2O2 in the hypoxic and acidic biofilm microenvironment (BME), promoting oxygen-dependent photodynamic therapy efficacy while ensuring continuous release of manganese ions. Notably, targeted BMCV can penetrate biofilms, producing ROS that degrade extracellular DNA, disrupting the biofilm structure and impairing its barrier function, making it vulnerable to infiltration and elimination by the immune system. Furthermore, light-induced reactive oxygen species (ROS) around the biofilm can lyse S. aureus, triggering bacterium-like immunogenic cell death (ICD), releasing abundant immune costimulatory factors, facilitating the recognition and maturation of antigen-presenting cells (APCs), and activating adaptive immunity. Additionally, manganese ions in the BME act as immunoadjuvants, further amplifying macrophage-mediated innate and adaptive immune responses and reversing the immunologically cold BME to an immunologically hot BME. We prove that our synthesized BMCV elicits a robust adaptive immune response in vivo, effectively clearing primary IAIs and inducing long-term immune memory to prevent recurrence. Our study introduces a potent light-induced immunomodulatory nanoplatform capable of reversing the biofilm-induced immunosuppressive microenvironment and disrupting biofilm-mediated protective barriers, offering a promising immunotherapeutic strategy for addressing challenging S. aureus IAIs.

Neutrophil Function Conversion Driven by Immune Switchpoint Regulator against Diabetes-Related Biofilm Infections.

Reinforced biofilm structures and dysfunctional neutrophils induced by excessive oxidative stress contribute to the refractoriness of diabetes-related biofilm infections (DRBIs). Herein, in contrast to traditional antibacterial therapies, an immune switchpoint-driven neutrophil immune function conversion strategy based on a deoxyribonuclease I loaded vanadium carbide MXene (DNase-I@V2 C) nanoregulator is proposed to treat DRBIs via biofilm lysis and redirecting neutrophil functions from NETosis to phagocytosis in diabetes. Owing to its intrinsic superoxide dismutase/catalase-like activities, DNase-I@V2 C effectively scavenges reactive oxygen species (ROS) in a high oxidative stress microenvironment to maintain the biological activity of DNase-I. By increasing the depth of biofilm penetration of DNase-I, DNase-I@V2 C thoroughly degrades extracellular DNA and neutrophil extracellular traps (NETs) in extracellular polymeric substances, thus breaking the physical barrier of biofilms. More importantly, as an immune switchpoint regulator, DNase-I@V2 C can skew neutrophil functions from NETosis toward phagocytosis by intercepting ROS-NE/MPO-PAD4 and activating ROS-PI3K-AKT-mTOR pathways in diabetic microenvironment, thereby eliminating biofilm infections. Biofilm lysis and synergistic neutrophil function conversion exert favorable therapeutic effects on biofilm infections in vitro and in vivo. This study serves as a proof-of-principle demonstration of effectively achieving DRBIs with high therapeutic efficacy by regulating immune switchpoint to reverse neutrophil functions.

Trends in microbiological epidemiology of orthopedic infections: a large retrospective study from 2008 to 2021.

BACKGROUND: This study assessed the distribution characteristics of pathogens isolated from cases of orthopedic infections and focused on the antimicrobial susceptibility of the main pathogens. METHODS: This retrospective study involved patients with orthopedic infection in a tertiary medical center located in Shanghai, China, from 2008 to 2021.Pathogen information and the basic information of patients were identified from clinical microbiology laboratory data and the institutional medical record system. RESULTS: In total, the pathogen information of 2821 patients were enrolled in the study. S. aureus (37.71%) was the main causative pathogen responsible for orthopedic infection. Gender, pathogens distribution and polymicrobial infection rates were significantly different (P < 0.05) among patients with different orthopedic infection diseases.The trends in the distribution of pathogens in the total cohort, implant-related infection group (Group A), non-implant-related infection group (Group B), and the sub-group of cases with arthroplasty showed significant linear changes over time. And the polymicrobial infection rates of the total cohort (from 17.17% to 11.00%), Group B(from 24.35% to 14.47%), and the sub-group of cases with internal fixation (from 10.58% to 4.87%) decreased significantly. The antimicrobial susceptibility showed changing trends with time for some main pathogens, especially for S.aureus and Enterobacter spp. CONCLUSIONS: Our research indicated that the pathogen distribution and antimicrobial susceptibility in orthopedic infections changed over time. And the distribution of pathogens varied significantly among different types of orthopedic infectious diseases. These findings may serve as a reference for prophylaxis and empirical treatment strategies of orthopedic infection.

