Ultrasound-Triggered Piezoelectric Catalysis of Zinc Oxide@Glucose Derived Carbon Spheres for the Treatment of MRSA Infected Osteomyelitis.

Currently, methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis is a clinically life-threatening disease, however, long-term antibiotic treatment can lead to bacterial resistance, posing a huge challenge to treatment and public health. In this study, glucose-derived carbon spheres loaded with zinc oxide (ZnO@HTCS) are successfully constructed. This composite demonstrates the robust ability to generate reactive oxygen species (ROS) under ultrasound (US) irradiation, eradicating 99.788% ± 0.087% of MRSA within 15 min and effectively treating MRSA-induced osteomyelitis infection. Piezoelectric force microscopy tests and finite element method simulations reveal that the ZnO@HTCS composite exhibits superior piezoelectric catalytic performance compared to pure ZnO, making it a unique piezoelectric sonosensitizer. Density functional theory calculations reveal that the formation of a Mott-Schottky heterojunction and an internal piezoelectric field within the interface accelerates the electron transfer and the separation of electron-hole pairs. Concurrently, surface vacancies of the composite enable the adsorption of a greater amount of oxygen, enhancing the piezoelectric catalytic effect and generating a substantial quantity of ROS. This work not only presents a promising approach for augmenting piezoelectric catalysis through construction of a Schottky heterojunction interface but also provides a novel, efficient therapeutic strategy for treating osteomyelitis.

Electron Aggregation and Oxygen Fixation Reinforced Microwave Dynamic and Thermal Therapy for Effective Treatment of MRSA-Induced Osteomyelitis.

Antibiotics are frequently used to clinically treat osteomyelitis caused by bacterial infections. However, extended antibiotic use may result in drug resistance, which can be life threatening. Here, a heterojunction comprising Fe2O3/Fe3S4 magnetic composite is constructed to achieve short-term and efficient treat osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA). The Fe2O3/Fe3S4 composite exhibits powerful microwave (MW) absorption properties, thereby effectively converting incident electromagnetic energy into thermal energy. Density functional theory calculations demonstrate that Fe2O3/Fe3S4 possesses significant charge accumulation and oxygen-fixing capacity at the heterogeneous interface, which provides more active sites and oxygen sources for trapping electromagnetic hotspots. The finite element analysis indicates that Fe2O3/Fe3S4 displays a larger electromagnetism field enhancement parameter than Fe2O3 owing to a significant increase in electromagnetic hotspots. These hotspots contribute to charge differential accumulation and depletion motions at the interface, thereby augmenting the release of free electrons that subsequently combine with the oxygen adsorbed by Fe2O3/Fe3S4 to generate reactive oxygen species (ROS) and heat. This research, which achieves extraordinary bacterial eradication through the synergistic effect of microwave thermal therapy (MWTT) and microwave dynamic therapy (MDT), presents a novel strategy for treating deep-tissue bacterial infections.

A Smart Bacteria-Capture-Killing Vector for Effectively Treating Osteomyelitis Through Synergy Under Microwave Therapy.

Osteomyelitis caused by deep tissue infections is difficult to cure through phototherapy due to the poor penetration depth of the light. Herein, Cu/C/Fe3O4-COOH nanorod composites (Cu/C/Fe3O4-COOH) with nanoscale tip convex structures are successfully fabricated as a microwave-responsive smart bacteria-capture-killing vector. Cu/C/Fe3O4-COOH exhibited excellent magnetic targeting and bacteria-capturing ability due to its magnetism and high selectivity affinity to the amino groups on the surface of Staphylococcus aureus (S. aureus). Under microwave irradiation, Cu/C/Fe3O4-COOH efficiently treated S. aureus-infected osteomyelitis through the synergistic effects of microwave thermal therapy, microwave dynamic therapy, and copper ion therapy. It is calculated the electric field intensity in various regions of Cu/C/Fe3O4-COOH under microwave irradiation, demonstrating that it obtained the highest electric field intensity on the surface of copper nanoparticles of Cu/C/Fe3O4-COOH due to its high-curvature tips and metallic properties. This led to copper nanoparticles attracted more charged particles compared with other areas in Cu/C/Fe3O4-COOH. These charges are easier to escape from the high curvature surface of Cu/C/Fe3O4-COOH, and captured by adsorbed oxygen, resulting in the generation of reactive oxygen species. The Cu/C/Fe3O4-COOH designed in this study is expected to provide insight into the treatment of deep tissue infections under the irradiation of microwave.

