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.

Correction: Xiang, Y.M.; Pan, W.F.; Jiang, H.B.; Zhu, Y.F.; Li, H. Measuring Software Modularity Based on Software Networks. Entropy 2019, 21, 344.

The authors wish to make the following corrections to the paper [...].

Exploration of the selective binding mechanism of protein kinase Aurora A selectivity via a comprehensive molecular modeling study.

BACKGROUND: The kinase of Aurora A has been regarded as a promising therapeutic target due to its altered expression in various human cancers. However, given the high similarity of the active binding site of Aurora A to other kinases, designing highly selective inhibitors towards Aurora A remains a challenge. Recently, two potential small-molecule inhibitors named AT9283 and Danusertib were reported to exhibit significant selectivity to Aurora A, but not to Gleevec. It was argued that protein dynamics is crucial for drug selectivity to Aurora A. However, little computational research has been conducted to shed light on the underlying mechanisms. METHODS: In this study, MM/GBSA calculations based on conventional molecular dynamics (cMD) simulations and enhanced sampling simulations including Gaussian accelerated MD (GaMD) simulations and umbrella sampling were carried out to illustrate the selectivity of inhibitors to Aurora A. RESULTS: The calculation results from cMD simulation showed that the binding specificity is primarily controlled by conformational change of the kinase hinge. The protein dynamics and energetic differences were further supported by the GaMD simulations. Umbrella sampling further proved that AT9283 and Danusertib have similar potential of mean force (PMF) profiles toward Aurora A in terms of PMF depth. Compared with AT9283 and Danusertib, Gleevec has much lower PMF depth, indicating that Gleevec is more easily dissociated from Aurora A than AT9283 and Danusertib. These results not only show the selective determinants of Aurora A, but also provide valuable clues for the further development of novel potent Aurora A selective inhibitors.

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.

Measuring Software Modularity Based on Software Networks.

Modularity has been regarded as one of the most important properties of a successful software design. It has significant impact on many external quality attributes such as reusability, maintainability, and understandability. Thus, proposing metrics to measure the software modularity can be very useful. Although several metrics have been proposed to characterize some modularity-related attributes, they fail to characterize software modularity as a whole. A complex network uses network models to abstract the internal structure of complex systems, providing a general way to analyze complex systems as a whole. In this paper, we introduce the complex network theory into software engineering and employ modularity, a metric widely used in the field of community detection in complex network research, to measure software modularity as a whole. First, a specific piece of software is represented by a software network, feature coupling network (FCN), where methods and attributes are nodes, couplings between methods and attributes are edges, and the weight on the edges denotes the coupling strength. Then, modularity is applied to the FCN to measure software modularity. We apply the Weyuker's criteria which is widely used in the field of software metrics, to validate the modularity as a software metric theoretically, and also perform an empirical evaluation using open-source Java software systems to show its effectiveness as a software metric to measure software modularity.

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.

Construction of poly(lactic-co-glycolic acid)/ZnO nanorods/Ag nanoparticles hybrid coating on Ti implants for enhanced antibacterial activity and biocompatibility.

Poly(lactic-co-glycolic acid)/Ag/ZnO nanorods coating were successfully prepared on the surface of Ti metallic implants using a hydrothermal method and subsequent spin-coating of mixtures of poly(lactic-co-glycolic acid) and silver nanoparticles. The poly(lactic-co-glycolic acid)/Ag/ZnO nanorods coating exhibited excellent antibacterial efficacy of over 96% against both Staphylococcus aureus and Escherichia coli when the initial content of Ag nanoparticles was over 3wt%. In addition, the release of both silver and zinc could last for over a hundred days due to the enwrapping of poly(lactic-co-glycolic acid). Proliferation of mouse calvarial cells exhibited minimal cytotoxicity on the poly(lactic-co-glycolic acid)/Ag/ZnO coating with an initial content of Ag nanoparticles of 1wt% and 3wt%, while it inhibited cell proliferation once this value was increased to 6wt%. The results revealed that this poly(lactic-co-glycolic acid)/Ag/ZnO composite could provide a long-lasting antibacterial approach and good cytocompatibility, thus exhibiting considerable potential for biomedical application in orthopedic and dental implants with excellent self-antibacterial activity and good biocompatibility.