Visualization of photothermal therapy by semiconducting polymer dots mediated photoacoustic detection in NIR II.

Visualization of photothermal therapy mediated by photothermal transduction agents (PTAs) is important to promote individual treatment of patients with low side effects. Photoacoustic detection has emerged as a promising noninvasive method for the visualization of PTAs distribution but still has limitations in temperature measurement, including poor measurement accuracy and low tissue penetration depth. In this study, we developed biocompatible semiconducting polymer dots (SPD) for in situ coupling of photothermal and photoacoustic detection in the near-infrared II window. SPD has dual photostability under pulsed laser and continuous-wave laser irradiation with a photothermal conversion efficiency of 42.77%. Meanwhile, a strong correlation between the photoacoustic signal and the actual temperature of SPD can be observed. The standard deviation of SPD-mediated photoacoustic thermometry can reach 0.13 °C when the penetration depth of gelatin phantom is 9.49 mm. Preliminary experimental results in vivo show that SPD-mediated photoacoustic signal has a high signal-to-noise ratio, as well as good performance in temperature response and tumor enrichment. Such a study not only offers a new nanomaterial for the visualization of photothermal therapy but will also promote the theranostic platform for clinical applications.

Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rabbit vein graft model.

OBJECTIVE: Inflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model. METHODS: Ipsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3-4 kg; N = 80). RvD1 (1 µg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling. RESULTS: Perivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%-72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%-50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days. CONCLUSIONS: Local perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair.

Perivascular delivery of resolvin D1 inhibits neointimal hyperplasia in a rat model of arterial injury.

OBJECTIVE: Lipid mediators derived from omega-3 polyunsaturated fatty acids such as resolvin D1 (RvD1) accelerate the resolution of inflammation and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury. METHODS: Smooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smooth muscle cell responses in vitro, with focus on inflammation, proliferation, migration, cytoskeletal changes, and cytotoxicity. The safety and efficacy of perivascular delivery of RvD1 through thin biodegradable three-layered poly(lactic-co-glycolic acid) wraps or 25% Pluronic F127 gels were studied in a rat model of carotid angioplasty. A total of 200 ng of RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14 days after injury. RESULTS: RvD1 attenuated rat arterial vascular smooth muscle cell inflammatory pathways, proliferation, migration, and mitogen-induced cytoskeletal changes in vitro, without evidence of cytotoxicity. RvD1-loaded wraps reduced neointimal formation after carotid angioplasty by 59% vs no-wrap controls (P = .001) and by 45% vs vehicle-wrap controls (P = .002). RvD1-loaded Pluronic gels similarly reduced neointimal formation by 49% vs no-gel controls (P = .02) and by 52% vs vehicle-gel controls (P = .02). No group was associated with infection, thrombosis, or negative vessel remodeling. Wraps were found to be easier to apply than gel constructs. Ki67 proliferation index was significantly lower in RvD1-loaded wrap-treated arteries compared with both no-wrap and vehicle-wrap controls at both 3 and 14 days after injury (65% vs no-wrap group and 70% vs vehicle-wrap group at day 3, 49% vs both control groups at day 14; P < .05). Similarly, oxidative stress (30% and 29%; P < .05) and nuclear factor κB activation (42% and 45%; P < .05) were significantly lower in the RvD1-loaded wrap group compared with both no-wrap and vehicle-wrap controls at 3 days after injury. CONCLUSIONS: Local perivascular delivery of RvD1 attenuates formation of neointimal hyperplasia without associated toxicity in a rat model of carotid angioplasty. This effect is likely due to attenuation of inflammatory pathways as well as decreased arterial smooth muscle cell proliferation and migration.

Fast and Stable Antibacterial Coating of Photosensitive Aggregation-Induced Emission Luminogens for Disinfection on Medical Devices.

