Transforming layered 2D mats into multiphasic 3D nanofiber scaffolds with tailored gradient features for tissue regeneration.

Multiphasic scaffolds with tailored gradient features hold significant promise for tissue regeneration applications. Herein, this work reports the transformation of two-dimensional (2D) layered fiber mats into three dimensional (3D) multiphasic scaffolds using a 'solids-of-revolution' inspired gas-foaming expansion technology. These scaffolds feature precise control over fiber alignment, pore size, and regional structure. Manipulating nanofiber mat layers and Pluronic F127 concentrations allows further customization of pore size and fiber alignment within different scaffold regions. The cellular response to multiphasic scaffolds demonstrates the number of cells migrated and proliferated onto the scaffolds are mainly dependent on the pore size rather than fiber alignment. In vivo subcutaneous implantation of multiphasic scaffolds to rats reveals substantial cell infiltration, neo tissue formation, collagen deposition, and new vessel formation within scaffolds, greatly surpassing the capabilities of traditional nanofiber mats. Histological examination indicates the importance of optimizing pore size and fiber alignment for promotion of cell infiltration and tissue regeneration. Overall, these scaffolds have potential applications in tissue modeling, studying tissue-tissue interactions, interface tissue engineering, and high-throughput screening for optimized tissue regeneration.

Copper-Cystine Biohybrid-Embedded Nanofiber Aerogels Show Antibacterial and Angiogenic Properties.

Copper-cystine-based high aspect ratio structures (CuHARS) possess exceptional physical and chemical properties and exhibit remarkable biodegradability in human physiological conditions. Extensive testing has confirmed the biocompatibility and biodegradability of CuHARS under diverse biological conditions, making them a viable source of essential Cu2+. These ions are vital for catalyzing the production of nitric oxide (NO) from the decomposition of S-nitrosothiols (RSNOs) found in human blood. The ability of CuHARS to act as a Cu2+ donor under specific concentrations has been demonstrated in this study, resulting in the generation of elevated levels of NO. Consequently, this dual function makes CuHARS effective as both a bactericidal agent and a promoter of angiogenesis. In vitro experiments have shown that CuHARS actively promotes the migration and formation of complete lumens by redirecting microvascular endothelial cells. To maximize the benefits of CuHARS, they have been incorporated into biomimetic electrospun poly(ε-caprolactone)/gelatin nanofiber aerogels. Through the regulated release of Cu2+ and NO production, these channeled aerogels not only provide antibacterial support but also promote angiogenesis. Taken together, the inclusion of CuHARS in biomimetic scaffolds could hold great promise in revolutionizing tissue regeneration and wound healing.

Mechanically resilient hybrid aerogels containing fibers of dual-scale sizes and knotty networks for tissue regeneration.

The structure and design flexibility of aerogels make them promising for soft tissue engineering, though they tend to come with brittleness and low elasticity. While increasing crosslinking density may improve mechanics, it also imparts brittleness. In soft tissue engineering, resilience against mechanical loads from mobile tissues is paramount. We report a hybrid aerogel that consists of self-reinforcing networks of micro- and nanofibers. Nanofiber segments physically entangle microfiber pillars, allowing efficient stress distribution through the intertwined fiber networks. We show that optimized hybrid aerogels have high specific tensile moduli (~1961.3 MPa cm3 g-1) and fracture energies (~7448.8 J m-2), while exhibiting super-elastic properties with rapid shape recovery (~1.8 s). We demonstrate that these aerogels induce rapid tissue ingrowth, extracellular matrix deposition, and neovascularization after subcutaneous implants in rats. Furthermore, we can apply them for engineering soft tissues via minimally invasive procedures, and hybrid aerogels can extend their versatility to become magnetically responsive or electrically conductive, enabling pressure sensing and actuation.

It Takes Two to Tangle: Microneedle Patches Co-delivering Monoclonal Antibodies and Engineered Antimicrobial Peptides Effectively Eradicate Wound Biofilms.