Natural Extracts for Antibacterial Applications.

Bacteria-induced epidemics and infectious diseases are seriously threatening the health of people around the world. In addition, antibiotic therapy has been inducing increasingly more serious bacterial resistance, which makes it urgent to develop new treatment strategies to combat bacteria, including multidrug-resistant bacteria. Natural extracts displaying antibacterial activity and good biocompatibility have attracted much attention due to greater concerns about the safety of synthetic chemicals and emerging drug resistance. These antibacterial components can be isolated and utilized as antimicrobials, as well as transformed, combined, or wrapped with other substances by using modern assistive technologies to fight bacteria synergistically. This review summarizes recent advances in natural extracts from three kinds of sources-plants, animals, and microorganisms-for antibacterial applications. This work discusses the corresponding antibacterial mechanisms and the future development of natural extracts in antibacterial fields.

Lattice Strain Engineering of Ti3C2 Narrows Band Gap for Realizing Extraordinary Sonocatalytic Bacterial Killing.

The rapid development of sonodynamic therapy (SDT) provides a promising strategy for treating deep-seated multidrug-resistant (MDR) bacterial infection. However, the extreme scarcity of biologically functional and highly efficient sonosensitizers severely limits the further clinical practice of SDT. Herein, the lattice-strain-rich Ti3C2 (LS-Ti3C2) with greatly improved sonosensitizing effect is one-step synthesized using Ti3C2 and meso-tetra(4-carboxyphenyl)porphine (TCPP) by the solvothermal method for realizing extraordinary SDT. The intervention of TCPP causes all the Ti-O chemical bonds and most of the Ti-F chemical bonds on the surface layer of Ti3C2 to break down. The amino groups of TCPP are then recombined with these exposed Ti atoms to perturb the order of the Ti atoms, resulting in displacement of the Ti atoms and final lattice structural distortion of Ti3C2. The inherent lattice strain narrows the band gap of Ti3C2, which mainly facilitates the electron-hole pair separation and electron transfer under ultrasound irradiation, thereby resulting in US-mediated reactive oxygen species (ROS) production and the subsequent robust bactericidal capability (99.77 ± 0.16%) against methicillin-resistant Staphylococcus aureus (MRSA). Overall, this research offers a perspective into the development of Ti-familial sonosensitizers toward SDT practice.

Ultrasound-triggered interfacial engineering-based microneedle for bacterial infection acne treatment.

Acne is an inflammatory skin disease mainly caused by Propionibacterium acnes, which can cause local inflammatory reactions and develop into chronic inflammatory diseases in severe cases. To avoid the use of antibiotics and to effectively treat the site of acne, we report a sodium hyaluronate microneedle patch that mediates the transdermal delivery of ultrasound-responsive nanoparticles for the effective treatment of acne. The patch contains nanoparticles formed by zinc porphyrin-based metal-organic framework and zinc oxide (ZnTCPP@ZnO). We demonstrated activated oxygen-mediated killing of P. acnes with an antibacterial efficiency of 99.73% under 15 min of ultrasound irradiation, resulting in a decrease in levels of acne-related factors, including tumor necrosis factor-α, interleukins, and matrix metalloproteinases. The zinc ions up-regulated DNA replication-related genes, promoting the proliferation of fibroblasts and, consequently, skin repair. This research leads to a highly effective strategy for acne treatment through the interface engineering of ultrasound response.

Realizing Highly Efficient Sonodynamic Bactericidal Capability through the Phonon-Electron Coupling Effect Using Two-Dimensional Catalytic Planar Defects.

