Smart Bactericidal Capsules Based on Cationic Luminescent Nanoclusters for Controllable Treatment of Drug-Resistant Bacterial Infection.

Effective treatment of drug-resistant bacteria infected wound has been a longstanding challenge for healthcare systems. In particular, the development of novel strategies for controllable delivery and smart release of antimicrobial agents is greatly demanded. Herein, the design of biodegradable microcapsules carrying bactericidal gold nanoclusters (AuNCs) as an attractive platform for the effective treatment of drug-resistant bacteria infective wounds is reported. AuNC capsules are fabricated via the well-controlled layer-by-layer strategy, which possess intrinsic near-infrared fluorescence and good biocompatibility. Importantly, these AuNC capsules exhibit strong, specific antibacterial activity toward both S. aureus and methicillin-resistant S. aureus (MRSA). Further mechanistic studies by fluorescence confocal imaging and inductively coupled plasma mass spectrometry reveal that these AuNC capsules will be degraded in the S. aureus environment rather than E. coli, which then controllably release the loaded cationic AuNCs to exert antibacterial effect. Consequently, these AuNC capsules show remarkable therapeutic effect for the MRSA infected wound on a mouse model, and intrinsic fluorescence property of AuNC capsules enables in situ visualization of wound dressings. This study suggests the great potential of microcapsule-based platform as smart carriers of bactericidal agents for the effective treatment of drug-resistant bacterial infection as well as other therapeutic purposes.

Reducing Ambiguities in Line-Based Density Plots by Image-Space Colorization.

Line-based density plots are used to reduce visual clutter in line charts with a multitude of individual lines. However, these traditional density plots are often perceived ambiguously, which obstructs the user's identification of underlying trends in complex datasets. Thus, we propose a novel image space coloring method for line-based density plots that enhances their interpretability. Our method employs color not only to visually communicate data density but also to highlight similar regions in the plot, allowing users to identify and distinguish trends easily. We achieve this by performing hierarchical clustering based on the lines passing through each region and mapping the identified clusters to the hue circle using circular MDS. Additionally, we propose a heuristic approach to assign each line to the most probable cluster, enabling users to analyze density and individual lines. We motivate our method by conducting a small-scale user study, demonstrating the effectiveness of our method using synthetic and real-world datasets, and providing an interactive online tool for generating colored line-based density plots.

Self-Healing Hydrogel Bioelectronics.

Hydrogels have emerged as powerful building blocks to develop various soft bioelectronics because of their tissue-like mechanical properties, superior bio-compatibility, the ability to conduct both electrons and ions, and multiple stimuli-responsiveness. However, hydrogels are vulnerable to mechanical damage, which limits their usage in developing durable hydrogel-based bioelectronics. Self-healing hydrogels aim to endow bioelectronics with the property of repairing specific functions after mechanical failure, thus improving their durability, reliability, and longevity. This review discusses recent advances in self-healing hydrogels, from the self-healing mechanisms, material chemistry, and strategies for multiple properties improvement of hydrogel materials, to the design, fabrication, and applications of various hydrogel-based bioelectronics, including wearable physical and biochemical sensors, supercapacitors, flexible display devices, triboelectric nanogenerators (TENGs), implantable bioelectronics, etc. Furthermore, the persisting challenges hampering the development of self-healing hydrogel bioelectronics and their prospects are proposed. This review is expected to expedite the research and applications of self-healing hydrogels for various self-healing bioelectronics.

Gold Nanocluster-Based Fluorescent Microneedle Platform toward Visual Detection of ATP.