Wound biofilms pose a great clinical challenge. Herein, this work reports a dissolvable microneedle patch for dual delivery of monoclonal antibodies anti-PBP2a and engineers antimicrobial peptides W379. In vitro antibacterial efficacy testing with microneedle patches containing a combination of 250 ng mL-1 W379 and 250 ng mL-1 anti-BPB2a decreases the bacterial count from ≈3.31 × 107 CFU mL-1 to 1.28 × 102 CFU mL-1 within 2 h without eliciting evident cytotoxicity. Ex vivo testing indicates W379 and anti-PBP2a co-loaded microneedle patch displayed a remarkable reduction of bacterial load by ≈7.18 log CFU after administered only once within 48 h. The bacterial count is significantly diminished compared to the treatment by either W379 or anti-PBP2a-loaded alone microneedle patches. When administered twice within 48 h, no bacteria are identified. Further in vivo study also reveals that after two treatments of W379 and anti-PBP2a co-loaded PVP microneedle patches within 48 h, the bacterial colonies are undetectable in a type II diabetic mouse wound biofilm model. Taken together, W379 and anti-PBP2a co-loaded PVP microneedle patches hold great promise in treating wound biofilms.

Enhanced Antimicrobial Screening Sensitivity Enabled the Identification of an Ultrashort Peptide KR-8 for Engineering of LL-37mini to Combat Drug-Resistant Pathogens.

Identification of novel antibiotics is of top importance because of the threat of antibiotic-resistant pathogens. Antimicrobial screening in Mueller-Hinton broth is frequently the first step in antimicrobial discovery. Although widely utilized, this medium is not ideal as it could mask activity of candidates such as human cathelicidin LL-37 against methicillin-resistant Staphylococcus aureus (MRSA). This study identified a sensitive medium where LL-37 displayed excellent activity against numerous pathogens, including MRSA. Our screen of ultrashort overlapping LL-37 peptides in this medium led to the identification of KR-8, four residues shorter than KR-12. Hence, our screen condition may increase positive compound hits during antimicrobial screening. KR-8 provided an appealing template for us to design LL-37mini, which was potent against MRSA, Escherichia coli, and Pseudomonas aeruginosa but not toxic to mammalian cells. LL-37mini also inhibited bacterial attachment and biofilm formation and disrupted preformed biofilms in vitro and killed MRSA in murine wound biofilms in vivo. Consistent with membrane targeting, MRSA failed to develop resistance to LL-37mini in a multiple-passage experiment. Because LL-37mini can be made cost effectively, it can be developed into new antibiofilm and antimicrobial agents.

Balance between the diffraction efficiency and process robustness for plasmonic lithographic alignment technology considering the Fabry-Perot resonator effect.

Different from traditional lithography, metal material with high absorptivity and high reflectivity is introduced into plasmonic lithography technology. In particular, a silver/photo resist/silver film stack can form a Fabry-Perot (F-P) resonator structure, which can greatly change the behavior of the light reflection and transmission. Since the silver layer has a strong absorption ability to the alignment probe light with a wavelength of 532 or 633 nm, the quality of the alignment signal is seriously affected. In this paper, a thin film Fourier transfer model is established to quantitatively calculate the amplitude and phase information of the diffraction light with different orders. The results show that the diffraction optical power can be enhanced by the thickness optimization of all film stacks, and the maximum wafer quality (normalized diffraction efficiency) can be increased to 25.7%. The mechanism analysis of alignment signal enhancement is based on the F-P resonator phase oscillation amplification effect. However, it can also bring the reverse of both the power and phase for the alignment probe signal when the thickness fluctuation of the F-P resonator exists, which will be a great challenge for through-the-mask moiré fringe alignment technology. To obtain the optical power distribution of the structure surface and image of moiré fringes, a transfer matrix method is given to point-by-point calculate the incidence and reflection of the probe light in the vertical direction. The finite-difference time-domain method is also used to demonstrate alignment performance. It is proved that the subtle fluctuation of the photoresist thickness can make a huge difference to moiré fringes. A balance between the diffraction efficiency and process robustness can be achieved for plasmonic lithographic alignment technology by controlling the thickness range of the F-P resonator structure. In addition, the metal-insulator-metal structure has excellent thickness sensitivity and is applicable to optical signal detection and material property monitoring.