Conferring catalytic defects in sonosensitizers is of paramount importance in reinforcing sonodynamic therapy. However, the formation of such 0D defects is governed by the Schottky defect principle. Herein, 2D catalytic planar defects are designed within Ti3 C2  sheets to address this challenge. These specific planar slip dislocations with abundant Ti3+ species (Ti3 C2 -SD(Ti3+ )) can yield surface-bound O due to the effective activation of O2 , thus resulting in a substantial amount of 1 O2  generation and the 99.72% ± 0.03% bactericidal capability subject to ultrasound (US) stimulation. It is discovered that the 2D catalytic planar defects can intervene in electron transfer through the phonon drag effect-a coupling effect between surface electrons and US-triggered phonons-that simultaneously contributes to a dramatic decrease in O2  activation energy from 1.65 to 0.06 eV. This design has achieved a qualitative leap in which the US catalytic site has transformed from 0D to 2D. Moreover, it is revealed that the electron origin, electron transfer, and visible O2  activation pathway triggered by US can be attributed to the phonon-electron coupling effect. After coating with neutrophil membrane (NM) proteins, the NM-Ti3 C2 -SD(Ti3+ ) sheets further demonstrate a 6-log10  reduction in methicillin-resistant Staphylococcus aureus burden in the infected bony tissue.

Rapid bacterial elimination achieved by sonodynamic Au@Cu2O hybrid nanocubes.

Although efforts have been devoted to develop new antibacterial agents and techniques, the challenge of bacterial infection remains unresolved and is even increasing. Sonodynamic therapy (SDT) driven by ultrasound (US) has demonstrated effectiveness in terms of penetration and it can help to clinically address the problem of deep tissue bacterial infection. In recent years, a variety of sonosensitizers, which were originally designed for photodynamic therapy, have been adopted for SDT. Yet, their unstable chemical stability and ineffective electron-hole separation are not favorable for clinical applications. Hence, we designed a new type of antibacterial sonosensitizer-namely, Au@Cu2O hybrid nanocubes-in which an interfacial Schottky junction was built between a p-type semiconductor Cu2O and a noble metal Au. When US stimulation was applied, the electrons from Cu2O could be excited at the junction and transferred to Au. Since the formed Schottky barrier could block the backflow of US-excited electrons, a prolonged electron-hole separation can be successfully established. Additionally, because of the boosted sonocatalytic activity, the Au@Cu2O hybrid nanocubes could produce a large amount of reactive oxygen species (ROS), which are subject to US stimulation. Furthermore, we found that the sonocatalytic activity of the Au@Cu2O hybrid nanocubes could be reinforced by increasing the amount of Au, enabling 99.67% of Staphylococcus aureus (S. aureus) to be killed by US stimulation for 15 minutes. The cytocompatibility of Au@Cu2O hybrid nanocubes was improved by a red blood cell membrane (RBC) coating over the surface, and the membrane did not sacrifice its superior antibacterial properties.

Enhanced Near-Infrared Photocatalytic Eradication of MRSA Biofilms and Osseointegration Using Oxide Perovskite-Based P-N Heterojunction.

Methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections after orthopedic implant increase the risk of failure and potentially cause amputation of limbs or life-threatening sepsis in severe cases. Additionally, satisfactory bone-implant integration is another important indicator of an ideal implant. Here, an antibiotic-free antibacterial nanofilm based on oxide perovskite-type calcium titanate (CTO)/fibrous red phosphorus (RP) on titanium implant surface (Ti-CTO/RP) in which the P-N heterojunction and internal electric field are established at the heterointerface, is designed. Near-infrared light-excited electron-hole pairs are effectively separated and transferred through the synergism of the internal electric field and band offset, which strongly boosts the photocatalytic eradication of MRSA biofilms by reactive oxygen species with an efficacy of 99.42% ± 0.22% in vivo. Additionally, the charge transfer endows the heterostructure with hyperthermia to assist biofilm eradication. Furthermore, CTO/RP nanofilm provides a superior biocompatible and osteoconductive platform that enables the proliferation and osteogenic differentiation of mesenchymal stem cells, thus contributing to the subsequent implant-to-bone osseointegration after eradicating MRSA biofilms.