Identification of Staphylococcus aureus virulence-modulating RNA from transcriptomics data with machine learning.

The virulence factors of Staphylococcus aureus are tightly controlled by two-component systems (TCSs) and small RNA (sRNA). TCSs have been well studied over the past several decades, but our understanding of sRNA functions lags far behind that of TCS functions. Here, we studied the biological role of sRNA from 506 S. aureus RNA-seq datasets using independent component analysis (ICA). We found that a previously neglected sRNA, Sau-41, functions in the Agr system. Sau-41 is located within the PSMα operon and controlled by the Agr system. It was predicted to share 22-base complementarity with RNAIII, a major regulator of S. aureus virulence. The EMSA results demonstrated that Sau-41 directly binds to RNAIII. Furthermore, our results found that Sau-41 is capable of repressing S. aureus haemolysin activity by downregulating α-haemolysin and δ-toxin. The repression of α-haemolysin was attributed to the competition between the 5' UTR of hla and Sau-41 for binding RNAIII. We observed that Sau-41 mitigated S. aureus virulence in an orthopaedic implant infection mouse model and alleviated osteolysis. Together, our results indicate that Sau-41 is a virulence-regulating RNA and suggest that Sau-41 might be involved in a negative feedback mechanism to control the Agr system. This work is a demonstration of using ICA in sRNA identification by mining high-throughput data and could be extended to other organisms as well.

Interactions between Macrophages and Biofilm during Staphylococcus aureus-Associated Implant Infection: Difficulties and Solutions.

Staphylococcus aureus (S. aureus) biofilm is the major cause of failure of implant infection treatment that results in heavy social and economic burden on individuals, families, and communities. Planktonic S. aureus attaches to medical implant surfaces where it proliferates and is wrapped by extracellular polymeric substances, forming a solid and complex biofilm. This provides a stable environment for bacterial growth, infection maintenance, and diffusion and protects the bacteria from antimicrobial agents and the immune system of the host. Macrophages are an important component of the innate immune system and resist pathogen invasion and infection through phagocytosis, antigen presentation, and cytokine secretion. The persistence, spread, or clearance of infection is determined by interplay between macrophages and S. aureus in the implant infection microenvironment. In this review, we discuss the interactions between S. aureus biofilm and macrophages, including the effects of biofilm-related bacteria on the macrophage immune response, roles of myeloid-derived suppressor cells during biofilm infection, regulation of immune cell metabolic patterns by the biofilm environment, and immune evasion strategies adopted by the biofilm against macrophages. Finally, we summarize the current methods that support macrophage-mediated removal of biofilms and emphasize the importance of considering multi-dimensions and factors related to implant-associated infection such as immunity, metabolism, the host, and the pathogen when developing new treatments.

Single-cell transcriptome reveals Staphylococcus aureus modulating fibroblast differentiation in the bone-implant interface.

BACKGROUND: This study aimed to delineate the cell heterogeneity in the bone-implant interface and investigate the fibroblast responses to implant-associated S. aureus infection. METHODS: Single-cell RNA sequencing of human periprosthetic tissues from patients with periprosthetic joint infection (PJI, n = 3) and patients with aseptic loosening (AL, n = 2) was performed. Cell type identities and gene expression profiles were analyzed to depict the single-cell landscape in the periprosthetic environment. In addition, 11 publicly available human scRNA-seq datasets were downloaded from GSE datasets and integrated with the in-house sequencing data to identify disease-specific fibroblast subtypes. Furthermore, fibroblast pseudotime trajectory analysis and Single-cell regulatory network inference and clustering (SCENIC) analysis were combined to identify transcription regulators responsible for fibroblast differentiation. Immunofluorescence was performed on the sequenced samples to validate the protein expression of the differentially expressed transcription regulators. RESULTS: Eight major cell types were identified in the human bone-implant interface by analyzing 36,466 cells. Meta-analysis of fibroblasts scRNA-seq data found fibroblasts in the bone-implant interface express a high level of CTHRC1. We also found fibroblasts could differentiate into pro-inflammatory and matrix-producing phenotypes, each primarily presented in the PJI and AL groups, respectively. Furthermore, NPAS2 and TFEC which are activated in PJI samples were suggested to induce pro-inflammatory polarization in fibroblasts, whereas HMX1, SOX5, SOX9, ZIC1, ETS2, and FOXO1 are matrix-producing regulators. Meanwhile, we conducted a CMap analysis and identified forskolin as a potential regulator for fibroblast differentiation toward matrix-producing phenotypes. CONCLUSIONS: In this study, we discovered the existence of CTHRC1+ fibroblast in the bone-implant interface. Moreover, we revealed a bipolar mode of fibroblast differentiation and put forward the hypothesis that infection could modulate fibroblast toward a pro-inflammatory phenotype through NPAS2 and TFEC.

