ABSTRACT
The oral cavity, a warm and moist environment, is prone to the proliferation of microorganisms like Candida albicans (C. albicans), which forms robust biofilms on biotic and abiotic surfaces, leading to challenging infections. These biofilms are resistant to conventional treatments due to their resilience against antimicrobials and immune responses. The dynamic nature of the oral cavity, including the salivary flow and varying surface properties, complicates the delivery of therapeutic agents. To address these challenges, we introduce dendritic microparticles engineered for enhanced adhesion to dental surfaces and effective delivery of antifungal agents and antibiofilm enzymes. These microparticles are fabricated using a water-in-oil-in-water emulsion process involving a blend of poly(lactic-co-glycolic acid) (PLGA) random copolymer (RCP) and PLGA-b-poly(ethylene glycol) (PLGA-b-PEG) block copolymer (BCP), resulting in particles with surface dendrites that exhibit strong adhesion to oral surfaces. Our study demonstrates the potential of these adhesive microparticles for oral applications. The adhesion tests on various oral surfaces, including dental resin, hydroxyapatite, tooth enamel, and mucosal tissues, reveal superior adhesion of these microparticles compared to conventional spherical ones. Furthermore, the release kinetics of nystatin from these microparticles show a sustained release pattern that can kill C. albicans. The biodegradation of these microparticles on tooth surfaces and their efficacy in preventing fungal biofilms have also been demonstrated. Our findings highlight the effectiveness of adhesive microparticles in delivering therapeutic agents within the oral cavity, offering a promising approach to combat biofilm-associated infections.
Subject(s)
Antifungal Agents , Biofilms , Candida albicans , Surface Properties , Biofilms/drug effects , Candida albicans/drug effects , Candida albicans/physiology , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , Humans , Mouth/microbiology , Adhesives/chemistry , Adhesives/pharmacology , Particle Size , Polyethylene Glycols/chemistry , Drug Carriers/chemistryABSTRACT
The eradication of drug-resistant microbial biofilms remains an unresolved global health challenge. Small-scale robotics are providing innovative therapeutic and diagnostic approaches with high precision and efficacy. These approaches are rapidly moving from proof-of-concept studies to translational biomedical applications using ex vivo, animal, and clinical models. Here, we discuss the fundamental and translational aspects of how microrobots target the infection sites to disrupt the structural and functional traits of biofilms and their antimicrobial resistance mechanisms. We emphasize current approaches of mechanochemical disruption and on-site drug delivery that are supported by in vivo models and preclinical testing, while also highlighting diagnostics potential. We also discuss clinical translation challenges and provide perspectives for development of microrobotics approaches to combat biofilm infections and biofouling in humans.
Subject(s)
Biofilms , Biofouling , Animals , Humans , Drug Delivery Systems , Anti-Bacterial AgentsABSTRACT
Fungal pathogens have been designated by the World Health Organization as microbial threats of the highest priority for global health. It remains a major challenge to improve antifungal efficacy at the site of infection while avoiding off-target effects, fungal spreading, and drug tolerance. Here, a nanozyme-based microrobotic platform is developed that directs localized catalysis to the infection site with microscale precision to achieve targeted and rapid fungal killing. Using electromagnetic field frequency modulation and fine-scale spatiotemporal control, structured iron oxide nanozyme assemblies are formed that display tunable dynamic shape transformation and catalysis activation. The catalytic activity varies depending on the motion, velocity, and shape providing controllable reactive oxygen species (ROS) generation. Unexpectedly, nanozyme assemblies bind avidly to fungal (Candida albicans) surfaces to enable concentrated accumulation and targeted ROS-mediated killing in situ. By exploiting these tunable properties and selective binding to fungi, localized antifungal activity is achieved using in vivo-like cell spheroid and animal tissue infection models. Structured nanozyme assemblies are directed to Candida-infected sites using programmable algorithms to perform precisely guided spatial targeting and on-site catalysis resulting in fungal eradication within 10 min. This nanozyme-based microrobotics approach provides a uniquely effective and targeted therapeutic modality for pathogen elimination at the infection site.
