Co-delivery of saxagliptin and dapagliflozin by electrosprayed trilayer poly (D,l-lactide-co-glycolide) nanoparticles for controlled drug delivery.

Coaxial electrospray is advantageous for the production of multidrug-releasing nanocarriers because it permits precise control over particle size, inhibits initial burst release, and offers moderate preparation conditions. In this study, a single-step coaxial electrospray technique is presented that achieves over 90 % co-encapsulation of the saxagliptin and dapagliflozin, two drugs treating type 2 diabetes, into biodegradable poly (d,l-lactide-co-glicolide) (PLGA) nanoparticles. Scanning electron microscopy reveals spherical and smooth shapes with diameters ranging from 534.8 to 708.6 nm. Transmission electron microscopy revealed clear core-shell and trilayer nanostructures. Fourier transform infrared spectroscopy confirmed the presence of PLGA, saxagliptin, and dapagliflozin in all the evaluated formulations. The results of the drug release investigation indicated the prolonged and regulated release of saxagliptin and dapagliflozin from bi- and trilayer structures, as compared to monolayer particles. Computational modelling showed good agreement with the experimental drug release profile in vitro. Further, cytotoxicity assay demonstrates that the formulated nanoparticles display good cytocompatibility. This study indicates that with the controllable and distinctive sustained release profiles, the hybrid nanoparticle-based drug delivery system can effectively co-encapsulate multiple drugs treating type 2 diabetes in a protectively shell of PLGA for therapeutically-benefit controlled release.

Generating Lifetime-Enhanced Microbubbles by Decorating Shells with Silicon Quantum Nano-Dots Using a 3-Series T-Junction Microfluidic Device.

Long-term stability of microbubbles is crucial to their effectiveness. Using a new microfluidic device connecting three T-junction channels of 100 µm in series, stable monodisperse SiQD-loaded bovine serum albumin (BSA) protein microbubbles down to 22.8 ± 1.4 µm in diameter were generated. Fluorescence microscopy confirmed the integration of SiQD on the microbubble surface, which retained the same morphology as those without SiQD. The microbubble diameter and stability in air were manipulated through appropriate selection of T-junction numbers, capillary diameter, liquid flow rate, and BSA and SiQD concentrations. A predictive computational model was developed from the experimental data, and the number of T-junctions was incorporated into this model as one of the variables. It was illustrated that the diameter of the monodisperse microbubbles generated can be tailored by combining up to three T-junctions in series, while the operating parameters were kept constant. Computational modeling of microbubble diameter and stability agreed with experimental data. The lifetime of microbubbles increased with increasing T-junction number and higher concentrations of BSA and SiQD. The present research sheds light on a potential new route employing SiQD and triple T-junctions to form stable, monodisperse, multi-layered, and well-characterized protein and quantum dot-loaded protein microbubbles with enhanced stability for the first time.

Metformin-Loaded Polymer-Based Microbubbles/Nanoparticles Generated for the Treatment of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that is increasingly common all over the world with a high risk of progressive hyperglycemia and high microvascular and macrovascular complications. The currently used drugs in the treatment of T2DM have insufficient glucose control and can carry detrimental side effects. Several drug delivery systems have been investigated to decrease the side effects and frequency of dosage, and also to increase the effect of oral antidiabetic drugs. In recent years, the use of microbubbles in biomedical applications has greatly increased, and research into microactive carrier bubbles continues to generate more and more clinical interest. In this study, various monodisperse polymer nanoparticles at different concentrations were produced by bursting microbubbles generated using a T-junction microfluidic device. Morphological analysis by scanning electron microscopy, molecular interactions between the components by FTIR, drug release by UV spectroscopy, and physical analysis such as surface tension and viscosity measurement were carried out for the particles generated and solutions used. The microbubbles and nanoparticles had a smooth outer surface. When the microbubbles/nanoparticles were compared, it was observed that they were optimized with 0.3 wt % poly(vinyl alcohol) (PVA) solution, 40 kPa pressure, and a 110 µL/min flow rate, thus the diameters of the bubbles and particles were 100 ± 10 µm and 70 ± 5 nm, respectively. Metformin was successfully loaded into the nanoparticles in these optimized concentrations and characteristics, and no drug crystals and clusters were seen on the surface. Metformin was released in a controlled manner at pH 1.2 for 60 min and at pH 7.4 for 240 min. The process and structures generated offer great potential for the treatment of T2DM.

Copolymer Composition and Nanoparticle Configuration Enhance in vitro Drug Release Behavior of Poorly Water-soluble Progesterone for Oral Formulations.