Self-Homeostasis Immunoregulatory Strategy for Implant-Related Infections through Remodeling Redox Balance.

Implant-related infections (IRIs) are catastrophic complications after orthopedic surgery. Excess reactive oxygen species (ROS) accumulated in IRIs create a redox-imbalanced microenvironment around the implant, which severely limits the curing of IRIs by inducing biofilm formation and immune disorders. However, current therapeutic strategies commonly eliminate infection utilizing the explosive generation of ROS, which exacerbates the redox imbalance, aggravating immune disorders and promoting infection chronicity. Herein, a self-homeostasis immunoregulatory strategy based on a luteolin (Lut)-loaded copper (Cu2+)-doped hollow mesoporous organosilica nanoparticle system (Lut@Cu-HN) is designed to cure IRIs by remodeling the redox balance. In the acidic infection environment, Lut@Cu-HN is continuously degraded to release Lut and Cu2+. As both an antibacterial and immunomodulatory agent, Cu2+ kills bacteria directly and promotes macrophage pro-inflammatory phenotype polarization to activate the antibacterial immune response. Simultaneously, Lut scavenges excessive ROS to prevent the Cu2+-exacerbated redox imbalance from impairing macrophage activity and function, thus reducing Cu2+ immunotoxicity. The synergistic effect of Lut and Cu2+ confers excellent antibacterial and immunomodulatory properties to Lut@Cu-HN. As demonstrated in vitro and in vivo, Lut@Cu-HN self-regulates immune homeostasis through redox balance remodeling, ultimately facilitating IRI eradication and tissue regeneration.

Congener-Induced Sulfur-Related Metabolism Interference Therapy Promoted by Photothermal Sensitization for Combating Bacteria.

Metabolic homeostasis is vital for individual cells to keep alive. Stronger metabolic homeostasis allows bacteria to survive in vivo and do persistent harm to hosts, which is especially typical in implant-associated infection (IAI) with biofilm intervention. Herein, based on the competitive role of selenium (Se) and sulfur (S) in bacteria metabolism as congeners, a congener-induced sulfur-related metabolism interference therapy (SMIT) eradicating IAI is proposed by specific destruction of bacteria metabolic homeostasis. The original nanodrug manganese diselenide (MnSe2 ) is devised to generate permeable H2 Se in bacteria, triggered by the acidic microenvironment. H2 Se, the congener substitution of H2 S, as a bacteria-specific intermediate metabolite, can embed itself into the H2 S-utilization pathway and further alternatively disrupt the downstream sulfur-related metabolism state inside bacteria. A proteomic study indicates ribosome-related proteins are heavily downregulated and the basic metabolic pathways are mainly disordered after SMIT, revealing the destruction of bacteria metabolic homeostasis. The efficiency of SMIT is significantly promoted with the mild temperature sensitization provided by the photothermal treatment (PTT) of MnSe2 nanoparticles, verified by the proteomic study and the anti-IAI effect in vitro and in vivo. With the intelligent nanodrug, a PTT-promoted SMIT strategy against IAI is provided and a new insight into the interference design toward metabolic homeostasis with biochemical similarity is demonstrated.

Antibacterial application of gentamicin-silk protein coating with smart release function on titanium, polyethylene, and Al2O3 materials.

