Mg-based implants with a sandwiched composite coating simultaneously facilitate antibacterial and osteogenic properties.

Insufficient antibacterial effects and over-fast degradation are the main limitations of magnesium (Mg)-based orthopedic implants. In this study, a sandwiched composite coating containing a triclosan (TCS)-loaded poly(lactic acid) (PLA) layer inside and brushite (DCPD) layer outside was prepared on the surface of the Mg-Nd-Zn-Zr (denoted as JDBM) implant. In vitro degradation tests revealed a remarkable improvement in the corrosion resistance and moderate degradation rate. The drug release profile demonstrated a controllable and sustained TCS release for at least two weeks in vitro. The antibacterial rates of the implant were all over 99.8% for S. aureus, S. epidermidis, and E. coli, demonstrating superior antibacterial effects. Additionally, this coated JDBM implant exhibited no cytotoxicity but improved cell adhesion and proliferation, indicating excellent cytocompatibility. In vivo assays were conducted by implant-related femur osteomyelitis and osseointegration models in rats. Few bacteria were attached to the implant surface and the surrounding bone tissue. Furthermore, the coated JDBM implant exhibited more new bone formation than other groups due to the synergistic biological effects of released TCS and Mg2+, revealing excellent osteogenic ability. In summary, the JDBM implant with the sandwiched composite coating could significantly enhance the antibacterial activities and osteogenic properties simultaneously by the controllable release of TCS and Mg2+, presenting great potential for clinical transformation.

Immunomodulatory biomaterials against bacterial infections: Progress, challenges, and future perspectives.

Bacterial infectious diseases are one of the leading causes of death worldwide. Even with the use of multiple antibiotic treatment strategies, 4.95 million people died from drug-resistant bacterial infections in 2019. By 2050, the number of deaths will reach 10 million annually. The increasing mortality may be partly due to bacterial heterogeneity in the infection microenvironment, such as drug-resistant bacteria, biofilms, persister cells, intracellular bacteria, and small colony variants. In addition, the complexity of the immune microenvironment at different stages of infection makes biomaterials with direct antimicrobial activity unsatisfactory for the long-term treatment of chronic bacterial infections. The increasing mortality may be partly attributed to the biomaterials failing to modulate the active antimicrobial action of immune cells. Therefore, there is an urgent need for effective alternatives to treat bacterial infections. Accordingly, the development of immunomodulatory antimicrobial biomaterials has recently received considerable interest; however, a comprehensive review of their research progress is lacking. In this review, we focus mainly on the research progress and future perspectives of immunomodulatory antimicrobial biomaterials used at different stages of infection. First, we describe the characteristics of the immune microenvironment in the acute and chronic phases of bacterial infections. Then, we highlight the immunomodulatory strategies for antimicrobial biomaterials at different stages of infection and their corresponding advantages and disadvantages. Moreover, we discuss biomaterial-mediated bacterial vaccines' potential applications and challenges for activating innate and adaptive immune memory. This review will serve as a reference for future studies to develop next-generation immunomodulatory biomaterials and accelerate their translation into clinical practice.

In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations.

Most recently, the adenosine is considered as one of the most promising targets for treating pain, with few side effects. It exists in the central nervous system, and plays a key role in nociceptive afferent pathway. It is reported that the A1 receptor (A1R) could inhibit Ca2+ channels to reduce the pain like analgesic mechanism of morphine. And, A2a receptor (A2aR) was reported to enhance the accumulation of AMP (cAMP) and released peptides from sensory neurons, resulting in constitutive activation of pain. Much evidence showed that A1R and A2aR could be served as the interesting targets for the treatment of pain. Herein, virtual screening was utilized to identify the small molecule compounds towards A1R and A2aR, and top six molecules were considered as candidates via amber scores. The molecular dynamic (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) were employed to further analyze the affinity and binding stability of the six molecules towards A1R and A2aR. Moreover, energy decomposition analysis showed significant residues in A1R and A2aR, including His1383, Phe1276, and Glu1277. It provided basics for discovery of novel agonists and antagonists. Finally, the agonists of A1R (ZINC19943625, ZINC13555217, and ZINC04698406) and inhibitors of A2aR (ZINC19370372, ZINC20176051, and ZINC57263068) were successfully recognized. Taken together, our discovered small molecules may serve as the promising candidate agents for future pain research.