Local Photothermal/Photodynamic Synergistic Therapy by Disrupting Bacterial Membrane To Accelerate Reactive Oxygen Species Permeation and Protein Leakage.

Bacterial infection is still a ticklish clinical challenge even though some advanced antibacterial materials and techniques have been put forward. This work reports that rapid and effective antibacterial performance is achieved by the synergistic local photothermal and photodynamic therapy (PTDT). Within 10 min of light irradiation, both Escherichia coli and Staphylococcus aureus are almost completely eliminated by the action of photothermy (52.1 °C) and limited reactive oxygen species (ROS), the corresponding bacterial killing efficiencies are 99.91 and 99.97%, respectively, which are far higher than single modal therapy, i.e., photothermal therapy or photodynamic therapy with antibacterial efficacy of 50 or 70%, respectively. The mechanism is that bacterial membrane permeation is increased by PTDT because photothermy shows more severe impact only on E. coli by destroying the outmost bacterial panniculus, whereas the inner panniculus of the two kinds of bacteria is more sensitive to ROS. Hence, ROS penetrates the bacterial membrane more easily, and meanwhile, the proteins in the bacteria are severely lost after the bacterial membrane disruption, which leads to bacterial death. In vivo results reveal that rapid and effective sterilization is an important process to accelerate wound healing, and the traumas on the rats' backbones heal well within 12 days by PTDT. Furthermore, the PTDT is friendly to major organs of rats during the therapeutic process. Therefore, the synergistic therapy system can be a safe therapeutic system for clinical sterilization with great potential. More importantly, the antibacterial mechanism presented in this work has great guiding significance for the design of other advanced antibacterial systems and techniques.

Rapid and Superior Bacteria Killing of Carbon Quantum Dots/ZnO Decorated Injectable Folic Acid-Conjugated PDA Hydrogel through Dual-Light Triggered ROS and Membrane Permeability.

One of the most difficult challenges in the biomedical field is bacterial infection, which causes tremendous harm to human health. In this work, an injectable hydrogel is synthesized through rapid assembly of dopamine (DA) and folic acid (FA) cross-linked by transition metal ions (TMIs, i.e., Zn2+ ), which was named as DFT-hydrogel. Both the two carboxyl groups in the FA molecule and catechol in polydopamine (PDA) easily chelates Zn2+ to form metal-ligand coordination, thereby allowing this injectable hydrogel to match the shapes of wounds. In addition, PDA in the hydrogel coated around carbon quantum dot-decorated ZnO (C/ZnO) nanoparticles (NPs) to rapidly generate reactive oxygen species (ROS) and heat under illumination with 660 and 808 nm light, endows this hybrid hydrogel with great antibacterial efficacy against Staphylococcus aureus (S. aureus, typical Gram-positive bacteria) and Escherichia coli (E. coli, typical Gram-negative bacteria). The antibacterial efficacy of the prepared DFT-C/ZnO-hydrogel against S. aureus and E. coli under dual-light irradiation is 99.9%. Importantly, the hydrogels release zinc ions over 12 days, resulting in a sustained antimicrobial effect and promoted fibroblast growth. Thus, this hybrid hydrogel exhibits great potential for the reconstruction of bacteria-infected tissues, especially exposed wounds.

Tuning the Bandgap of Photo-Sensitive Polydopamine/Ag3PO4/Graphene Oxide Coating for Rapid, Noninvasive Disinfection of Implants.

Bacterial infection and associated complications are threats to human health especially when biofilms form on biomedical devices and artificial implants. Herein, a hybrid polydopamine (PDA)/Ag3PO4/graphene oxide (GO) coating is designed and constructed to achieve rapid bacteria killing and eliminate biofilms in situ. By varying the amount of GO in the hybrid coating, the bandgap can be tuned from 2.52 to 2.0 eV so that irradiation with 660 nm visible light produces bacteria-killing effects synergistically in concert with reactive oxygen species (ROS). GO regulates the release rate of Ag+ to minimize the cytotoxicity while maintaining high antimicrobial activity, and a smaller particle size enhances the yield of ROS. After irradiation with 660 nm visible light for 15 min, the antimicrobial rates of the PDA/Ag3PO4/GO hybrid coating against Escherichia coli and Staphylococcus aureus are 99.53% and 99.66%, respectively. In addition, this hybrid coating can maintain a repeatable and sustained antibacterial efficacy. The released Ag+ and photocatalytic Ag3PO4 produce synergistic antimicrobial effects in which the ROS increases the permeability of the bacterial membranes to increase the probability of Ag+ to enter the cells to kill them together with ROS synergistically.