Peri-implant infection after hip and knee arthroplasty is a common and serious complication. Titanium (Ti), polyethylene (PE), and Al2O3 materials used as joint prosthesis materials have good biocompatibility and mechanical strength but no antibacterial effect. This study aimed to provide a theoretical basis for the design and manufacture of joint prosthesis materials with antibacterial effect. We applied a coating of gentamicin-silk protein (GS-Silk) on the surface of these materials. We characterized the Ti, PE, and Al2O3 materials coated with GS-Silk (experimental group) and performed in vivo and in vitro experiments to test antibacterial activity. Scanning electron microscopy confirmed successful GS-Silk coating, and infrared spectroscopy confirmed successful loading of gentamicin onto the three materials. Nanoscratch test proved that the GS-Silk coating is relatively reliable on the surface of these three materials. The antibacterial effect of the coating in vitro and in vivo was verified by performing bacteriostatic ring test in vitro, bacterial adhesion test, and subendothelial implant infection test. We demonstrated that GS-Silk coating can effectively load gentamicin onto Ti, PE, and Al2O3 materials and change the gentamicin release rate with a change in the solution pH to achieve intelligent release. The GS-Silk coating is relatively reliable on the surface of these three materials. Ti, PE, and Al2O3 materials coated with GS-Silk have good antibacterial ability, both in vivo and in vitro.

Space-Selective Chemodynamic Therapy of CuFe5O8 Nanocubes for Implant-Related Infections.

Implant-related infections (IRIs) are a serious complication after orthopedic surgery, especially when a biofilm develops and establishes physical and chemical barriers protecting bacteria from antibiotics and the hosts local immune system. Effectively eliminating biofilms is essential but difficult, as it requires not only breaking the physical barrier but also changing the chemical barrier that induces an immunosuppressive microenvironment. Herein, tailored to a biofilm microenvironment (BME), we proposed a space-selective chemodynamic therapy (CDT) strategy to combat IRIs using metastable CuFe5O8 nanocubes (NCs) as smart Fenton-like reaction catalysts whose activity can be regulated by pH and H2O2 concentration. In the biofilm, extracellular DNA (eDNA) was cleaved by high levels of hydroxyl radicals (•OH) catalyzed by CuFe5O8 NCs, thereby disrupting the rigid biofilm. Outside the biofilm with relatively higher pH and lower H2O2 concentration, lower levels of generated •OH effectively reversed the immunosuppressive microenvironment by inducing pro-inflammatory macrophage polarization. Biofilm fragments and exposed bacteria were then persistently eliminated through the collaboration of pro-inflammatory immunity and •OH. The spatially selective activation of CDT and synergistic immunomodulation exerted excellent effects on the treatment of IRIs in vitro and in vivo. The anti-infection strategy is expected to provide a method to conquer IRIs.

Antimicrobial characteristics of Berberine against prosthetic joint infection-related Staphylococcus aureus of different multi-locus sequence types.

BACKGROUND: Staphylococcal aureus (S. aureus) has become the leading causative pathogen of Prosthetic Joint Infection (PJI), which is the most devastating complication after arthroplasty surgeries. Due to the biofilm formation ability and emergence of multiple-drugs resistance strains of S. aureus, it has become an urgency to find new anti-staphylococcal agents to establish effective prophylaxis and treatment strategy for PJI. Extracted from a traditional Chinese herb, berberine is proved active in inhibiting S. aureus, while whether it exerts the same effect on PJI-related S. aureus remains unknown. This study aims to investigate the antimicrobial activity of berbrine against clinical derived PJI-related S. aureus and whether its inhibiting efficacy is associated with subtypes of S. aureus. METHODS: Eighteen PJI-associated S. aureus were collected and their Multi-locus Sequence Types (MLST) and susceptibility to berberine both in planktonic and biofilm form were investigated. Additionally, one S. aureus strain (ST1792) was selected from the group and its transcriptomic profiling in berberine incubation was performed. The statistical analyses were conducted using Student's t-test with SPSS 24.0(SPSS, IBM, USA). The data were expressed as the means ± standard deviation. Values of p < 0.05 were considered statistically significant. RESULTS: It was found out that the Minimum Inhibitory Concentration values of PJI-related S. aureus varied in a broad range (from 64 to 512 µg/ml) among different MLST subtypes and the bacteria were able to regain growth after 24 h in berberine of MIC value or higher concentrations. In addition, sub-inhibitory concentrations of berberine surprisingly enhanced biofilm formation in some S. aureus strains. CONCLUSION: Traditional medicine is utilised by a large number of individuals, which provides abundant resources for modern medical science. In our study, berberine was found bactericidal against PJI related S. aureus, however, its antibacterial property was impacted by the MLST subtypes of the bacteria, both in planktonic and biofilm growth forms.