Adenosine triphosphate (ATP) participates in the regulation of most biological processes, and the ATP level is closely associated with many diseases. However, it still remains challenging to achieve on-site monitoring of ATP in an equipment-free and efficient way. Microneedles, a minimally invasive technology that can extract biomarkers from liquid biopsies, have recently emerged as useful tools for early diagnosis of a broad range of diseases. In this work, we developed hydrogel microneedles that are loaded with ATP-specific dual-emitting gold nanoclusters (RhE-AuNCs) for fast sampling and on-needle detection of ATP. These RhE-AuNCs were photo-crosslinked to the hydrogel matrix to form a fluorescent microneedle patch. Based on the ATP-induced Förster resonance energy transfer in RhE-AuNCs, a highly selective, sensitive, and reliable ATP sensor was developed. Moreover, simultaneous capture and visual detection of ATP was achieved by the AuNC-loaded microneedle sensing platform, which exhibits promising sensing performance. This work provides a new approach to design a point-of-care ATP sensing platform, which also holds great potential for the further development of microneedle-based analytical devices.

Chirality-Dependent Angiogenic Activity of MoS2 Quantum Dots toward Regulatable Tissue Regeneration.

Despite great advances in understanding the biological behaviors of chiral materials, the effect of chirality-configured nanoparticles on tissue regeneration-related biological processes remains poorly understood. Herein, the chirality of MoS2 quantum dots (QDs) is tailored by functionalization with l-/d-penicillamine, and the profound chiral effects of MoS2 QDs on cellular activities, angiogenesis, and tissue regeneration are thoroughly investigated. Specifically, d-MoS2 QDs show a positive effect in promoting the growth, proliferation, and migration of human umbilical vein endothelial cells. The expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), and fibroblast growth factor (FGF) in d-MoS2 QDs group is substantially up-regulated, resulting in enhanced tube formation activity. This distinct phenomenon is largely due to the higher internalization efficiency of d-MoS2 QDs than l-MoS2 QDs and chirality-dependent nano-bio interactions. In vivo angiogenic assay shows the expression level of angiogenic markers in newly-formed skin tissues of d-MoS2 QDs group is higher than that in l-MoS2 QDs group, leading to an accelerated re-epithelialization and improved skin regeneration. The findings of chirality-dependent angiogenesis activity of MoS2 QDs provide new insights into the biological activity of MoS2 nanomaterials, which also opens up a new path to the rational design of chiral nanomaterials for tissue regeneration application.

Bio-inspired peptide-conjugated liposomes for enhanced planktonic bacteria killing and biofilm eradication.

Developing new antimicrobial agents has become an urgent task to address the increasing prevalence of multidrug-resistant pathogens and the emergence of biofilms. Cationic antimicrobial peptides (AMPs) have been regarded as promising candidates due to their unique non-specific membrane rupture mechanism. However, a series of problems with the peptides hindered their practical application due to their high toxicity and low bioactivity and stability. Here, inspired by broadening the application of cell-penetrating peptides (CPPs), we selected five different sequences of cationic peptides which are considered as both CPPs and AMPs, and developed a biomimetic strategy to construct cationic peptide-conjugated liposomes with the virus-like structure for both enhancements of antibacterial efficacy and biosafety. The correlation between available peptide density/peptide variety and antimicrobial capabilities was evaluated from quantitative perspectives. Computational simulation and experimental investigations assisted to identify the optimal peptide-conjugated liposomes and revealed that the designed system provides high charge density for enhanced anionic bacterial membrane binding capability without compromised cytotoxicity, being capable of enhanced antibacterial efficacy of bacteria/biofilm of clinically important pathogens. The bio-inspired design has shown enhanced therapeutic efficiency of peptides and may promote the development of next-generation antimicrobials.

Effects of material nano-topography on the angiogenesis of type H vessels: Size dependence, cell heterogeneity and intercellular communication.