Peptides for diagnosis and treatment of ovarian cancer.

Ovarian cancer is the most deadly gynecologic malignancy, and its incidence is gradually increasing. Despite improvements after treatment, the results are unsatisfactory and survival rates are relatively low. Therefore, early diagnosis and effective treatment remain two major challenges. Peptides have received significant attention in the search for new diagnostic and therapeutic approaches. Radiolabeled peptides specifically bind to cancer cell surface receptors for diagnostic purposes, while differential peptides in bodily fluids can also be used as new diagnostic markers. In terms of treatment, peptides can exert cytotoxic effects directly or act as ligands for targeted drug delivery. Peptide-based vaccines are an effective approach for tumor immunotherapy and have achieved clinical benefit. In addition, several advantages of peptides, such as specific targeting, low immunogenicity, ease of synthesis and high biosafety, make peptides attractive alternative tools for the diagnosis and treatment of cancer, particularly ovarian cancer. In this review, we focus on the recent research progress regarding peptides in the diagnosis and treatment of ovarian cancer, and their potential applications in the clinical setting.

Triggered release of antimicrobial peptide from microneedle patches for treatment of wound biofilms.

Biofilms pose a great challenge for wound management. Herein, this study describes a near-infrared (NIR) light-responsive microneedle patch for on-demand release of antimicrobial peptide for treatment of wound biofilms. IR780 iodide as a photothermal conversion agent and molecularly engineered peptide W379 as an antimicrobial agent are loaded in dissolvable poly(vinylpyrrolidone) (PVP) microneedle patches followed by coating with a phase change material 1-tetradecanol (TD). After placing in an aqueous solution or biofilm containing wounds ex vivo and in vivo, upon exposure to NIR light, the incorporated IR780 induces light-to-heat conversion, causing the melting of TD. This leads to the dissolution of PVP microneedles, enabling the release of loaded W379 peptide from the microneedles into surrounding regions (e.g., solution, biofilm, wound bed). Compared with traditional microneedle patches, NIR light responsive microneedle patches can program the release of antimicrobial peptide and show high antibacterial efficacy in vitro. Meanwhile, this work indicates that NIR light responsive TD-coated, W379-loaded PVP microneedle patches show excellent antibiofilm activities ex vivo and in vivo. Additionally, this microneedle system could be a promising platform for delivering other antimicrobial agents.

Differential Roles of CD36 in Regulating Muscle Insulin Response Depend on Palmitic Acid Load.

The possible role of fatty acid translocase (CD36) in the treatment of obesity has gained increasing research interest since researchers recognized its coordinated function in fatty acid uptake and oxidation. However, the effect of CD36 deficiency on intracellular insulin signaling is complex and its impact may depend on different nutritional stresses. Therefore, we investigated the various effects of CD36 deletion on insulin signaling in C2C12 myotubes with or without palmitic acid (PA) overload. In the present work, we reported the upregulated expression levels of CD36 in the skeletal muscle tissues of obese humans and mice as well as in C2C12 myotubes with PA stimulation. CD36 knockdown using RNA interference showed that insulin signaling was impaired in CD36-deficient C2C12 cells in the absence of PA loading, suggesting that CD36 is essential for the maintenance of insulin action, possibly resulting from increased mitochondrial dysfunction and endoplasmic reticulum (ER) stress; however, CD36 deletion improved insulin signaling in the presence of PA overload due to a reduction in lipid overaccumulation. In conclusion, we identified differential roles of CD36 in regulating muscle insulin response under conditions with and without PA overload, which provides supportive evidence for further research into therapeutic approaches to diabetes.

Nanofiber Aerogels with Precision Macrochannels and LL-37-Mimic Peptides Synergistically Promote Diabetic Wound Healing.