Channel Selection of Ultracold Atom-Molecule Scattering in Dynamic Magnetic Fields.

We demonstrate that final states of ultracold molecules by scattering with atoms can be selectively produced using dynamic magnetic fields of multiple frequencies. We develop a multifrequency Floquet coupled channel method to study the channel selection by dynamic magnetic field control, which can be interpreted by a generalized quantum Zeno effect for the selected scattering channels. In particular, we use an atom-molecule spin-flip scattering to show that the transition to certain final states of the molecules in the inelastic scattering can be suppressed by engineered coupling between the Floquet states.

Approaches to Biofunctionalize Polyetheretherketone for Antibacterial: A Review.

Due to excellent mechanical properties and similar elastic modulus compared with human cortical bone, polyetheretherketone (PEEK) has become one of the most promising orthopedic implant materials. However, implant-associated infections (IAIs) remain a challenging issue since PEEK is bio-inert. In order to fabricate an antibacterial bio-functional surface, modifications of PEEK had been widely investigated. This review summarizes the modification strategies to biofunctionalize PEEK for antibacterial. We will begin with reviewing different approaches, such as surface-coating modifications and controlled release of antimicrobials. Furthermore, blending modifications and 3D printing technology were discussed. Finally, we compare the effects among different approaches. We aimed to provide an in-depth understanding of the antibacterial modification and optimize the design of the PEEK orthopedic implant.

AmV2O5 with Binary Phases as High-Performance Cathode Materials for Zinc-Ion Batteries: Effect of the Pre-Intercalated Cations A and Reversible Transformation of Coordination Polyhedra.

In this work, five vanadium oxide materials with a series of pre-intercalated cations A (AmV2O5), including Zn2+, Mg2+, NH4+, Li+, and Ag+, have been successfully prepared by a two-step method. All of them possess binary monoclinic and orthorhombic V2O5 phases with an open layered structure that allows the ionic storage and diffusion of hydrated cations. The interlayer space for the monoclinic V2O5 phase is strongly dependent on the radii of hydrated cations A, while the one for the orthorhombic V2O5 phase remains the same regardless of the radii of cations A. Among them, AmV2O5 with pre-intercalated Zn2+ (ZVO) has the best storage ability of Zn2+ with a reversible capacity close to 400 mAh g-1, and AmV2O5 with pre-intercalated Ag+ shows the highest rate capacity with a nearly 40% capacity retention at a current of 20 A g-1 (≈25 C). Kinetic studies have clearly shown that pseudocapacitive behavior dominates the electrochemical reaction on ZVO. During the Zn2+ (de)intercalation reaction, a highly reversible transformation of binary monoclinic or orthorhombic V2O5 phases into a single triclinic ZnxV2O5·nH2O phase is demonstrated on ZVO. Vanadium atoms are identified as the redox centers that undergo the mutual transition among the chemical states of V3+, V4+, and V5+. They together with oxygen atoms constitute reasonable V-O coordination polyhedra to generate a layered structure with a suitable interlayer space for the insertion or removal of zinc ions. Actually, the intrinsic coordination chemistry changes between VO5 square pyramids and VO6 octahedra account for the phase transformation during the Zn2+-(de)intercalation reaction.

Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms.

Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters.

Multi-Mode Antibacterial Strategies Enabled by Gene-Transfection and Immunomodulatory Nanoparticles in 3D-Printed Scaffolds for Synergistic Exogenous and Endogenous Treatment of Infections.

As research on refractory Staphylococcus aureus-related implant infection intensifies, certain challenges remain, including low antibiotic concentrations within infected areas, immune escape achieved by intracellular bacteria, myeloid-derived suppressor cells (MDSCs) inducing regional immunosuppression, and recurrence of residual pathogenic bacteria after drug suspension. Herein, a novel antimicrobial system to simultaneously address these issues is proposed. Specifically, an oxygen-species-responsive 3D-printed scaffold with shell-core nanoparticles is designed, which are loaded with an antimicrobial peptide plasmid (LL37 plasmid) and have LL37 grafted on their surface (LL37@ZIF8-LL37). The surface-grafted LL37 directly kills S. aureus and, following entry into cells, the nanoparticles kill intracellular bacteria. Moreover, in vitro and in vivo, following translation of the LL37 plasmid, cells function as factories of the antimicrobial peptide, thereby generating a continuous, prolonged antibacterial effect at the site of infection. This system significantly reduces the abnormal increase in MDSCs within the infected microenvironment, thus relieving the immunosuppressive state and restoring a protective antimicrobial immune response. Hence, this proposed antimicrobial system provides an antimicrobial immune response and a novel strategy for S. aureus-related infections by offering a combined active antimicrobial and immunotherapeutic strategy, thereby significantly reducing the recurrence rate following recovery from implant-associated infections.