Infection-prevention on Ti implants by controlled drug release from folic acid/ZnO quantum dots sealed titania nanotubes.

Bacterial infections and related complications are predominantly responsible for the failure of artificial biomaterials assisted tissue regeneration in clinic. In this work, a hybrid surface system is applied to prolong the drug release duration from dug-loaded titania nanotubes and thus to prevent Ti implants-associated bacterial infections. This feature is endowed by conjugating folic acid (FA) onto the surface of ZnO quantum dots (QDs)-NH2 via an amidation reaction. Titania nanotubes (TNTs) loaded with vancomycin (Van) are capped by these FA functionalized ZnO (ZnO-FA) QDs that keep stable in normal physiological environments but dissolves to Zn2+ in the mildly acidic environment after bacterial infections as validated by the drug release profile. The antibacterial ratio of TNTs-Van@ZnO-FA QDs against Staphylococcus aureus is enhanced from 60.8% to 98.8%while this value is only increased from 85.2% to 95.1% for TNTs-Van once the pH value of the environment is decreased from 7.4 to 5.5. This is due to the synergistic effects of Van and Zn2+ because the gradual dissolution of ZnO-FA caps on TNTs with the decrease of pH value can induce the acceleration of both Van and Zn2+ release. In addition, this TNTs-Van@ZnO-FA system also exhibits excellent biocompatibility because of the folic acid and sustained release of Zn ions. Hence, this surface system can be potentially used as a promising bioplatform on Ti-based metallic implants to prevent bacterial infection with a long-lasting effect.

Repeatable Photodynamic Therapy with Triggered Signaling Pathways of Fibroblast Cell Proliferation and Differentiation To Promote Bacteria-Accompanied Wound Healing.

Despite the development of advanced antibacterial materials, bacterial infection is still a serious problem for wound healing because it usually induces severe complications and cannot be eradicated completely. Most current materials cannot simultaneously provide antibacterial activity, reusability, and biocompatibility as well as participate in stimulating cell behaviors to promote bacteria-accompanied wound healing. This work fabricated a hybrid hydrogel embedded with two-dimensional (2D) few-layer black phosphorus nanosheets (BPs) via simple electrostatic interaction. Within 10 min, 98.90% Escherichia coli and 99.51% Staphylococcus aureus can be killed rapidly by this hybrid, due to its powerful ability to produce singlet oxygen (1O2) under simulated visible light. In addition, this hydrogel also shows a high repeatability; that is, the antibacterial efficacy can still reach up to 95.6 and 94.58% against E. coli and S. aureus, respectively, even after challenging bacteria up to four times repeatedly. In vitro and in vivo results reveal that BPs in this hybrid hydrogel can promote the formation of the fibrinogen at the early stages during the tissue reconstruction process for accelerated incrustation. In addition, BPs can also trigger phosphoinositide 3-kinase (PI3K), phosphorylation of protein kinase B (Akt), and extracellular signal-regulated kinase (ERK1/2) signaling pathways for enhanced cellular proliferation and differentiation. Moreover, the hydrogel causes no appreciable abnormalities or damage to major organs (heart, liver, spleen, lung, and kidney) in rats during the wound healing process. Therefore, this BP-based hydrogel will have great potential as a safe multimodal therapeutic system for active wound healing and sterilization.

Photo-Inspired Antibacterial Activity and Wound Healing Acceleration by Hydrogel Embedded with Ag/Ag@AgCl/ZnO Nanostructures.