Type H vessel, a vascular subtype in bone, is a critical regulator of osteogenesis, but how material properties affect this organ-specific vessel remains unknown. Here, titania nanotubes were fabricated on bone implant surface to investigate the effects of nano-topography on type H vessels. In vivo, surface nanotubes with 20-100 nm diameters promoted the angiogenesis of type H vessels and bone regeneration in mouse femurs to different extents, with the best effects induced by 70 nm diameter. In vitro, bone-specific endothelial cells (BECs) and artery endothelial cells (AECs) presented significantly different behaviors on the same material. Nanotubes with 20 nm small diameters significantly improved the adhesion, proliferation, type H differentiation of BECs and their paracrine function to regulate pre-osteoblasts (POBs), possibly via binding integrin ß1 on the cell membrane, but these effects weakened when tube diameter increased, which conflicted with the results in vivo. Further study suggested that the better in vivo effects by larger diameters of 70-100 nm might be exerted indirectly through remodeling the regulation from POBs to BECs, highlighting the underappreciated indirect bio-effects of materials via intercellular communication. These suggest that nanoscale material topography makes significant impact on the angiogenesis of type H vessels, directly via binding integrins on the cell membrane of BECs and indirectly via modulating the regulation from osteoblastic cells to BECs, both in a size-dependent manner. Cells of the same type but from different tissues may show different responses to the same material, thus material properties should be tailored to the specific cell population. In research on material-tissue interactions, conclusions from in vitro experiments exposing a single type of cell to material might deviate from the truth in vivo, because materials may indirectly influence the targeted cells through modulating intercellular communication. These provide new insights into material-tissue interactions.

Highly biocompatible Ag nanocluster-reinforced wound dressing with long-term and synergistic bactericidal activity.

Clinical application of antibiotic-free agents like silver nanoparticle-derived materials remains a critical challenge due to their limited long-term antibacterial activity and potential system toxicity. Herein, a highly biocompatible Ag nanocluster-reinforced hydrogel with enhanced synergistic antibacterial ability has been developed. Specifically, bioactive curcumin was incorporated into lysozyme-protected ultrasmall Ag nanoclusters (LC-AgNCs) and further integrated with sodium alginate (Sa) hydrogel (LC-AgNCs@Sa) through multiple interaction forces. Due to the synergistic antibacterial activity, LC-AgNCs could effectively kill both S. aureus and E. coli bacteria with a concentration down to 2.5 µg mL-1. In-depth mechanism investigations revealed that the bactericidal effect of LC-AgNCs lies in their bacterial membrane destruction, reactive oxygen species (ROS) production, glutathione depletion and prooxidant-antioxidant system disruption ability. Curcumin can mediate the intracellular ROS balance to protect NIH 3T3 cells from oxidative stress and improve the biocompatibility of LC-AgNCs@Sa. LC-AgNCs@Sa with long-term antibacterial ability can effectively protect the wound from bacterial invasion in vivo, and significantly accelerate the wound healing process due to their distinctive functions of inhibiting inflammatory factor (TNF-α) production, promoting collagen deposit and facilitating re-epithelization. This study provides a new, versatile strategy for the design of high-performance antibacterial dressing for broad infectious disease therapy.

Erratum: Bioactive antibacterial silica-based nanocomposites hydrogel scaffolds with high angiogenesis for promoting diabetic wound healing and skin repair: Erratum.

[This corrects the article DOI: 10.7150/thno.41839.].

Co-Electrospun Silk Fibroin and Gelatin Methacryloyl Sheet Seeded with Mesenchymal Stem Cells for Tendon Regeneration.

Silk fibroin (SF) is a promising biomaterial for tendon repair, but its relatively rigid mechanical properties and low cell affinity have limited its application in regenerative medicine. Meanwhile, gelatin-based polymers have advantages in cell attachment and tissue remodeling but have insufficient mechanical strength to regenerate tough tissue such as tendons. Taking these aspects into account, in this study, gelatin methacryloyl (GelMA) is combined with SF to create a mechanically strong and bioactive nanofibrous scaffold (SG). The mechanical properties of SG nanofibers can be flexibly modulated by varying the ratio of SF and GelMA. Compared to SF nanofibers, mesenchymal stem cells (MSCs) seeded on SG fibers with optimal composition (SG7) exhibit enhanced growth, proliferation, vascular endothelial growth factor production, and tenogenic gene expression behavior. Conditioned media from MSCs cultured on SG7 scaffolds can greatly promote the migration and proliferation of tenocytes. Histological analysis and tenogenesis-related immunofluorescence staining indicate SG7 scaffolds demonstrate enhanced in vivo tendon tissue regeneration compared to other groups. Therefore, rational combinations of SF and GelMA hybrid nanofibers may help to improve therapeutic outcomes and address the challenges of tissue-engineered scaffolds for tendon regeneration.

