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Fungal infections affect over 13 million people worldwide and are responsible for 1.5 million deaths annually. Some deep cutaneous fungal infections may extend the dermal barriers to cause systemic infection, resulting in substantial morbidity and mortality. However, the management of deep cutaneous fungal infection is challenging and yet overlooked by traditional treatments, which only offer limited drug availability within deep tissue. In this study, we have developed an electrically stimulated microneedle patch to deliver miconazole into the subcutaneous layer. We tested its antifungal efficacy using in vitro and ex vivo models that mimic fungal infection. Moreover, we confirmed its anti-fungal and wound-healing effects in a murine subcutaneous fungal infection model. Furthermore, our findings also showed that the combination of miconazole and applied current synergistically stimulated the nociceptive sensory nerves, thereby activating protective cutaneous immunity mediated by dermal dendritic and γδ-T cells. Collectively, this study provides a new strategy for minimally invasive delivery of therapeutic agents and the modulation of the neuro-immune axis in deep tissue., (Copyright © 2024. Published by Elsevier Ltd.)

Macrophage has been gradually recognized as a central regulator in tissue regeneration, and the study of how macrophage mediates biomaterials-induced bone regeneration through immunomodulatory pathway becomes popular. However, the current understanding on the roles of different macrophage phenotypes in regulating bone tissue regeneration remains controversial. In this study, we demonstrate that sequential infiltration of heterogeneous phenotypes of macrophages triggered by bio-metal ions effectively facilitates bone healing in bone defect. Indeed, M1 macrophages promote the recruitment and early commitment of osteogenic and angiogenic progenitors, while M2 macrophages and osteoclasts support the deposition and mineralization of the bone matrix, as well as the maturation of blood vessels. Moreover, we have identified a group of bone biomaterial-related multinucleated cells that behave similarly to M2 macrophages with wound-healing features rather than participate in the bone resorption cascade similarly to osteoclasts. Our study shows how sequential activation of macrophage-osteoclast lineage contribute to a highly orchestrated immune response in the bone tissue microenvironment around biomaterials to regulate the complex biological process of bone healing. Therefore, we believe that the temporal activation pattern of heterogeneous macrophage phenotypes should be considered when the next generation of biomaterials for bone regeneration is engineered., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rapid corrosion of biodegradable magnesium alloys under in vivo condition is a major concern for clinical applications. Inspired by the stability and biocompatibility of titanium oxide (TiO 2 ) passive layer, a functionalized TiO 2 /Mg 2 TiO 4 nano-layer has been constructed on the surface of WE43 magnesium implant by using plasma ion immersion implantation (PIII) technique. The customized nano-layer not only enhances corrosion resistance of Mg substrates significantly, but also elevates the osteoblastic differentiation capability in vitro due to the controlled release of magnesium ions. In the animal study, the increase of new bone formation adjacent to the PIII-treated magnesium substrate is 175% higher at post-operation 12 weeks, whereas the growth of new bone on titanium control and untreated magnesium substrate are only 97% and 29%, respectively. In addition, its Young's modulus can be restored to about 82% as compared with the surrounding matured bone. Furthermore, this specific TiO 2 /Mg 2 TiO 4 layer even exhibits photoactive bacteria disinfection capability when irradiated by ultraviolet light which is attributed to the intracellular reactive oxygen species (ROS) production. With all these constructive observations, it is believed that the TiO 2 /Mg 2 TiO 4 nano-layer on magnesium implants can significantly promote new bone formation and suppress bacterial infection, while the degradation behavior can be controlled simultaneously., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Metal ions or nanoparticles are believed to be promising additives in developing antibacterial biomaterials, owing to possessing favorable bactericidal effects against antibiotic-resistant bacteria. However, the immunomodulatory antibacterial activity of metal ions has seldom been reported. Herein, a porous microstructure designed to trap methicillin-resistant Staphylococcus aureus (MRSA) is fabricated on polyetheretherketone biomaterial surface through sulfonation (SPEEK), following which copper (Cu) nanoparticles, which can kill the trapped MRSA, are immobilized on SPEEK surface using a customized magnetron sputtering technique. In vitro antibacterial and immunological experiments indicate that the Cu-incorporated SPEEK can exert a desirable bactericidal effect against MRSA through the combination of "trap killing" and "contact killing" actions; meanwhile, macrophages cultured on the Cu-incorporated SPEEK can be activated and polarized