Enhanced Anti-Infective Efficacy of ZnO Nanoreservoirs through a Combination of Intrinsic Anti-Biofilm Activity and Reinforced Innate Defense.

The increasing prevalence of implant-associated infections (IAIs) imposes a heavy burden on patients and medical providers. Bacterial biofilms are recalcitrant to antiseptic drugs and local immune defense and can attenuate host proinflammatory response to interfere with bacterial clearance. Zinc oxide nanoparticles (ZnO NPs) play a dual role in antibacterial and immunomodulatory activities but compromise the cytocompatibility because of their intracellular uptake. Here, ZnO NPs were immobilized on titanium to form homogeneous nanofilms (from discontinuous to continuous) through magnetron sputtering, and the possible antimicrobial activity and immunomodulatory effect of nano-ZnO films were investigated. Nano-ZnO films were found to prohibit sessile bacteria more than planktonic bacteria in vitro, and the antibacterial effect occurred in a dose-dependent manner. Using a novel mouse soft tissue IAI model, the in vivo results revealed that nano-ZnO films possessed outstanding antimicrobial efficacy, which could not be ascribed solely to the intrinsic anti-infective activity of nano-ZnO films observed in vitro. Macrophages and polymorphonuclear leukocytes (PMNs), two important factors in innate immune response, were cocultured with nano-ZnO and bacteria/lipopolysaccharide in vitro, and the nano-ZnO films could enhance the antimicrobial efficacy of macrophages and PMNs through promoting phagocytosis and secretion of inflammatory cytokines. This study provides insights into the anti-infective activity and mechanism of ZnO and consolidates the theoretical basis for future clinical applications of ZnO.

Band Gap Engineering of Titania Film through Cobalt Regulation for Oxidative Damage of Bacterial Respiration and Viability.

Biomaterial-related bacterial infections cause patient suffering, mortality, and extended periods of hospitalization and impose a substantial burden on medical systems. In this context, understanding the interactions between nanomaterials and bacteria is clinically significant. Herein, TiO2-based heterojunctions, including Co-TiO2, CoO-TiO2, and Co3O4-TiO2, were first designed by optimizing magnetron sputtering to establish a platform to explore the interactions between nanomaterials and bacteria. We found that the energy band bending and band gap narrowing were effectively promoted at the contact interface of the heterojunctions, which have the ability to induce abiotic reactive oxygen species formation. Using methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, in vitro studies showed that the heterojunctions of Co-TiO2, CoO-TiO2, and especially Co3O4-TiO2 can effectively downregulate the expression levels of bacterial respiratory genes and cause oxidative damage to bacterial membrane respiration and viability. As a result, the surfaces of the heterojunctions possess a favorable antiadherent bacterial activity. Moreover, using an osteomyelitis model, the preclinical study on rats further confirmed the favorable anti-infection effect of the elaborately designed heterojunctions (especially Co3O4-TiO2). We hope this study can provide new insights into the surface antibacterial design of biomaterials using energy band engineering for both basic research and clinical needs. Meanwhile, this attempt may also contribute to expanding the biomedical applications of cobalt-based nanoparticles for the treatment of antibiotic-resistant infections.

Distribution characteristics of Staphylococcus spp. in different phases of periprosthetic joint infection: A review.

Periprosthetic joint infection (PJI) is a devastating condition and Staphylococcus spp. are the predominant pathogens responsible, particularly coagulase-negative staphylococci (CoNS) and Staphylococcus aureus. The aim of the present systematic review was to evaluate the distribution characteristics of specific Staphylococcus spp. in different PJI phases, reveal the effect of pathogens' feature on their distribution and suggest recommendations for antibiotic treatment of Staphylococcal PJI. The present systematic review was performed using PubMed and EMBASE databases with the aim to identify existing literature that presented the spectrum of Staphylococcus spp. that occur in PJI. Once inclusion and exclusion criteria were applied, 20 cohort studies involving 3,344 cases in 3,199 patients were included. The predominant pathogen involved in PJI was indicated to be CoNS (31.2%), followed by S. aureus (28.8%). This trend was more apparent in hip replacement procedures. In addition, almost equal proportions of CoNS and S. aureus (28.6 and 30.0%, respectively) were indicated in the delayed phase. CoNS (36.6%) were the predominant identified organism in the early phase, whereas S. aureus (38.3%) occurred primarily in the late phase. In PJI caused by S. aureus, the number of cases of methicillin-sensitive Staphylococcus aureus (MSSA) was ~2.5-fold greater than that of methicillin-resistant Staphylococcus aureus (MRSA). MRSA occurred predominantly in the early phase, whereas MSSA was largely observed in the delayed and late phases. With regards to antibiotic treatment, the feature of various pathogens and the phases of PJI were the primary considerations. The present review provides useful information for clinical practice and scientific research of PJI.