Flexible patch with printable and antibacterial conductive hydrogel electrodes for accelerated wound healing.

Electrical stimulation can facilitate wound healing with high efficiency and limited side effects. However, current electrical stimulation devices have poor conformability with wounds due to their bulky nature and the rigidity of electrodes utilized. Here, a flexible electrical patch (ePatch) made with conductive hydrogel as electrodes to improve wound management was reported. The conductive hydrogel was synthesized using silver nanowire (AgNW) and methacrylated alginate (MAA), with the former chosen as the electrode material considering its antibacterial properties, and the latter used due to its clinical suitability in wound healing. The composition of the hydrogel was optimized to enable printing on medical-grade patches for personalized wound treatment. The ePatch was shown to promote re-epithelization, enhance angiogenesis, mediate immune response, and prevent infection development in the wound microenvironment. In vitro studies indicated an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to electrical stimulation. An in vivo study in the Sprague-Dawley rat model revealed a rapid wound closure within 7 days compared to 20 days of usual healing process in rodents.

A Dual-Cross-Linked Hydrogel Patch for Promoting Diabetic Wound Healing.

Diabetic wound treatment faces significant challenges in clinical settings. Alternative treatment approaches are needed. Continuous bleeding, disordered inflammatory regulation, obstruction of cell proliferation, and disturbance of tissue remodeling are the main characteristics of diabetic wound healing. Hydrogels made of either naturally derived or synthetic materials can potentially be designed with a variety of functions for managing the healing process of chronic wounds. Here, a hemostatic and anti-inflammatory hydrogel patch is designed for promoting diabetic wound healing. The hydrogel patch is derived from dual-cross-linked methacryloyl-substituted Bletilla Striata polysaccharide (B) and gelatin (G) via ultraviolet (UV) light. It is demonstrated that the B-G hydrogel can effectively regulate the M1/M2 phenotype of macrophages, significantly promote the proliferation and migration of fibroblasts in vitro, and accelerate angiogenesis. It can boost wound closure by normalizing epidermal tissue regeneration and depositing collagen appropriately in vivo without exogenous cytokine supplementation. Overall, the B-G bioactive hydrogel can promote diabetic wound healing in a simple, economical, effective, and safe manner.

Protein adsorption onto nanomaterials engineered for theranostic applications.

The key role of biomolecule adsorption onto engineered nanomaterials for therapeutic and diagnostic purposes has been well recognized by the nanobiotechnology community, and our mechanistic understanding of nano-bio interactions has greatly advanced over the past decades. Attention has recently shifted to gaining active control of nano-bio interactions, so as to enhance the efficacy of nanomaterials in biomedical applications. In this review, we summarize progress in this field and outline directions for future development. First, we briefly review fundamental knowledge about the intricate interactions between proteins and nanomaterials, as unraveled by a large number of mechanistic studies. Then, we give a systematic overview of the ways that protein-nanomaterial interactions have been exploited in biomedical applications, including the control of protein adsorption for enhancing the targeting efficiency of nanomedicines, the design of specific protein adsorption layers on the surfaces of nanomaterials for use as drug carriers, and the development of novel nanoparticle array-based sensors based on nano-bio interactions. We will focus on particularly relevant and recent examples within these areas. Finally, we conclude this topical review with an outlook on future developments in this fascinating research field.

Multimodal channel cancer chemotherapy by 2D functional gadolinium metal-organic framework.