Aggregation-induced emission luminogens (AIEgens) are promising photosensitizers that have exhibited excellent antibacterial ability with abundant reactive oxygen species (ROS) generation. TTCPy-PF6 and TTCPy-Br are deposited on the surface of diverse solid substrates through plasma-assistant electrostatic self-assembly. The AIEgens-covered coating can effectively eliminate different pathogenic Gram-positive (G+) bacteria and even their multidrug-resistant (MDR) mutants with negligible side effects such as cytotoxicity, hemolysis, and inflammation. Moreover, the AIEgen-coated surface can maintain high stability for long-time antibacterial usage, which is dependent on the ROS-mediated disruption of the attached bacteria. The AIEgen-based coatings with broad surface applicability have many advantages in high antibacterial ability, great biocompatibility, and low possibility of antibiotic pollution. The robust antibacterial ability and excellent biological safety of the AIEgen-based coatings would be helpful for the disinfection of medical devices.

Preparation, function, and safety evaluation of a novel degradable dermal filler, the cross-linked poly-γ-glutamic acid hydrogel particles.

Poly-γ-glutamic acid (PGA) is a naturally degradable hydrophilic linear microbial polymer with moisturizing, immunogenic, cross-linking, and hydrogel water absorption properties similar to hyaluronic acid, a biomaterial that is commonly used as a dermal filler. To explore the development feasibility of cross-linked PGA as a novel dermal filler, we studied the local skin response to PGA fillers and the effect of various cross-linking preparations on the average longevity of dermal injection. Injection site inflammation and the formation of collagen and elastin were also determined. PGA hydrogel particles prepared using 28% PGA and 10% 1,4-butanediol diglycidyl ether showed optimal filler properties, resistance to moist heat sterilization, and an average filling longevity of 94.7 ± 61.6 days in the dermis of rabbit ears. Local redness and swelling due to filler injection recovered within 14.2 ± 3.6 days. Local tissue necrosis or systemic allergic reactions were not observed, and local collagen formation was promoted. Preliminary results suggested that dermal injection of cross-linked PGA particles appeared safe and effective, suggesting that cross-linked PGA particles could be developed as a new hydrogel dermal filler.

The osteoimmunomodulatory effect of nanostructured TiFx/TiOxcoating on osteogenesis induction.

Macrophages play a central role in the host response and the integration of implant materials. The nanostructured TiFx/TiOxcoating (FOTi) on titanium surfaces has shown multiple properties, including antibacterial properties and bioactivity. However, little is known about the effects of these coatings on the regulation of macrophage activity and the subsequent immunomodulatory effects on osteogenesis. In this study, the behavior of macrophages on the FOTi samples was evaluated, and conditioned medium was collected and used to stimulate MC3T3-E1 cellsin vitro. The results showed that the FOTi samples stimulated macrophage elongation and promoted the production of proinflammatory cytokines at 24 h, while induced macrophage polarization to the anti-inflammatory M2 phenotype at 72 h. Furthermore, the immune microenvironment generated by macrophage/ FOTi samples interactions effectively promoted the osteogenic differentiation of MC3T3-E1 cells, as evidenced by improved cell adhesion, enhanced alkaline phosphatase activity and extracellular matrix mineralization, and upregulated osteogenesis-related gene expression. In summary, the FOTi samples mediated macrophage phenotype behaviors and induced beneficial immunomodulatory effects on osteogenesis, which could be a potential strategy for the surface modification of bone biomaterials.

Highly Stretchable Metal-Polymer Conductor Electrode Array for Electrophysiology.

Narrowing the mechanical mismatch between biological tissues (typically soft) and neural interfaces (hard) is essential for maintaining signal quality for the electrical recording of neural activity. However, only a few materials can satisfy all requirements for such electronics, which need to be both biocompatible and sufficiently soft. Here, a highly stretchable electrode array (SEA) is introduced, based on the liquid metal-polymer conductor (MPC), achieving high mechanical flexibility and good cytocompatability for neural interfaces. By utilizing the MPC, the SEA exhibits high stretchability (≈100%) and excellent cycling stability (>400 cycles). The cytocompatability of the SEA can allow for long-term culturing of primary neurons and enable signal recording of primary hippocampal neurons. In the future, the SEA could serve as a reliable and robust platform for diagnostics in neuronal tissues and greatly advance brain-machine interfaces.

Enhanced Physicochemical and Biological Properties of a Low-Temperature Copperized Layer on Gradient Nanograined Pure Titanium.