Subject(s)
Antifungal Agents , Mycoses , Animals , Antifungal Agents/chemistry , Antifungal Agents/metabolism , Antifungal Agents/pharmacology , Reactive Oxygen Species/metabolism , Candida albicans/metabolism , Models, AnimalABSTRACT
Dental caries is the most common human disease caused by oral biofilms despite the widespread use of fluoride as the primary anticaries agent. Recently, an FDA-approved iron oxide nanoparticle (ferumoxytol, Fer) has shown to kill and degrade caries-causing biofilms through catalytic activation of hydrogen peroxide. However, Fer cannot interfere with enamel acid demineralization. Here, we show notable synergy when Fer is combined with stannous fluoride (SnF2), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, we discover that the stability of SnF2 is enhanced when mixed with Fer in aqueous solutions while increasing catalytic activity of Fer without any additives. Notably, Fer in combination with SnF2 is exceptionally effective in controlling dental caries in vivo, even at four times lower concentrations, without adverse effects on host tissues or oral microbiome. Our results reveal a potent therapeutic synergism using approved agents while providing facile SnF2 stabilization, to prevent a widespread oral disease with reduced fluoride exposure.
Subject(s)
Dental Caries , Tin Fluorides , Humans , Tin Fluorides/pharmacology , Tin Fluorides/therapeutic use , Fluorides/pharmacology , Dental Caries/prevention & control , Biofilms , Sodium Fluoride/pharmacologyABSTRACT
Dental caries (tooth decay) is the most prevalent human disease caused by oral biofilms, affecting nearly half of the global population despite increased use of fluoride, the mainstay anticaries (tooth-enamel protective) agent. Recently, an FDA-approved iron oxide nanozyme formulation (ferumoxytol, Fer) has been shown to disrupt caries-causing biofilms with high specificity via catalytic activation of hydrogen peroxide, but it is incapable of interfering with enamel acid demineralization. Here, we find notable synergy when Fer is combined with stannous fluoride (SnF 2 ), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, our data show that SnF 2 enhances the catalytic activity of Fer, significantly increasing reactive oxygen species (ROS) generation and antibiofilm activity. We discover that the stability of SnF 2 (unstable in water) is markedly enhanced when mixed with Fer in aqueous solutions without any additives. Further analyses reveal that Sn 2+ is bound by carboxylate groups in the carboxymethyl-dextran coating of Fer, thus stabilizing SnF 2 and boosting the catalytic activity. Notably, Fer in combination with SnF 2 is exceptionally effective in controlling dental caries in vivo , preventing enamel demineralization and cavitation altogether without adverse effects on the host tissues or causing changes in the oral microbiome diversity. The efficacy of SnF 2 is also enhanced when combined with Fer, showing comparable therapeutic effects at four times lower fluoride concentration. Enamel ultrastructure examination shows that fluoride, iron, and tin are detected in the outer layers of the enamel forming a polyion-rich film, indicating co-delivery onto the tooth surface. Overall, our results reveal a unique therapeutic synergism using approved agents that target complementary biological and physicochemical traits, while providing facile SnF 2 stabilization, to prevent a widespread oral disease more effectively with reduced fluoride exposure.