2D nanomaterials generally exhibit enhanced physiochemical and biological functions in biomedical applications due to their high surface-to-volume ratio and surface charge. Conventional cancer chemotherapy based on nanomaterials has been hindered by their low drug loading and poor penetration in tumor tissue. To overcome these difficulties, novel materials systems are urgently needed. Hereby, the lanthanide-based porphyrin metal-organic framework (MOF) nanosheets (NSs) with promising cancer imaging/chemotherapy capacities are fabricated, which display superior performance in the drug loading and tumor tissue penetration. The biodegradable PPF-Gd NSs deliver an ultrahigh drug loading (>1500%) and demonstrate the stable and highly sensitive stimuli-responsive degradation/release for multimodal tumor imaging and cancer chemotherapy. Meanwhile, PPF-Gd NSs also exhibit excellent fluorescence and magnetic resonance imaging capability in vitro and in vivo. Compared to the traditional doxorubicin (DOX) chemotherapy, the in vivo results confirm the evident suppression of the tumor growth by the PPF-Gd/DOX drug delivery system with negligible side effects. This work further supports the potential of lanthanide-based MOF nanomaterials as biodegradable systems to promote the cancer theranostics technology development in the future.

Fabrication of NiS2 Nanomaterials for Cd2+ Sensing.

Heavy metal Cadmium (Cd) will continuously pollute the atmosphere, soil and various water environments through material circulation, and even pose a threat to human safety. It has been designated as a first-class pollutant in sewage by China, therefore there is an urgent need to find new, more effective, and low-cost method to accurately detect Cadmium ion (Cd2+) concentration. We experimentally prepared a new Cd2+ sensor based on NiS2 nanomaterials capable of measuring Cd2+ concentration. The corresponding relationship between over potential of NiS2 nanomaterials in H2SO4 electrolyte solutions with different Cd2+ concentration and reduction peak with change of Cd2+ concentration was obtained by electrochemical method.

Cancer-on-a-Chip for Modeling Immune Checkpoint Inhibitor and Tumor Interactions.

Cancer immunotherapies, including immune checkpoint inhibitor (ICI)-based therapies, have revolutionized cancer treatment. However, patient response to ICIs is highly variable, necessitating the development of methods to quickly assess efficacy. In this study, an array of miniaturized bioreactors has been developed to model tumor-immune interactions. This immunotherapeutic high-throughput observation chamber (iHOC) is designed to test the effect of anti-PD-1 antibodies on cancer spheroid (MDA-MB-231, PD-L1+) and T cell (Jurkat) interactions. This system facilitates facile monitoring of T cell inhibition and reactivation using metrics such as tumor infiltration and interleukin-2 (IL-2) secretion. Status of the tumor-immune interactions can be easily captured within the iHOC by measuring IL-2 concentration using a micropillar array where sensitive, quantitative detection is allowed after antibody coating on the surface of array. The iHOC is a platform that can be used to model and monitor cancer-immune interactions in response to immunotherapy in a high-throughput manner.

Implicit Multidimensional Projection of Local Subspaces.

We propose a visualization method to understand the effect of multidimensional projection on local subspaces, using implicit function differentiation. Here, we understand the local subspace as the multidimensional local neighborhood of data points. Existing methods focus on the projection of multidimensional data points, and the neighborhood information is ignored. Our method is able to analyze the shape and directional information of the local subspace to gain more insights into the global structure of the data through the perception of local structures. Local subspaces are fitted by multidimensional ellipses that are spanned by basis vectors. An accurate and efficient vector transformation method is proposed based on analytical differentiation of multidimensional projections formulated as implicit functions. The results are visualized as glyphs and analyzed using a full set of specifically-designed interactions supported in our efficient web-based visualization tool. The usefulness of our method is demonstrated using various multi- and high-dimensional benchmark datasets. Our implicit differentiation vector transformation is evaluated through numerical comparisons; the overall method is evaluated through exploration examples and use cases.