3D Printing for Bone-Cartilage Interface Regeneration.

Due to the vasculature defects and/or the avascular nature of cartilage, as well as the complex gradients for bone-cartilage interface regeneration and the layered zonal architecture, self-repair of cartilage and subchondral bone is challenging. Currently, the primary osteochondral defect treatment strategies, including artificial joint replacement and autologous and allogeneic bone graft, are limited by their ability to simply repair, rather than induce regeneration of tissues. Meanwhile, over the past two decades, three-dimension (3D) printing technology has achieved admirable advancements in bone and cartilage reconstruction, providing a new strategy for restoring joint function. The advantages of 3D printing hybrid materials include rapid and accurate molding, as well as personalized therapy. However, certain challenges also exist. For instance, 3D printing technology for osteochondral reconstruction must simulate the histological structure of cartilage and subchondral bone, thus, it is necessary to determine the optimal bioink concentrations to maintain mechanical strength and cell viability, while also identifying biomaterials with dual bioactivities capable of simultaneously regenerating cartilage. The study showed that the regeneration of bone-cartilage interface is crucial for the repair of osteochondral defect. In this review, we focus on the significant progress and application of 3D printing technology for bone-cartilage interface regeneration, while also expounding the potential prospects for 3D printing technology and highlighting some of the most significant challenges currently facing this field.

Construction and Comparison of Predictive Models for Length of Stay after Total Knee Arthroplasty: Regression Model and Machine Learning Analysis Based on 1,826 Cases in a Single Singapore Center.

The purpose of this study was to develop a predictive model for length of stay (LOS) after total knee arthroplasty (TKA). Between 2013 and 2014, 1,826 patients who underwent TKA from a single Singapore center were enrolled in the study after qualification. Demographics of patients with normal and prolonged LOS were analyzed. The risk variables that could affect LOS were identified by univariate analysis. Predictive models for LOS after TKA by logistic regression or machine learning were constructed and compared. The univariate analysis showed that age, American Society of Anesthesiologist level, diabetes, ischemic heart disease, congestive heart failure, general anesthesia, and operation duration were risk factors that could affect LOS (p < 0.05). Comparing with logistic regression models, the machine learning model with all variables was the best model to predict LOS after TKA, of whose area of operator characteristic curve was 0.738. Machine learning algorithms improved the predictive performance of LOS prediction models for TKA patients.

Photosensitizer Nanodot Eliciting Immunogenicity for Photo-Immunologic Therapy of Postoperative Methicillin-Resistant Staphylococcus aureus Infection and Secondary Recurrence.

The treatment of postoperative infection caused by multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), has become an intractable clinical challenge owing to its low therapeutic efficacy and high risk of recurrence. Apart from imperfect antibacterial therapies, induction of insufficient immunogenicity, required for the successful clearance of a pathogen, may also contribute to the problem. Herein, an ultra-micro photosensitizer, AgB nanodots, using photothermal therapy, photodynamic therapy, and Ag+ ion sterilization, are utilized to efficiently clear invading MRSA both in vitro and in vivo. AgB nanodots are also found to upregulate host immunogenicity in a murine model and establish immunological memory by promoting the upregulated expression of danger signals that are commonly induced by stress-related responses, including sudden temperature spikes or excess reactive oxygen production. These stimulations boost the antibacterial effects of macrophages, dendritic cells, T cells, or even memory B cells, which is usually defined as infection-related immunogenic cell death. Hence, the proposed AgB nanodot strategy may offer a novel platform for the effective treatment of postoperative infection while providing a systematic immunotherapeutic strategy to combat persistent infections, thereby markedly reducing the incidence of recurrence following recovery from primary infections.

Cognitive Matching of Design Subjects in Product Form Evolutionary Design.