Fast healing of diabetic wounds remains a major clinical challenge. Herein, this work reports a strategy to combine nanofiber aerogels containing precision macrochannels and the LL-37-mimic peptide W379 for rapid diabetic wound healing. Nanofiber aerogels consisting of poly(glycolide-co-lactide) (PGLA 90:10)/gelatin and poly-p-dioxanone (PDO)/gelatin short electrospun fiber segments were prepared by partially anisotropic freeze-drying, crosslinking, and sacrificial templating with three-dimensional (3D)-printed meshes, exhibiting nanofibrous architecture and precision micro-/macrochannels. Like human cathelicidin LL-37, W379 peptide at a concentration of 3 µg/mL enhanced the migration and proliferation of keratinocytes and dermal fibroblasts in a cell scratch assay and a proliferation assay. In vivo studies show that nanofiber aerogels with precision macrochannels can greatly promote cell penetration compared to aerogels without macrochannels. Relative to control and aerogels with and without macrochannels, adding W379 peptides to aerogels with precision macrochannels shows the best efficacy in healing diabetic wounds in mice in terms of cell infiltration, neovascularization, and re-epithelialization. The fast re-epithelization could be due to upregulation of phospho-extracellular signal-regulated kinase (p38 MAPK) after treatment with W379. Together, the approach developed in this work could be promising for the treatment of diabetic wounds and other chronic wounds.

Porous liquid metal-elastomer composites with high leakage resistance and antimicrobial property for skin-interfaced bioelectronics.

Liquid metal-elastomer composite is a promising soft conductor for skin-interfaced bioelectronics, soft robots, and others due to its large stretchability, ultrasoftness, high electrical conductivity, and mechanical-electrical decoupling. However, it often suffers from deformation-induced leakage, which can smear skin, deteriorate device performance, and cause circuit shorting. Besides, antimicrobial property is desirable in soft conductors to minimize microbial infections. Here, we report phase separation-based synthesis of porous liquid metal-elastomer composites with high leakage resistance and antimicrobial property, together with large stretchability, tissue-like compliance, high and stable electrical conductivity over deformation, high breathability, and magnetic resonance imaging compatibility. The porous structures can minimize leakage through damping effects and lower percolation thresholds to reduce liquid metal usage. In addition, epsilon polylysine is loaded into elastic matrices during phase separation to provide antimicrobial property. The enabled skin-interfaced bioelectronics can monitor cardiac electrical and mechanical activities and offer electrical stimulations in a mechanically imperceptible and electrically stable manner even during motions.

Peptide Stability Is Important but Not a General Requirement for Antimicrobial and Antibiofilm Activity In Vitro and In Vivo.

Peptide stability to proteases has been a major requirement for developing peptide therapeutics. This study investigates the effects of peptide stability on antimicrobial and antibiofilm activity under various conditions. For this purpose, two human cathelicidin-derived peptides differing in stability to proteases were utilized. While GF-17, a peptide derived from the major antimicrobial region of human LL-37, can be rapidly cleaved by proteases, the engineered peptide 17BIPHE2 is resistant to multiple proteases. In the standard antimicrobial susceptibility, killing kinetics, and membrane permeabilization assays conducted in vitro using planktonic bacteria, these two peptides displayed similar potency. The two peptides were also similarly active against methicillin-resistant Staphylococcus aureus (MRSA) USA300 prior to biofilm formation. However, 17BIPHE2 was superior to GF-17 in disrupting preformed biofilms probably due to both enhanced stability and slightly higher DNA binding capacity. In a wax moth model, 17BIPHE2 better protected insects from MRSA infection-caused death than GF-17, consistent with the slower degradation of 17BIPHE2 than GF-17. Here, peptide antimicrobial activity was found to be critical for in vivo efficacy. When incorporated in the nanofiber/microneedle delivery device, GF-17 and 17BIPHE2 displayed a similar effect in eliminating MRSA in murine chronic wounds, underscoring the advantage of nanofibers in protecting the peptide from degradation. Since nanoformulation can ease the requirement of peptide stability, it opens the door to a direct use of natural peptides or their cocktails for antimicrobial treatment, accelerating the search of effective antibiofilm peptides to treat chronic wounds.