The application of titanium as medical implants is limited to a certain extent due to its insufficient corrosion resistance, biological activity, and antibacterial ability. In this work, a gradient nanograined (GNG) layer was fabricated on the titanium surface by surface ultrasonic rolling treatment (SURT). The subsequent copperizing kinetics was greatly enhanced so that a thick copperized layer could be obtained on the surface of GNG Ti at a relatively low diffusion temperature (450 °C). Meanwhile, the GNG structure accelerated the release rate of Cu2+, which endows GNG Cu/Ti with strong antibacterial activity. Moreover, the corrosion resistance and cytocompatibility of GNG Cu/Ti were also evidently improved compared with coarse-grained Ti, indicating a good biomedical application prospect.

Effect of ultrasonic micro-arc oxidation on the antibacterial properties and cell biocompatibility of Ti-Cu alloy for biomedical application.

In order to improve antibacterial properties and cell biocompatibility of Ti-Cu alloy, an ultrasonic micro-arc oxidation (UMAO) has been applied to Ti-Cu alloy. The corrosion resistance, antibacterial activity and cell compatibility of Ti-Cu alloy before and after UMAO were studied in detail by means of electrochemical test, plate count method and CCK-8 test scanning electron microscopy (SEM) technology to evaluate the application possibilities of UMAO as a surface bio-modification method for Ti-Cu alloy. The surface microstructure characterisation showed that a typical porous coating with a pore diameter of 3-8 µm and a thickness of 5-15 µm was formed on the surface of the Ti-Cu alloy, which significantly improved the surface roughness and hydrophilicity. The plate count method demonstrated that UMAO coatings on Ti-Cu alloy showed strong antibacterial activity (≥99%) against Staphylococcus aureus (S. aureus) even after being immersed in a physiological saline for up to 20 days, indicating that UMAO-treated Ti-Cu alloy had very strong long-term antibacterial properties. It is believed that the strong long-term antimicrobial properties of Ti-Cu-UMAO samples were mainly due to the formation of Cu2O and CuO in UMAO coatings. The results of cell compatibility evaluation showed that UMAO treatment did not bring about cytotoxicity but improved the early adhesion of MC3T3 cell.

Effect of nano/micro-Ag compound particles on the bio-corrosion, antibacterial properties and cell biocompatibility of Ti-Ag alloys.

In this research, Ti-Ag alloys were prepared by powder metallurgy, casting and heat treatment method in order to investigate the effect of Ag compound particles on the bio-corrosion, the antibacterial property and the cell biocompatibility. Ti-Ag alloys with different sizes of Ag or Ag-compounds particles were successfully prepared: small amount of submicro-scale (100nm) Ti2Ag precipitates with solid solution state of Ag, large amount of nano-scale (20-30nm) Ti2Ag precipitates with small amount of solid solution state of Ag and micro-scale lamellar Ti2Ag phases, and complete solid solution state of Ag. The mechanical tests indicated that both nano/micro-scale Ti2Ag phases had a strong dispersion strengthening ability and Ag had a high solid solution strengthening ability. Electrochemical results shown the Ag content and the size of Ag particles had a limited influence on the bio-corrosion resistance although nano-scale Ti2Ag precipitates slightly improved corrosion resistance. It was demonstrated that the nano Ag compounds precipitates have a significant influence on the antibacterial properties of Ti-Ag alloys but no effect on the cell biocompatibility. It was thought that both Ag ions release and Ti2Ag precipitates contributed to the antibacterial ability, in which nano-scale and homogeneously distributed Ti2Ag phases would play a key role in antibacterial process.

Microstructure, mechanical properties, bio-corrosion properties and antibacterial properties of Ti-Ag sintered alloys.