A functionalized surface modification with vanadium nanoparticles of various valences against implant-associated bloodstream infection.

Bloodstream infection, especially with implants involved, is an often life-threatening condition with high mortality rates, imposing a heavy burden on patients and medical systems. Herein, we firstly deposited homogeneous vanadium metal, V2O3, VO2, and V2O5 nanofilms on quartz glass by magnetron sputtering. Using these platforms, we further investigated the potential antimicrobial efficiency of these nano-VOx films and the interactions of human erythrocytes and bacteria (methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa) with our samples in a novel cell-bacteria coculture model. It was demonstrated that these nano-VOx precipitated favorable antibacterial activity on both bacteria, especially on S. aureus, and this effect increased with higher vanadium valence. A possible mechanism accountable for these results might be elevated levels of vanadium-induced intracellular reactive oxygen species. More importantly, based on hemolysis assays, our nano-VOx films were found to be able to kill prokaryotic cells but were not toxic to mammalian cells, holding the potential for the prevention of implant-related hematogenous infections. As far as we know, this is the first report wherein such nano-VOx films have assisted human erythrocytes to combat bacteria in a valence-dependent manner. Additionally, vanadium ions were released from these nano-VOx films in a sustained manner, and low-valence films possessed better biocompatibility with human fibroblasts. This work may provide new insights for biomedical applications of inorganic vanadium compounds and attract growing attention in this field. From the perspective of surface modification and functionalization, this study holds promise to avail the prophylaxis of bloodstream infections involving implantable biomedical devices.

Anti-biofouling function of amorphous nano-Ta2O5 coating for VO2-based intelligent windows.

From environmental and health perspectives, the acquisition of a surface anti-biofouling property holds important significance for the usability of VO2 intelligent windows. Herein, we firstly deposited amorphous Ta2O5 nanoparticles on VO2 film by the magnetron sputtering method. It was found that the amorphous nano-Ta2O5 coating possessed a favorable anti-biofouling capability against Pseudomonas aeruginosa as an environmental microorganism model, behind which lay the mechanism that the amorphous nano-Ta2O5 could interrupt the microbial membrane electron transport chain and significantly elevate the intracellular reactive oxygen species (ROS) level. A plausible relationship was established between the anti-biofouling activity and physicochemical nature of amorphous Ta2O5 nanoparticles from the perspective of defect chemistry. ROS-induced oxidative damage gave rise to microbial viability loss. In addition, the amorphous nano-Ta2O5 coating can endow VO2 with favorable cytocompatibility with human skin fibroblasts. This study may provide new insights into understanding the anti-biofouling and antimicrobial actions of amorphous transition metal oxide nanoparticles, which is conducive to expanding their potential applications in environmental fields.

Nano-layered magnesium fluoride reservoirs on biomaterial surfaces strengthen polymorphonuclear leukocyte resistance to bacterial pathogens.