to a pro-inflammatory phenotype along with improved phagocytic ability on the MRSA. Further in vivo implant-associated infection models evidence the superior antibacterial activity of the Cu-incorporated SPEEK. These results demonstrate multimodal antibacterial actions of the Cu-incorporated SPEEK, which is capable of imposing direct antibacterial and indirect immunomodulatory antibacterial effects simultaneously, in order to prevent and cure MRSA infection. It is believed that this study may shed light on developing novel biomaterial implants that combine antibacterial and immunomodulatory functions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A range of magnesium ions (Mg 2+ ) used has demonstrated osteogenic tendency in vitro. Hence, we propose to actualize this concept by designing a new system to precisely control the Mg 2+ delivery at a particular concentration in vivo in order to effectively stimulate in-situ bone regeneration. To achieve this objective, a monodisperse core-shell microsphere delivery system comprising of poly (lactic-co-glycolic acid) (PLGA) biopolymer, alginate hydrogel, and magnesium oxide nano-particles has been designed by using customized microfluidic capillary device. The PLGA-MgO sponge-like spherical core works as a reservoir of Mg 2+ while the alginate shell serves as physical barrier to control the outflow of Mg 2+ at ∼50 ppm accurately for 2 weeks via its adjustable surface micro-porous network. With the aid of controlled release of Mg 2+ , the new core-shell microsphere system can effectively enhance osteoblastic activity in vitro and stimulate in-situ bone regeneration in vivo in terms of total bone volume, bone mineral density (BMD), and trabecular thickness after operation. Interestingly, the Young's moduli of formed bone on the core-shell microsphere group have been restored to ∼96% of that of the surrounding matured bone. These findings indicate that the concept of precisely controlled release of Mg 2+ may potentially apply for in-situ bone regeneration clinically., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Stable and cytocompatible hybrid PEGylated micelles with multimodal imaging capabilities are described. The F3O4-encapsulated polymeric micelles composed of cores containing magnetic nanoparticles and polyethylene glycol (PEG) shells are synthesized by self-assembly of amphiphilic poly(HFMA-co-VBK)-g-PEG copolymers and oleic acid stabilized Fe3O4 nanoparticles. The Fe3O4 magnetic nanoparticles in the core produce T2-weighted MR imaging functionalities, whereas the small fluorescent monomer carbazole in the polymer shell introduces good fluorescent properties. The multifunctional micelles exhibit excellent paramagnetic properties with the maximum saturation magnetization of 9.61 emu/g and transverse relaxivity rate of 157.44 mM(-1) S(-1). In vivo magnetic resonance imaging (MRI) studies reveal enhanced contrast between the liver and spleen. Fluorescence spectra show characteristic emission peaks from carbazole at 350 nm and 365 nm and vivid blue fluorescence can be observed by 2-photon confocal scanning laser microscopy (CLSM). In vivo optical imaging demonstrates the unique fluorescent characteristics of the Fe3O4-encapsulated polymeric micelles in the liver and spleen and the excellent multifunctional properties suggest potential clinical use as nanocarriers in magnetic resonance imaging and optical imaging., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Porous biomaterials with the proper three-dimensional (3D) surface network can enhance biological functionalities especially in tissue engineering, but it has been difficult to accomplish this on an important biopolymer, polyetheretherketone (PEEK), due to its inherent chemical inertness. In this study, a 3D porous and nanostructured network with bio-functional groups is produced on PEEK by sulfonation and subsequent water immersion. Two kinds of sulfonation-treated PEEK (SPEEK) samples, SPEEK-W (water immersion and rinsing after sulfonation) and SPEEK-WA (SPEEK-W with further acetone rinsing) are prepared. The surface characteristics, in vitro cellular behavior, in vivo osseointegration, and apatite-forming ability are systematically investigated by X-ray photoelectron spectroscopy, Fourier-transform infrared spectroscopy, scanning electron microscopy, cell adhesion and cell proliferation assay, real-time RT-PCR analysis, micro-CT evaluation, push-out tests, and immersion tests. SPEEK-WA induces pre-osteoblast functions including initial cell adhesion, proliferation, and osteogenic differentiation in vitro as well as substantially enhanced osseointegration and bone-implant bonding strength in vivo and apatite-forming ability. Although SPEEK-W has a similar surface morphology and chemical composition as SPEEK-WA, its cytocompatibility is inferior due to residual sulfuric acid. Our results reveal that the pre-osteoblast functions, bone growth, and apatite formation on the SPEEK surfaces are affected by many factors, including positive effects introduced by the 3D porous structure and SO3H groups as well as negative ones due to the low pH environment. Surface functionalization broadens the use of PEEK in orthopedic implants., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A