ABSTRACT
The precise spatiotemporal control and manipulation of fluid dynamics on a small scale granted by lab-on-a-chip devices provide a new biomedical research realm as a substitute for in vivo studies of host-pathogen interactions. While there has been a rise in the use of various medical devices/implants for human use, the applicability of microfluidic models that integrate such functional biomaterials is currently limited. Here, we introduced a novel dental implant-on-a-chip model to better understand host-material-pathogen interactions in the context of peri-implant diseases. The implant-on-a-chip integrates gingival cells with relevant biomaterials - keratinocytes with dental resin and fibroblasts with titanium while maintaining a spatially separated co-culture. To enable this co-culture, the implant-on-a-chip's core structure necessitates closely spaced, tall microtrenches. Thus, an SU-8 master mold with a high aspect-ratio pillar array was created by employing a unique backside UV exposure with a selective optical filter. With this model, we successfully replicated the morphology of keratinocytes and fibroblasts in the vicinity of dental implant biomaterials. Furthermore, we demonstrated how photobiomodulation therapy might be used to protect the epithelial layer from recurrent bacterial challenges (â¼3.5-fold reduction in cellular damage vs. control). Overall, our dental implant-on-a-chip approach proposes a new microfluidic model for multiplexed host-material-pathogen investigations and the evaluation of novel treatment strategies for infectious diseases.
Subject(s)
Biomedical Research , Dental Implants , Humans , Microfluidics , Host-Pathogen InteractionsABSTRACT
Ammonia is a promising carbon-free hydrogen carrier. Owing to their nickel-rich anodes and high operating temperatures, solid oxide fuel cells (SOFCs) can directly utilize NH3 fuel-direct-ammonia SOFCs (DA-SOFCs). Lowering the operating temperature can diversify application areas of DA-SOFCs. We tested direct-ammonia operation using two types of thin-film SOFCs (TF-SOFCs) under 500 to 650°C and compared these with a conventional SOFC. The TF-SOFC with a nickel oxide gadolinium-doped ceria anode achieved a peak power density of 1330 mW cm-2 (NH3 fuel under 650°C), which is the best performance reported to date. However, the performance difference between the NH3 and H2 operations was significant. Electrochemical impedance analyses, ammonia conversion quantification, and two-dimensional multi-physics modeling suggested that reduced ammonia conversion at low temperatures is the main cause of the performance gap. A comparative study with previously reported DA-SOFCs clarified that incorporating a more active ammonia decomposition catalyst will further improve low-temperature DA-SOFCs.
ABSTRACT
Biofilms are communities of microbes that colonize surfaces. While several biofilm experimental models exist, they often have limited replications of spatiotemporal dynamics surrounding biofilms. For a better understanding dynamic and complex biofilm development, this manuscript presents a customizable platform compatible with off-the-shelf well plates that can monitor microbial adhesion, growth, and associated parameters under various relevant scenarios by taking advantage of 3D printing. The system i) holds any substrate in a stable, vertical position, ii) subjects samples to flow at different angles, iii) switches between static and dynamic modes during an experiment, and iv) allows multiplexing and real-time monitoring of biofilm parameters. Simulated fluid dynamics is employed to estimate flow patterns around discs and shear stresses at disc surfaces. A 3D printed peristaltic pump and a customized pH measurement system for real-time tracking of spent biofilm culture media are equipped with a graphical user interface that grants control over all experimental parameters. The system is tested under static and dynamic conditions with Streptococcus mutans using different carbon sources. By monitoring the effluent pH and characterizing biochemical, microbiological, and morphological properties of cultured biofilms, distinct properties are demonstrated. This novel platform liberates designing experimental strategies for investigations of biofilms under various conditions.
ABSTRACT
The ability to control the shape of hollow particles (e.g., capsules or bubbles) holds great promise for enhancing the encapsulation efficiency and mechanical/optical properties. However, conventional preparation methods suffer from a low yield, difficulty in controlling the shape, and a tedious production process, limiting their widespread application. Here, we present a method for fabricating polyhedral graphene oxide (GO)-shelled microbubbles with sharp edges and vertices, which is based on the microfluidic generation of spherical compound bubbles followed by shell deformation. Sphere-to-polytope deformation is a result of the shell instability due to gradual outward gas transport, which is dictated by Laplace pressure across the shell. The shape-variant behaviours of the bubbles can also be attributed to the compositional heterogeneity of the shells. In particular, the high degree of control of microfluidic systems enables the formation of non-spherical bubbles with various shapes; the structural motifs of the bubbles are easily controlled by varying the size and thickness of the mid-shell in compound bubbles, ranging from tetrahedra to octahedra. The strategy presented in this study provides a new route for fabricating 3D structured solid bubbles, which is particularly advantageous for the development of high-performance mechanical or thermal material applications.