Biomaterial-related bacterial infections cause patient suffering, mortality and extended periods of hospitalization, imposing a substantial burden on medical systems. In this context, understanding of nanomaterials-bacteria-cells interactions is of both fundamental and clinical significance. Herein, nano-MgF2 films were deposited on titanium substrate via magnetron sputtering. Using this platform, the antibacterial behavior and mechanism of the nano-MgF2 films were investigated in vitro and in vivo. It was found that, for S. aureus (CA-MRSA, USA300) and S. epidermidis (RP62A), the nano-MgF2 films possessed excellent anti-biofilm activity, but poor anti-planktonic bacteria activity in vitro. Nevertheless, both the traditional SD rat osteomyelitis model and the novel stably luminescent mouse infection model demonstrated that nano-MgF2 films exerted superior anti-infection effect in vivo, which cannot be completely explained by the antibacterial activity of the nanomaterial itself. Further, using polymorphonuclear leukocytes (PMNs), the critical immune cells of innate immunity, a complementary investigation of MgF2-bacteria-PMNs co-culturing revealed that the nano-MgF2 films improved the antibacterial effect of PMNs through enhancing their phagocytosis and stability. To our knowledge, this is the first time of exploring the antimicrobial mechanism of nano-MgF2 from the perspective of innate immunity both in vitro and in vivo. Based on the research results, a plausible mechanism is put forward for the predominant antibacterial effect of nano-MgF2in vivo, which may originate from the indirect immune enhancement effect of nano-MgF2 films. In summary, this study of surface antibacterial design using MgF2 nanolayer is a meaningful attempt, which can promote the host innate immune response to bacterial pathogens. This may give us a new understanding towards the antibacterial behavior and mechanism of nano-MgF2 films and pave the way towards their clinical applications.

Silver-nanoparticles-modified biomaterial surface resistant to staphylococcus: new insight into the antimicrobial action of silver.

Titanium implants are widely used clinically, but postoperative implant infection remains a potential severe complication. The purpose of this study was to investigate the antibacterial activity of nano-silver(Ag)-functionalized Ti surfaces against epidemic Staphylococcus from the perspective of the regulation of biofilm-related genes and based on a bacteria-cell co-culture study. To achieve this goal, two representative epidemic Staphylococcus strains, Staphylococcus epidermidis (S. epidermidis, RP62A) and Staphylococcus aureus (S. aureus, USA 300), were used, and it was found that an Ag-nanoparticle-modified Ti surface could regulate the expression levels of biofilm-related genes (icaA and icaR for S. epidermidis; fnbA and fnbB for S. aureus) to inhibit bacterial adhesion and biofilm formation. Moreover, a novel bacteria-fibroblast co-culture study revealed that the incorporation of Ag nanoparticles on such a surface can help mammalian cells to survive, adhere and spread more successfully than Staphylococcus. Therefore, the modified surface was demonstrated to possess a good anti-infective capability against both sessile bacteria and planktonic bacteria through synergy between the effects of Ag nanoparticles and ion release. This work provides new insight into the antimicrobial action and mechanism of Ag-nanoparticle-functionalized Ti surfaces with bacteria-killing and cell-assisting capabilities and paves the way towards better satisfying the clinical needs.

Antibacterial Surface Design of Titanium-Based Biomaterials for Enhanced Bacteria-Killing and Cell-Assisting Functions Against Periprosthetic Joint Infection.

Periprosthetic joint infection (PJI) is one of the formidable and recalcitrant complications after orthopedic surgery, and inhibiting biofilm formation on the implant surface is considered crucial to prophylaxis of PJI. However, it has recently been demonstrated that free-floating biofilm-like aggregates in the local body fluid and bacterial colonization on the implant and peri-implant tissues can coexist and are involved in the pathogenesis of PJI. An effective surface with both contact-killing and release-killing antimicrobial capabilities can potentially abate these concerns and minimize PJI caused by adherent/planktonic bacteria. Herein, Ag nanoparticles (NPs) are embedded in titania (TiO2) nanotubes by anodic oxidation and plasma immersion ion implantation (PIII) to form a contact-killing surface. Vancomycin is then incorporated into the nanotubes by vacuum extraction and lyophilization to produce the release-killing effect. A novel clinical PJI model system involving both in vitro and in vivo use of methicillin-resistant Staphylococcus aureus (MRSA) ST239 is established to systematically evaluate the antibacterial properties of the hybrid surface against planktonic and sessile bacteria. The vancomycin-loaded and Ag-implanted TiO2 nanotubular surface exhibits excellent antimicrobial and antibiofilm effects against planktonic/adherent bacteria without appreciable silver ion release. The fibroblasts/bacteria cocultures reveal that the surface can help fibroblasts to combat bacteria. We first utilize the nanoarchitecture of implant surface as a bridge between the inorganic bactericide (Ag NPs) and organic antibacterial agent (vancomycin) to achieve total victory in the battle of PJI. The combination of contact-killing and release-killing together with cell-assisting function also provides a novel and effective strategy to mitigate bacterial infection and biofilm formation on biomaterials and has large potential in orthopedic applications.