newly developed magnesium implant is used to stimulate bone formation in vivo. The magnesium implant after undergoing dual aluminum and oxygen plasma implantation is able to suppress rapid corrosion, leaching of magnesium ions, as well as hydrogen gas release from the biodegradable alloy in simulated body fluid (SBF). No released aluminum is detected from the SBF extract and enhanced corrosion resistance properties are confirmed by electrochemical tests. In vitro studies reveal enhanced growth of GFP mouse osteoblasts on the aluminum oxide coated sample, but not on the untreated sample. In addition to that a small amount (50 ppm) of magnesium ions can enhance osteogenic differentiation as reported previously, our present data show a low concentration of hydrogen can give rise to the same effect. To compare the bone volume change between the plasma-treated magnesium implant and untreated control, micro-computed tomography is performed and the plasma-treated implant is found to induce significant new bone formation adjacent to the implant from day 1 until the end of the animal study. On the contrary, bone loss is observed during the first week post-operation from the untreated magnesium sample. Owing to the protection offered by the Al2O3 layer, the plasma-treated implant degrades more slowly and the small amount of released magnesium ions stimulate new bone formation locally as revealed by histological analyses. Scanning electron microscopy discloses that the Al2O3 layer at the bone-implant interface is still present two months after implantation. In addition, no inflammation or tissue necrosis is observed from both treated and untreated implants. These promising results suggest that the plasma-treated magnesium implant can stimulate bone formation in vivo in a minimal invasive way and without causing post-operative complications., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In this paper, we describe a new biodegradable composite composed of polycaprolactone and magnesium. Incorporation of magnesium micro-particles into the polycaprolactone matrix yields mechanical properties close to those of human cancellous bone, and in vitro studies indicate that the silane-coated Mg/PCL composites have excellent cytocompatibility and osteoblastic differentiation properties. The bioactivity of the composites is manifested by the formation of calcium and phosphate after immersion in simulated body fluids. The bulk mechanical properties can be maintained for 2 months before obvious degradation takes place. The in vivo animal study reveals a larger amount of new bone formation on the silane-coated Mg/PCL composites compared to conventional PMMA and pure polycaprolactone and our results suggest potential clinical applications of the sliane-coated Mg/PCL composites., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Multifunctional colloidal nanoparticles which exhibit fluorescence, superparamagnetism, and thermosensitivity are produced by two step seed emulsifier-free emulsion polymerization in the presence of oleic acid (OA) and sodium undecylenate (NaUA) modified Fe(3)O(4) nanoparticles. In the first step, St and NIPAM polymerize the NaUA on the surface of Fe(3)O(4) nanoparticles to form Fe(3)O(4)/poly(St-NIPAM) nanoparticles which act as seeds for the polymerization of Eu(AA)(3)Phen with the remaining St and NIPAM in the second step to form an outer fluorescent layer. The core-shell composite nanoparticles show reversible dimensional changes in response to external temperature stimuli. Fluorescence spectra acquired from the composites exhibit characteristic emission peaks of Eu(3+) at 594 and 619 nm and vivid red luminescence can be observed by 2-photon confocal scanning laser microscopy (CLSM). In vitro cytotoxicity tests based on the MTT assay demonstrate good cytocompatibility and the composites also possess paramagnetic properties with a maximum saturation magnetization of 6.45 emu/g and high transverse relaxivity rates (r(2)) of 411.78 mM(-1) s(-1). In vivo magnetic resonance imaging (MRI) studies show significant liver and spleen contrast with relative signal intensity reduction of about 86% 10 min after intravenous injection of the composites. These intriguing properties suggest that these nanocarriers have large clinical potential as multimodal optical/MRI probes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Although many studies have demonstrated that cell phenotype is affected by the surface properties of biomaterials, these materials often fail to mimic the complexity of the native tissue microenvironment (TME). In this study, we have developed a new experimental model that allows the characterisation and functional reconstruction of natural TME. We discovered that mesenchymal stem cells (MSC) cultured on cryostat sections of bovine Achilles tendon adopted an elongated and aligned morphology, and expressed tenocyte marker tenomodulin (TNMD). This suggests that tendon sections contain the signalling cues that guide MSCs to commit to the tenogenic lineage. To reconstruct this instructive niche, we prepared PDMS replica by using tendon sections as template. The resulting bioimprint faithfully copied the physical topography and elasticity of the section. This