ABSTRACT
The eradication of biofilms remains an unresolved challenge across disciplines. Furthermore, in biomedicine, the sampling of spatially heterogeneous biofilms is crucial for accurate pathogen detection and precise treatment of infection. However, current approaches are incapable of removing highly adhesive biostructures from topographically complex surfaces. To meet these needs, we demonstrate magnetic field-directed assembly of nanoparticles into surface topography-adaptive robotic superstructures (STARS) for precision-guided biofilm removal and diagnostic sampling. These structures extend or retract at multilength scales (micro-to-centimeter) to operate on opposing surfaces and rapidly adjust their shape, length, and stiffness to adapt and apply high-shear stress. STARS conform to complex surface topographies by entering angled grooves or extending into narrow crevices and "scrub" adherent biofilm with multiaxis motion while producing antibacterial reagents on-site. Furthermore, as the superstructure disrupts the biofilm, it captures bacterial, fungal, viral, and matrix components, allowing sample retrieval for multiplexed diagnostic analysis. We apply STARS using automated motion patterns to target complex three-dimensional geometries of ex vivo human teeth to retrieve biofilm samples with microscale precision, while providing "toothbrushing-like" and "flossing-like" action with antibacterial activity in real-time to achieve mechanochemical removal and multikingdom pathogen detection. This approach could lead to autonomous, multifunctional antibiofilm platforms to advance current oral care modalities and other fields contending with harmful biofilms on hard-to-reach surfaces.
Subject(s)
Nanoparticles , Robotic Surgical Procedures , Tooth , Humans , Biofilms , Anti-Bacterial Agents , Nanoparticles/chemistryABSTRACT
Severe tooth decay has been associated with iron deficiency anemia that disproportionally burdens susceptible populations. Current modalities are insufficient in severe cases where pathogenic dental biofilms rapidly accumulate, requiring new antibiofilm approaches. Here, we show that ferumoxytol, a Food and Drug Administration-approved nanoparticle formulation for treating iron deficiency, exerts an alternative therapeutic activity via the catalytic activation of hydrogen peroxide, which targets bacterial pathogens in biofilms and suppresses tooth enamel decay in an intraoral human disease model. Data reveal the potent antimicrobial specificity of ferumoxytol iron oxide nanoparticles (FerIONP) against biofilms harboring Streptococcus mutans via preferential binding that promotes bacterial killing through in situ free-radical generation. Further analysis indicates that the targeting mechanism involves interactions of FerIONP with pathogen-specific glucan-binding proteins, which have a minimal effect on commensal streptococci. In addition, we demonstrate that FerIONP can detect pathogenic biofilms on natural teeth via a facile colorimetric reaction. Our findings provide clinical evidence and the theranostic potential of catalytic nanoparticles as a targeted anti-infective nanomedicine.
Subject(s)
Ferrosoferric Oxide , Nanoparticles , Biofilms , Ferrosoferric Oxide/pharmacology , Humans , Mouth , Streptococcus mutans/metabolismABSTRACT
BACKGROUND: In patients with congenital melanocytic nevus (CMN), single-stage removal of large lesions can be difficult because the high tension created by excising and repairing a large lesion may result in scar widening. Herein, we introduce a method to effectively excise lesions while minimizing scarring and compare its outcomes to those of existing surgical methods. METHODS: We compared patients who underwent surgery using the anchoring technique (n=42) or the conventional elliptical technique (n=36). One side of the lesion was removed via en bloc resection up to the superficial fascia. The other side of the lesion was removed via de-epithelialization. The de-epithelialized dermal flap was then fixed by suturing it to the superficial fascia on the opposite side. The length of the lesion's long axis and amount of scar widening were measured immediately after surgery and at 2, 6, and 12 months postoperatively. At 12 months, patients were assessed using the Patient and Observer Scar Assessment Scale. RESULTS: The lesion locations included the face, arms, legs, back, and abdomen. The anchoring method resulted in shorter and smaller scars than the conventional method. There were no cases of postoperative hematoma or wound dehiscence. Significant differences in postoperative scar widening were found in the arm and leg areas (P<0.05). CONCLUSIONS: The anchoring method introduced in this study can provide much better outcomes than the conventional method. The anchoring method is particularly useful for the removal of CMN around the joints or extremities, where the surgical site is subjected to high tension.