In actual product development, the cognitive differences between users and designers make it difficult for the designed products to be recognized by users. To reduce the cognitive differences between these two design subjects, this paper proposes a method of cognitive matching of the design subjects. First, we use the relevant methods of Kansei engineering to quantify the Kansei image cognition of the two design subjects and construct a cognitive matching model of the design subjects with information entropy and the technique for order preference by similarity to ideal solution (TOPSIS). Second, according to the Kansei image, the Kansei image prototype cluster is constructed, and the representative Kansei image prototype is obtained. Then, we combine an artificial neural network (ANN) with a cognitive matching model of the design subjects to construct a product Kansei image evaluation system; this is used to evaluate the evolved forms. Finally, a product Kansei image form evolution system is constructed based on the genetic algorithm (GA). To some extent, the system simulates the cognitive matching process between designers and users in product design, helps designers to more accurately understand the cognitive trends of the two design subjects, and provides a theoretical basis for the intelligent design of product forms through the cognitive balance of multiple design subjects. This paper takes a beverage bottle as an example to verify the feasibility of the model through a comparative study.

Upper-Limb Muscle Synergy Features in Human-Robot Interaction with Circle-Drawing Movements.

The upper-limb rehabilitation robots can be developed as an efficient tool for motor function assessments. Circle-drawing has been used as a specific task for robot-based motor function measurement. The upper-limb movement-related kinematic and kinetic parameters measured by motion and force sensors embedded in the rehabilitation robots have been widely studied. However, the muscle synergies characterized by multiple surface electromyographic (sEMG) signals in upper limbs during human-robot interaction (HRI) with circle-drawing movements are rarely investigated. In this research, the robot-assisted and constrained circle-drawing movements for upper limb were used to increase the consistency of muscle synergy features. Both clockwise and counterclockwise circle-drawing tasks were implemented by all healthy subjects using right hands. The sEMG signals were recorded from six muscles in upper limb, and nonnegative matrix factorization (NMF) analysis was utilized to obtain muscle synergy information. Both synergy pattern and activation coefficient were calculated to represent the spatial and temporal features of muscle synergies, respectively. The results obtained from the experimental study confirmed that high structural similarity of muscle synergies was found among the subjects during HRI with circle-drawing movement by healthy subjects, which indicates healthy people may share a common underlying muscle control mechanism during constrained upper-limb circle-drawing movement. This study indicates the muscle synergy analysis during the HRI with constrained circle-drawing movement could be considered as a task for upper-limb motor function assessment.

Recent Advances in Research on Antibacterial Metals and Alloys as Implant Materials.

Implants are widely used in orthopedic surgery and are gaining attention of late. However, their use is restricted by implant-associated infections (IAI), which represent one of the most serious and dangerous complications of implant surgeries. Various strategies have been developed to prevent and treat IAI, among which the closest to clinical translation is designing metal materials with antibacterial functions by alloying methods based on existing materials, including titanium, cobalt, tantalum, and biodegradable metals. This review first discusses the complex interaction between bacteria, host cells, and materials in IAI and the mechanisms underlying the antibacterial effects of biomedical metals and alloys. Then, their applications for the prevention and treatment of IAI are highlighted. Finally, new insights into their clinical translation are provided. This review also provides suggestions for further development of antibacterial metals and alloys.

Diclofenac Resensitizes Methicillin-Resistant Staphylococcus aureus to ß-Lactams and Prevents Implant Infections.

Implant infections caused by methicillin-resistant Staphylococcus aureus (MRSA) can cause major complications during the perioperative period. Diclofenac, one of the most widely used nonsteroidal anti-inflammatory drugs, is often used to relieve pain and inflammation. In this study, it is found that high-dose diclofenac can inhibit the growth of MRSA, and does not easily induce drug-resistant mutations after continuous passage. However, low-doses diclofenac can resensitize bacteria to ß-lactams, which help to circumvent drug resistance and improve the antibacterial efficacy of conventional antibiotics. Further, low-dose diclofenac in combination with ß-lactams inhibit MRSA associated biofilm formation in implants. Transcriptomic and proteomic analyses indicate that diclofenac can reduce the expression of genes and proteins associated with ß-lactam resistance: mecA, mecR, and blaZ; peptidoglycan biosynthesis: murA, murC, femA, and femB; and biofilm formation: altE and fnbP. Murine implant infection models indicate that diclofenac combined with ß-lactams, can substantially alleviate MRSA infections in vivo. In addition, it is investigated that low dose diclofenac can inhibit MRSA antibiotic resistance via the mecA/blaZ pathway and related biofilms in implants. The synergistic effect of diclofenac and ß-lactams might have promising applications for preventing perioperative infection, considering its multitarget effects against MRSA.