replica, when coated with collagen 1, supported tenogenesis of MSC without requiring exogenous growth factors. This study illustrates how extracellular biophysical and biochemical features intertwines to form a niche that influences the cell fate and demonstrated that such complex information could be conveniently reconstructed with synthetic materials and purified extracellular matrix proteins., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The superelastic nature of bones requires matching biomechanical properties from the ideal artificial biomedical implants in order to provide smooth load transfer and foster the growth of new bone tissues. In this work, we determine the biomechanical characteristics of porous NiTi implants and investigate bone ingrowth under actual load-bearing conditions in vivo. In this systematic and comparative study, porous NiTi, porous Ti, dense NiTi, and dense Ti are implanted into 5 mm diameter holes in the distal part of the femur/tibia of rabbits for 15 weeks. The bone ingrowth and interfacial bonding strength are evaluated by histological analysis and push-out test. The porous NiTi materials bond very well to newly formed bone tissues and the highest average strength of 357 N and best ductility are achieved from the porous NiTi materials. The bonding curve obtained from the NiTi scaffold shows similar superelasticity as natural bones with a deflection of 0.30-0.85 mm thus shielding new bone tissues from large load stress. This is believed to be the reason why new bone tissues can penetrate deeply into the porous NiTi scaffold compared to the one made of porous Ti. Histological analysis reveals that new bone tissues adhere and grow well on the external surfaces as well as exposed areas on the inner pores of the NiTi scaffold. The in vitro study indicates that the surface chemical composition and topography of the porous structure leads to good cytocompatibility. Consequently, osteoblasts proliferate smoothly on the entire implant including the flat surface, embossed region, exposed area of the pores, and interconnected channels. In conjunction with the good cytocompatibility, the superelastic biomechanical properties of the porous NiTi scaffold bodes well for fast formation and ingrowth of new bones, and porous NiTi scaffolds are thus suitable for clinical applications under load-bearing conditions., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Because of emerging biomedical applications of nanoscale materials, the behavior of cells in contact with nanoscale materials must be better understood. SiC nanostructures constitute a new class of biomaterials and have potential in many applications. In this study, the cellular signal transduction processes and toxicity mechanisms of silicon carbide nanowires (SiCNWs) are investigated. The Chinese hamster ovary (CHO) cells in contact with SiCNWs have significantly lower reproduction rates and genomic instability which may be the upstream event of cell apoptosis. Expression of the phosphorylated form of the mitogen-activated protein kinases (MAPKs) family including phosphorylated signal-regulated kinases (p-ERKs), phosphorylated c-Jun NH2-terminal kinases (p-JNKs), and phosphorylated p38-mitogen-activated protein kinases (p-p38) are observed at different time points during exposure to SiCNWs. Moreover, activation of the MAPKs family by phosphorylation which is an upstream event giving rise to expression of cyclooxygenase-2 (COX-2) is also observed. The specific inhibitors of the MAPKs family are found to restrain COX-2 high expression at some time points. Our results show that activation of the MAPKs cellular signaling pathway and over-expression of COX-2 are the main toxicity mechanisms in SiCNWs irritation., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Magnesium and its alloys may potentially be applied as degradable metallic materials in orthopaedic implantations due to their degradability and resemblance to human cortical bone. However, the high corrosion rate and accumulation of hydrogen gas upon degradation hinders its clinical application. In this study, we adopt a new approach to control the corrosion rate by coating a controllable polymeric membrane fabricated by polycaprolactone and dichloromethane onto magnesium alloys, in which the pore size was controlled during the manufacturing process. The addition of the polymeric membrane was found to reduce the degradation rate of magnesium, and the bulk mechanical properties were shown to be maintained upon degradation. The in-vitro studies indicated good cytocompatibility of eGFP and SaOS-2 osteoblasts with the polymer-coated samples, which was not observed for the uncoated samples. The in-vivo study indicated that the uncoated sample degraded more rapidly than that of the polymer-coated samples. Although new bone formation was found on both samples, as determined by Micro-CT, higher volumes of new bone were observed on the polymer-coated samples. Histological analysis indicated no inflammation, necrosis or hydrogen gas accumulation on either of the samples during degradation. Collectively, these data suggest that the use of polymeric membrane may be potentially applied for future clinical use., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)