ABSTRACT
Carbon nanotubes (CNTs) have attracted considerable attention because of their high electrical conductivity and outstanding mechanical properties. As such, there have been numerous attempts to form CNTs into diverse structures for use in a wide range of applications. However, the intrinsic high aspect ratios of CNTs and resulting deformability have prevented the fabrication of sophisticated CNT-based structures, especially for three-dimensional (3D) cellular architectures. To challenge this limitation, we present a novel method to fabricate a 3D CNT cellular network from the assembly of microfluidically synthesized CNT-shelled microbubbles. We successfully generated stable spherical CNT-shelled bubbles with excellent size and shape uniformity by precisely controlling bubble dimensions by varying microfluidic variables. We also developed a fundamental understanding of the bubble stability, which allowed us to suppress shrinkage-induced deformation. The synthesized CNT-shelled bubbles were assembled into a 3D close-packed structure, followed by treatment with thermal reduction to induce interfacial bonding and transformation into a closed cellular network structure. Overall, this work provides a new strategy of assembling 1D nanomaterials as the building blocks for well-regulated 3D closed cellular architectures with improved structural or physical properties.
ABSTRACT
Transition metal oxide (TMO)-based anode materials for Li-ion batteries (LIBs) have generally suffered from limitations of intrinsically severe pulverization upon lithiation and reduced electrical conductivity. To address these issues, an approach of generating hollow nanostructures of TMOs complexed with highly conductive species has been attempted. As a novel means to implement highly electrochemically active TMO-based hollow nanostructures, a pre-synthesized template of a metal organic framework, zeolitic imidazolate framework (ZIF-8), was sequentially treated with partial carbonization and oxidation processes, whereby a hollow, nanocage-like structure of ZnO was obtained while preserving the carbonaceous frame as the electroconductive matrix. Furthermore, through additional incorporation of carbon nanotubes (CNTs), hollow nanocages of ZnO/N-doped carbon were successfully interwoven to form a well-complexed three-dimensional network, imparting enhanced electrical conductivity and mechanical stability to the complexes. When the synthesized ternary nanocomposites of ZnO/N-doped carbon/CNTs were used as anodes of LIBs, enhanced electrochemical performance was achieved, with high specific capacity, excellent rate capability, and greatly extended cycling stability, which could be attributed to the facilitated Li-ion diffusivity and improved electrical conductivity. Therefore, it is highly expected that the proposed strategy could be extended as a general platform for realizing uniquely structured TMO-based electrode materials for high-performance energy storage systems.
ABSTRACT
The design and synthesis of cellular structured materials are of both scientific and technological importance since they can impart remarkably improved material properties such as low density, high mechanical strength, and adjustable surface functionality compared to their bulk counterparts. Although reducing the density of porous structures would generally result in reductions in mechanical properties, this challenge can be addressed by introducing a structural hierarchy and using mechanically reinforced constituent materials. Thus, precise control over several design factors in structuring, including the type of constituent, symmetry of architectures, and dimension of the unit cells, is extremely important for maximizing the targeted performance. The feasibility of lightweight materials for advanced applications is broadly explored due to recent advances in synthetic approaches for different types of cellular architectures. Here, an overview of the development of lightweight cellular materials according to the structural interconnectivity and randomness of the internal pores is provided. Starting from a fundamental study on how material density is associated with mechanical performance, the resulting structural and mechanical properties of cellular materials are investigated for potential applications such as energy/mass absorption and electrical and thermal management. Finally, current challenges and perspectives on high-performance ultra-lightweight materials potentially implementable by well-controlled cellular architectures are discussed.