Fusion of Cognitive Information: Evaluation and Evolution Method of Product Image Form.

In order to realize the stability and inheritance of image characteristics in the development process of a series of products, we comprehensively analyzed the cognitive differences among users, designers, and engineers and propose a multicriteria decision system for an intelligent design method of product forms based on a logistic regression model, relative entropy theory, and preference mapping (PREFMAP). First, from the perspective of the role characteristics of the design subjects, an equilibrium evaluation model was constructed using the logistic regression model and relative entropy theory. Second, combining the multidimensional perception space and the characteristics measurement of the product form, the fitness function of the image form was constructed based on PREFMAP. Third, a genetic algorithm was applied to establish the intelligent image-style-oriented design method, which could guide the image form development of a product series through innovative design. Lastly, the method was verified by taking Audi A4L series headlights as an example. And the image evaluation of the two new schemes was greater than that of the previous seven generations of headlights. The results verify the effectiveness and feasibility of the method. In this paper, we structured a relatively preliminary model to explain the fusion of cognitive information. More subjective and objective factors, algorithms, and image recognition technology need to be further studied to improve the model in our future work.

Intelligent Design of Product Forms Based on Design Cognitive Dynamics and a Cobweb Structure.

Design is a complex, iterative, and innovative process. By traditional methods, it is difficult for designers to have an integral priori design experience to fully explore a wide range of design solutions. Therefore, refined intelligent design has become an important trend in design research. More powerful design thinking is needed in intelligent design process. Combining cognitive dynamics and a cobweb structure, an intelligent design method is proposed to formalize the innovative design process. The excavation of the dynamic mechanism of the product evolution process during product development is necessary to predict next-generation multi-image product forms from a larger design space. First, different design thinking stimulates the information source and is obtained by analyzing the designers' thinking process when designing and mining the dynamic mechanism behind it. Based on the nonlinear cognitive cobweb process proposed by Francisco and a natural cobweb structure, the product image cognitive cobweb model (PICCM) is constructed. Then, natural cobweb predation behavior is simulated using a stimulus information source to impact the PICCM. This process uses genetic algorithms to obtain numerous offspring forms, and the PICCM's mechanical properties are the energy loss parameters in the impact information. Furthermore, feasible solutions are selected from intelligent design sketches by the product artificial form evaluation system based on designers' cognition, and a new product image cognitive cobweb system is reconstructed. Finally, a case study demonstrates the efficiency and feasibility of the proposed approach.

p300/CBP inhibitor A-485 inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss.

Osteoporosis is one of the most common metabolic bone diseases among pre- and post-menopausal women. Despite numerous advances in the treatment of osteoporosis in recent years, the outcomes remain poor due to severe side effects. In this study, we investigated whether A-485, a highly selective catalytic p300/CBP inhibitor, could attenuate RANKL-induced osteoclast differentiation and explored the underlying molecular mechanisms. The protective role of A-485 in osteoporosis was verified using a mouse model of ovariectomy (OVX)-induced bone loss and micro-CT scanning. A-485 inhibited RANKL-induced osteoclast differentiation in vitro by reducing the number of tartrate-resistant acid phosphatase-positive osteoclasts without inducing significant cytotoxicity. In particular, A-485 dose-dependently disrupted F-actin ring formation and downregulated the expression of genes associated with osteoclast differentiation, such as CTSK, c-Fos, TRAF6, VATPs-d2, DC-STAMP, and NFATc1, in a time- and dose-dependent manner. Moreover, A-485 inhibited the RANKL-induced phosphorylation of MAPK pathways and attenuated OVX-induced bone loss in the mouse model while rescuing the loss of bone mineral density. Our in vitro and in vivo findings suggest for the first time that A-485 has the potential to prevent postmenopausal osteoporosis and could therefore be considered as a therapeutic molecule against osteoporosis.