Ag/Ag@AgCl/ZnO hybrid nanostructures are embedded in a hydrogel by a simple two-step technique. The Ag/Ag@AgCl nanostructures are assembled in the hydrogel via ultraviolet light chemical reduction followed by incorporation of ZnO nanostructures by NaOH precipitation. The hydrogel accelerates wound healing and exhibits high antibacterial efficiency against both Escherichia coli and Staphylococcus aureus under visible light irradiation. The Ag/Ag@AgCl nanostructures enhance the photocatalytic and antibacterial activity of ZnO due to the enhancement of reactive oxygen species by visible light. This hydrogel system kills 95.95% of E. coli and 98.49% of S. aureus within 20 min upon exposure to simulated visible light, and rapid sterilization plays a crucial role in wound healing. In addition, this system provides controllable, sustained release of silver and zinc ions over a period of 21 days arising from the reversible swelling-shrinking transition of the hydrogel triggered by the changing pH value in the biological environment. About 90% Zn2+ release is observed in the acidic environment after 3 days, whereas only 10% Zn2+ release occurs in the neutral environment after 21 days. In vivo results show that release of Ag+ and Zn2+ stimulates the immune function to produce a large number of white blood cells and neutrophils (2-4 times more than the control), thereby producing the synergistic antibacterial effects and accelerated wound healing.

Synergistic Bacteria Killing through Photodynamic and Physical Actions of Graphene Oxide/Ag/Collagen Coating.

Researchers have widely agreed that the broad spectrum antibacterial activity of silver nanoparticles (AgNPs) can be predominantly ascribed to the action of Ag+. This study marks the first report detailing the rapid and highly efficient synergistic bacteria killing of AgNPs, which is achieved by inspiring AgNPs' strong photocatalytic capability to rapidly produce radical oxygen species using 660 nm visible light together with the innate antimicrobial ability of Ag+. These AgNPs were uniformly distributed into well-defined graphene oxide (GO) nanosheets through an in situ reduction of Ag+ and subsequently wrapped with a thin layer of type I collagen. In vivo subcutaneous tests demonstrated that 20 min irradiation of 660 nm visible light could achieve a high antibacterial efficacy of 96.3% and 99.4% on the implant surface against Escherichia coli and Staphylococcus aureus, respectively. In addition, the collagen could reduce the coatings' possible cytotoxicity. The results of this work can provide a highly effective and universal GO-based bioplatform for combination with inorganic antimicrobial NPs (i.e., AgNPs) with excellent photocatalytic properties, which can be utilized for facile and rapid in situ disinfection, as well as long-term prevention of bacterial infection through the synergistic bacteria killing of both 660-nm light-inspired photodynamic action and their innate physical antimicrobial ability.

The controlled drug release by pH-sensitive molecularly imprinted nanospheres for enhanced antibacterial activity.

In this study, we prepared pH-sensitive hybrid nanospheres through the implementation of a facile molecularly imprinted polymer (MIP) technique combined with a UV-initiated precipitation polymerization method using vancomycin (VA) for the templates. During the course of this investigation, both 2-hydroxyethyl methacrylate (HEMA) and 2-(diethylamino) ethyl methacrylate (DEAEMA) were utilized as the functional monomers, while ethylene glycol dimethacrylate (EGDMA) was used as a cross-linker. The obtained MIP nanospheres exhibited well-controlled particle size, with a drug loading capacity of about 17%, much higher than that of the non-imprinted polymer (NIP) nanospheres (5%). In addition, the VA loading quantity was closely correlated with the dosage of the cross-linking agent, and the MIP nanospheres exhibited a slower and more controlled VA release rate than the NIP nanospheres. Moreover, these MIP nanospheres were sensitive to pH values, and consequently showed an increasing release rate of VA as the pH level was decreased. The VA-loaded MIP nanospheres showed the higher antibacterial ratio of over 92% against Staphylococcus aureus (S. aureus) while the NIP nanospheres were friendly to S. aureus. These MIP nanospheres can be promising for targeting drug delivery system to achieve specific therapies such as preventing bacterial infections and killing cancer cells without damaging health cells and tissues.