A Highly Efficacious Electrical Biofilm Treatment System for Combating Chronic Wound Bacterial Infections.

Biofilm infection has a high prevalence in chronic wounds and can delay wound healing. Current treatment using debridement and antibiotic administration imposes a significant burden on patients and healthcare systems. To address their limitations, a highly efficacious electrical antibiofilm treatment system is described in this paper. This system uses high-intensity current (75 mA cm-2 ) to completely debride biofilm above the wound surface and enhance antibiotic delivery into biofilm-infected wounds simultaneously. Combining these two effects, this system uses short treatments (≤2 h) to reduce bacterial count of methicillin-resistant S. aureus (MRSA) biofilm-infected ex vivo skin wounds from 1010 to 105.2 colony-forming units (CFU) g-1 . Taking advantage of the hydrogel ionic circuit design, this system enhances the in vivo safety of high-intensity current application compared to conventional devices. The in vivo antibiofilm efficacy of the system is tested using a diabetic mouse-based wound infection model. MRSA biofilm bacterial count decreases from 109.0 to 104.6 CFU g-1 at 1 day post-treatment and to 103.3 CFU g-1 at 7 days post-treatment, both of which are below the clinical threshold for infection. Overall, this novel technology provides a quick, safe, yet highly efficacious treatment to chronic wound biofilm infections.

CD36 deficiency inhibits proliferation by cell cycle control in skeletal muscle cells.

Obesity-related muscular dysfunction and relative muscle atrophy affect an increasing number of people. Elucidating the molecular mechanisms of skeletal muscle cell development and growth may contribute to the maintenance of skeletal muscle mass in obesity. Fatty acid translocase (FAT/CD36), as a long-chain fatty acid transport protein, is crucial for lipid metabolism and signaling. CD36 is known to function in myogenic differentiation, and whether it affects the proliferation of skeletal muscle cells and the underlying mechanisms remain unclear. In this study, the effect of CD36 deficiency on skeletal muscle cell viability and proliferation was examined using C2C12 myoblasts. Results showed that the deletion of CD36 enhanced the inhibitory effect of PA on the proliferation and the promotion of apoptosis in skeletal muscle cells. Intriguingly, the silencing of CD36 suppressed cell proliferation by preventing the cell cycle from the G0/G1 phase to the S phase in a cyclin D1/CDK4-dependent manner. Overall, we demonstrated that CD36 was involved in skeletal muscle cell proliferation by cell cycle control, and these findings might facilitate the treatment of obesity-related muscle wasting.

Analysis on the Development and Influence of National Fitness Environment on Youth Basketball Coordination and Mental Health.

In order to improve the basketball theory and provide theoretical and intellectual support for the scientific, mental health, and sustainable development of basketball, we propose to take the development dynamic mechanism of juvenile basketball as the research object and make a systematic and in-depth study on the dynamic mechanism, the cultivation of Chinese and foreign juvenile basketball reserve talents, and the dynamic dilemma and influencing factors of juvenile campus basketball development by using the methods of literature, questionnaire, and expert interview. A method of cultivating the ring tone of juvenile basketball is proposed. This method is based on Chan algorithm. When the target is close to each base station, the first estimation also needs an initial value to solve the initial solution estimation matrix. The method is also based on multivariate Taylor algorithm, taking into account the measured distance between the targets to be measured, so it will get some useful information, which will improve the positioning accuracy. The experimental results show that the accuracy of the algorithm used in this paper is more than 85%. However, the accuracy of rebounding and passing recognition and prediction is low. The recognition accuracy and prediction accuracy of the test set are slightly lower than that of the effective set, which shows that the performance of the target detection system model in this paper can be further improved through more significant training examples. It is proved that the algorithm based on Taylor ring can meet the needs of teenagers in the basketball coordination and mental health.