HYPOTHESIS: Developing oral formulations to enable effective release of poorly water-soluble drugs like progesterone is a major challenge in pharmaceutics. Coaxial electrospray can generate drug-loaded nanoparticles of strategic compositions and configurations to enhance physiological dissolution and bioavailability of poorly water-soluble drug progesterone. EXPERIMENTS: Six formulations comprising nanoparticles encapsulating progesterone in different poly(lactide-co-glycolide) (PLGA) matrix configurations and compositions were fabricated and characterized in terms of morphology, molecular crystallinity, drug encapsulation efficiency and release behavior. FINDINGS: A protocol of fabrication conditions to achieve 100% drug encapsulation efficiency in nanoparticles was developed. Scanning electron microscopy shows smooth and spherical morphology of 472.1±54.8 to 588.0±92.1 nm in diameter. Multiphoton Airyscan super-resolution confocal microscopy revealed core-shell nanoparticle configuration. Fourier transform infrared spectroscopy confirmed presence of PLGA and progesterone in all formulations. Diffractometry indicated amorphous state of the encapsulated drug. UV-vis spectroscopy showed drug release increased with hydrophilic copolymer glycolide ratio while core-shell formulations with progesterone co-dissolved in PLGA core exhibited enhanced release over five hours at 79.9±1.4% and 70.7±3.5% for LA:GA 50:50 and 75:25 in comparison with pure progesterone without polymer matrix in the core at 67.0±1.7% and 57.5±2.8%, respectively. Computational modeling showed good agreement with the experimental drug release behavior in vitro.

Videographic Analysis of Blink Dynamics following Upper Eyelid Blepharoplasty and Its Association with Dry Eye.

This study was undertaken to characterize the effects of upper eyelid blepharoplasty on blink dynamics and to evaluate the hypothesis that changes in blink dynamics following blepharoplasty are associated with postoperative dry eye. METHODS: The voluntary blink of 14 eyes of 7 patients with dermatochalasis undergoing upper eyelid blepharoplasty was recorded with a high-speed camera preoperatively and 6-8 months postoperatively, alongside a group of 11 controls. The images were analyzed for palpebral aperture, blink duration, and maximum velocity during opening and closing phases. Patients undergoing blepharoplasty were assessed for dry eye symptoms pre- and postoperatively at 6-8 months using the ocular surface disease index score. RESULTS: Despite intraoperative orbicularis oculi resection, there was no significant compromise of blink duration or maximum velocity of eyelid opening or closure post-blepharoplasty. Postoperatively, patients had an increase in palpebral aperture compared with both preoperatively (8.71 versus 7.85 mm; P = 0.013) and control groups (8.71 versus 7.87 mm; P = 0.04). Postoperatively at 6-8 months, there was an increase in dry eye symptoms in 6 of 7 patients compared with preoperatively (ocular surface disease index, 16.6 versus 12.5; P < 0.05). There was no positive correlation between the increase in palpebral aperture and the increase in dry eye symptoms (r = -0.4; P = 0.30). CONCLUSIONS: Using modern videographic technology, this study demonstrates that upper eyelid blepharoplasty results in an increase in resting palpebral aperture but has no effect on dynamic blink parameters. Changes in palpebral aperture or blink dynamics are unlikely to be the cause of dry eye syndrome following blepharoplasty.

A Portable Device for the Generation of Drug-Loaded Three-Compartmental Fibers Containing Metronidazole and Iodine for Topical Application.

The use of combination therapies for the treatment of a range of conditions is now well established, with the component drugs usually being delivered either as distinct medicaments or combination products that contain physical mixes of the two active ingredients. There is, however, a compelling argument for the development of compartmentalised systems whereby the release, stability and incorporation environment of the different drugs may be tailored. Here we outline the development of polymeric fine fiber systems whereby two drugs used for the treatment of wounds may be separately incorporated. Fibers were delivered using a newly developed handheld electrospinning device that allows treatment at the site of need. Crucially, the delivery system is portable and may be used for the administration of drug-loaded fibers directly into the wound in situ, thereby potentially allowing domiciliary or site-of-trauma administration. The three-layered fiber developed in this study has polyethylene glycol as the outermost layer, serving as a structural support for the inner layers. The inner layers comprised iodine complexed with polyvinylpyrrolidone (PVP) and metronidazole dispersed in polycaprolactone (PCL) as a slow release core. The systems were characterized in terms of structure and architecture using scanning electron microscopy, transmission electron microscopy, attenuated total reflection Fourier transform infrared spectroscopy and diffractometry. As antibacterial creams are still used for managing infected wounds, the performance of our trilayered fiber was studied in comparison with creams containing similar active drugs. Drug release was measured by UV analysis, while antimicrobial efficiency was measured using agar diffusion and suspension methods. It was found that the trilayered systems, averaging 3.16 µm in diameter, released more drug over the study period and were confirmed by the microbacterial studies to be more effective against P. aeruginosa, a bacterium commonly implicated in infected wounds. Overall, the portable system has been shown to be capable of not only incorporating the two drugs in distinct layers but also of delivering adequate amounts of drugs for a more effective antibacterial activity. The portability of the device and its ability to generate distinct layers of multiple active ingredients make it promising for further development for wound healing applications in terms of both practical applicability and antimicrobial efficacy.