ABSTRACT
With the advent of the era of consumer-oriented displays and mobile devices, the importance of barrier film coatings for securing devices from oxygen or moisture penetration has become more salient. Recently developed approaches to generate gas barrier films in a combination of polyelectrolyte multilayer matrices and incorporated inorganic nanosheets have shown great potential in outperforming conventional gas barrier films. However, these films have the intrinsic drawback of vulnerability to brittleness and inability to stretch for flexible device applications. To overcome this issue, we present a method in which we prepare multilayered films of complementarily charged polyurethane and graphene oxide platelets using spin-assisted, layer-by-layer self-assembly to obtain well-stacked film structures. As a result, the multilayered, thin films deposited on a poly(ethylene terephthalate) (PET) substrate can exhibit significantly reduced oxygen penetration properties (â¼30 cc m-2 day-1 for the oxygen transmission rate) while still demonstrating large bending or stretching deformations. Therefore, the proposed approach in this study is anticipated to be extensively utilized for surface coating and protection of flexible and stretchable devices under various operating conditions.
ABSTRACT
Advanced materials with low density and high strength impose transformative impacts in the construction, aerospace, and automobile industries. These materials can be realized by assembling well-designed modular building units (BUs) into interconnected structures. This study uses a hierarchical design strategy to demonstrate a new class of carbon-based, ultralight, strong, and even superelastic closed-cellular network structures. Here, the BUs are prepared by a multiscale design approach starting from the controlled synthesis of functionalized graphene oxide nanosheets at the molecular- and nanoscale, leading to the microfluidic fabrication of spherical solid-shelled bubbles at the microscale. Then, bubbles are strategically assembled into centimeter-scale 3D structures. Subsequently, these structures are transformed into self-interconnected and structurally reinforced closed-cellular network structures with plesiohedral cellular units through post-treatment, resulting in the generation of 3D graphene lattices with rhombic dodecahedral honeycomb structure at the centimeter-scale. The 3D graphene suprastructure concurrently exhibits the Young's modulus above 300 kPa while retaining a light density of 7.7 mg cm-3 and sustaining the elasticity against up to 87% of the compressive strain benefiting from efficient stress dissipation through the complete space-filling closed-cellular network. The method of fabricating the 3D graphene closed-cellular structure opens a new pathway for designing lightweight, strong, and superelastic materials.
ABSTRACT
Polymeric three-dimensional inverse-opal (IO) structures provide unique structural properties useful for various applications ranging from optics to separation technologies. Despite vast needs for IO functionalization to impart additional chemical properties, this task has been seriously challenged by the intrinsic limitation of polymeric porous materials that do not allow for the easy penetration of waterborne moieties or precursors. To overcome this restriction, we present a robust and straightforward method of employing a dipping-based surface modification with polydopamine (PDA) inside the IO structures, and demonstrate their application to catalytic membranes via synthetic incorporation of Ag nanoparticles. The PDA coating offers simultaneous advantages of achieving the improved hydrophilicity required for the facilitated infiltration of aqueous precursors and successful creation of nucleation sites for a reduction of growth of the Ag nanoparticles. The resulting Ag nanoparticle-incorporated IO structures are utilized as catalytic membranes for the reduction of 4-nitrophenol to its amino derivatives in the presence of NaBH4. Synergistically combined characteristics of high reactivity of Ag nanoparticles along with a greatly enhanced internal surface area of IO structures enable the implementation of remarkably improved catalytic performance, exhibiting a good conversion efficiency greater than 99% while minimizing loss in the membrane permeability.