Biofilms: Formation, Research Models, Potential Targets, and Methods for Prevention and Treatment.

Due to the continuous rise in biofilm-related infections, biofilms seriously threaten human health. The formation of biofilms makes conventional antibiotics ineffective and dampens immune clearance. Therefore, it is important to understand the mechanisms of biofilm formation and develop novel strategies to treat biofilms more effectively. This review article begins with an introduction to biofilm formation in various clinical scenarios and their corresponding therapy. Established biofilm models used in research are then summarized. The potential targets which may assist in the development of new strategies for combating biofilms are further discussed. The novel technologies developed recently for the prevention and treatment of biofilms including antimicrobial surface coatings, physical removal of biofilms, development of new antimicrobial molecules, and delivery of antimicrobial agents are subsequently presented. Finally, directions for future studies are pointed out.

Engineered Exosomes Containing Cathelicidin/LL-37 Exhibit Multiple Biological Functions.

Exosomes show great potential in diagnostic and therapeutic applications. Inspired by the human innate immune defense, herein, we report engineered exosomes derived from monocytic cells treated with immunomodulating compounds 1α,25-dihydroxyvitamin D3, and CYP24A1 inhibitor VID400 which are slowly released from electrospun nanofiber matrices. These engineered exosomes contain significantly more cathelicidin/LL-37 when compared with exosomes derived from either untreated cells or Cathelicidin Human Tagged ORF Clone transfected cells. In addition, such exosomes exhibit multiple biological functions evidenced by killing bacteria, facilitating human umbilical vein endothelial cell tube formation, and enhancing skin cell proliferation and migration. Taken together, the engineered exosomes developed in this study can be used as therapeutics alone or in combination with other biomaterials for effective infection management, wound healing, and tissue regeneration.

Identification of metabolic pathways underlying FGF1 and CHIR99021-mediated cardioprotection.

Acute myocardial infarction is a leading cause of death worldwide. We have previously identified two cardioprotective molecules - FGF1 and CHIR99021- that confer cardioprotection in mouse and pig models of acute myocardial infarction. Here, we aimed to determine if improved myocardial metabolism contributes to this cardioprotection. Nanofibers loaded with FGF1 and CHIR99021 were intramyocardially injected to ischemic myocardium of adult mice immediately following surgically induced myocardial infarction. Animals were euthanized 3 and 7 days later. Our data suggested that FGF1/CHIR99021 nanofibers enhanced the heart's capacity to utilize glycolysis as an energy source and reduced the accumulation of branched-chain amino acids in ischemic myocardium. The impact of FGF1/CHIR99021 on metabolism was more obvious in the first three days post myocardial infarction. Taken together, these findings suggest that FGF1/CHIR99021 protects the heart against ischemic injury via improving myocardial metabolism which may be exploited for treatment of acute myocardial infarction in humans.

Laser-scribed conductive, photoactive transition metal oxide on soft elastomers for Janus on-skin electronics and soft actuators.

Laser-assisted fabrication of conductive materials on flexible substrates has attracted intense interests because of its simplicity, easy customization, and broad applications. However, it remains challenging to achieve laser scribing of conductive materials on tissue-like soft elastomers, which can serve as the basis to construct bioelectronics and soft actuators. Here, we report laser scribing of metallic conductive, photoactive transition metal oxide (molybdenum dioxide) on soft elastomers, coated with molybdenum chloride precursors, under ambient conditions. Laser-scribed molybdenum dioxide (LSM) exhibits high electrical conductivity, biocompatibility, chemical stability, and compatibility with magnetic resonance imaging. In addition, LSM can be made on various substrates (polyimide, glass, and hair), showing high generality. Furthermore, LSM-based Janus on-skin electronics are developed to record information from human skin, human breath, and environments. Taking advantage of its outstanding photothermal effect, LSM-based soft actuators are developed to build light-driven reconfigurable three-dimensional architectures, reshapable airflow sensors, and smart robotic worms with bioelectronic sensors.