In this research, Ag element was selected as an antibacterial agent to develop an antibacterial Ti-Ag alloy by a powder metallurgy. The microstructure, phase constitution, mechanical properties, corrosion resistance and antibacterial properties of the Ti-Ag sintered alloys have been systematically studied by X-ray diffraction (XRD), scanning electron microscope (SEM), compressive test, electrochemical measurements and antibacterial test. The effects of the Ag powder size and the Ag content on the antibacterial property and mechanical property as well as the anticorrosion property have been investigated. The microstructure results have shown that Ti-Ag phase, residual pure Ag and Ti were the mainly phases in Ti-Ag(S75) sintered alloy while Ti2Ag was synthesized in Ti-Ag(S10) sintered alloy. The mechanical test indicated that Ti-Ag sintered alloy showed a much higher hardness and the compressive yield strength than cp-Ti but the mechanical properties were slightly reduced with the increase of Ag content. Electrochemical results showed that Ag powder size had a significant effect on the corrosion resistance of Ti-Ag sintered alloy. Ag content increased the corrosion resistance in a dose dependent way under a homogeneous microstructure. Antibacterial tests have demonstrated that antibacterial Ti-Ag alloy was successfully prepared. It was also shown that the Ag powder particle size and the Ag content influenced the antibacterial activity seriously. The reduction in the Ag powder size was benefit to the improvement in the antibacterial property and the Ag content has to be at least 3wt.% in order to obtain a strong and stable antibacterial activity against Staphylococcus aureus bacteria. The bacterial mechanism was thought to be related to the Ti2Ag and its distribution.

Effect of the existing form of Cu element on the mechanical properties, bio-corrosion and antibacterial properties of Ti-Cu alloys for biomedical application.

Ti-Cu alloys have exhibited strong antibacterial ability, but Ti-Cu alloys prepared by different processes showed different antibacterial ability. In order to reveal the controlling mechanism, Ti-Cu alloys with different existing forms of Cu element were prepared in this paper. The effects of the Cu existing form on the microstructure, mechanical, corrosion and antibacterial properties of Ti-Cu alloys have been systematically investigated. Results have shown that the as-cast Ti-Cu alloys showed a higher hardness and mechanical strength as well as a higher antibacterial rate (51-64%) but a relatively lower corrosion resistance than pure titanium. Treatment at 900°C/2h (T4) significantly increased the hardness and the strength, improved the corrosion resistance but had little effect on the antibacterial property. Treatment at 900°C/2h+400°C/12h (T6) increased further the hardness and the mechanical strength, improved the corrosion resistance and but also enhanced the antibacterial rate (>90%) significantly. It was demonstrated that the Cu element in solid solution state showed high strengthening ability but low antibacterial property while Cu element in Ti2Cu phase exhibited strong strengthening ability and strong antibacterial property. Ti2Cu phase played a key role in the antibacterial mechanism. The antibacterial ability of Ti-Cu alloy was strongly proportional to the Cu content and the surface area of Ti2Cu phase. High Cu content and fine Ti2Cu phase would contribute to a high strength and a strong antibacterial ability.

Polyacrylic acid modified upconversion nanoparticles for simultaneous pH-triggered drug delivery and release imaging.

A poly(acrylicacid)-modified NaYF4:Yb, Er upconversion nanoparticles (PAA-UCNPs) with dual functions of drug delivery and release imaging have been successfully developed. The PAA polymer coated on the surface of UCNPs serve as a pH-sensitive nanovalve for loading drug molecules via electrostatic interaction. The drug-loading efficiency of the PAA-UCNPs was investigated by using doxorubicin hydrochloride (DOX) as a model anticancer drug to evaluate their potential as a delivery system. Results showed loading and releasing of DOX from PAA-UCNPs were controlled by varying pH, with high encapsulation rate at weak alkaline conditions and an increased drug dissociation rate in acidic environment, which is favorable for construct a pH-responsive controlled drug delivery system. The in vitro cytotoxicity test using HeLa cell line indicated that the DOX loaded PAA-UCNPs (DOX@PAA-UCNPs) were distinctly cytotoxic to HeLa cells, while the PAA-UCNPs were highly biocompatible and suitable to use as drug carriers. Furthermore, the upconversion fluorescence resonance energy transfer (UFRET) imaging through the two-photon laser scanning microscopy (TLSM) revealed the time course of intracellular delivery of DOX from DOX@PAA-UCNPs. Thus, PAA-UCNPs are effective for constructing pH-responsive controlled drug delivery systems for multi-functional cancer therapy and imaging.