Empirical modelling and optimization of pressure-coupled infusion gyration parameters for the nanofibre fabrication.

Pressure-coupled infusion gyration (PCIG) is a novel promising technique for economical and effective mass production of nanofibres with desirable geometrical characteristics. The average diameter of spun fibres significantly influences the structural, mechanical and physical properties of the produced fibre mats. Having a comprehensive understanding of the significant effects of PCIG experimental variables on the spun fibres is beneficial. In this work, response surface methodology was used to explore the interaction effects and the optimal PCIG experimental variables for achieving the desired morphological characteristics of fibres. The effect of experimental variables, namely solution concentration, infusion (flow) rate, applied pressure and rotational speed, was studied on the average fibre diameter and standard deviations. A numerical model for the interactional influences of experimental variables was developed and optimized with a nonlinear interior point method that can be used as a framework for selecting the optimal conditions to obtain poly-ethylene oxide fibres with desired morphology (targeted average diameter and narrow standard deviation). The adequacy of the models was verified by a set of validation experiments. The results proved that the predicted optimal conditions were able to achieve the average diameter that matched the pre-set desired value with less than 10% of difference.

Novel Preparation of Monodisperse Microbubbles by Integrating Oscillating Electric Fields with Microfluidics.

Microbubbles generated by microfluidic techniques have gained substantial interest in various industries such as cosmetics, food engineering, and the biomedical field. The microfluidic T-junction provides exquisite control over processing parameters, however, it relies on pressure driven flows only; therefore, bubble size variation is limited especially for viscous solutions. A novel set-up to superimpose an alternating current (AC) oscillation onto a direct current (DC) field is invented in this work, capitalising on the possibility to excite bubble resonance phenomenon and properties, and introducing relevant parameters such as frequency, AC voltage, and waveform to further control bubble size. A capillary embedded T-junction microfluidic device fitted with a stainless-steel capillary was utilised for microbubble formation. Furthermore, a numerical model of the T-junction was developed by integrating the volume of fluid (VOF) method with the electric module; simulation results were attained for the formation of the microbubbles with a particular focus on the flow fields along the detachment of the emerging bubble. Two main types of experiments were conducted in this framework: the first was to test the effect of applied AC voltage magnitude and the second was to vary the applied frequency. Experimental results indicated that higher frequencies have a pronounced effect on the bubble diameter within the 100 Hz and 2.2 kHz range, whereas elevated AC voltages tend to promote bubble elongation and growth. Computational results suggest there is a uniform velocity field distribution along the bubble upon application of a superimposed field and that microbubble detachment is facilitated by the recirculation of the dispersed phase. Furthermore, an ideal range of parameters exists to tailor monodisperse bubble size for specific applications.

Process Modeling for the Fiber Diameter of Polymer, Spun by Pressure-Coupled Infusion Gyration.

Several new spinning methods have been developed recently to mass produce polymeric fibers. Pressure-coupled infusion gyration is one of them. Because the fiber diameter plays a pivotal role for the mechanical, electrical, and optical properties of the produced fiber mats, in this work, polyethylene oxide is used as a model polymer, and the processing parameters including polymer concentration, infusion (flow) rate, working pressure, and rotational speed are chosen as variables to control fiber diameters spanning the micro- to nanoscale. The experimental process is modeled using response surface methodology, both in linear and nonlinear fitting formats, to allow optimization of processing parameters. The successes of the fitted models are evaluated using adjusted R 2 and Akaike information criterion. A systematic description of the experimental process could be obtained according to the model in this study. From the analysis of variance, it is concluded that the polymer concentration of the solution and the working pressure affected the fiber diameters more strongly than other parameters.

Electrohydrodynamic fabrication of core-shell PLGA nanoparticles with controlled release of cisplatin for enhanced cancer treatment.

Increasing the clinical efficacy of toxic chemotherapy drugs such as cisplatin (CDDP), via targeted drug delivery, is a key area of research in cancer treatment. In this study, CDDP-loaded poly(lactic-co-glycolic acid) (PLGA) polymeric nanoparticles (NPs) were successfully prepared using electrohydrodynamic atomization (EHDA). The configuration was varied to control the distribution of CDDP within the particles, and high encapsulation efficiency (>70%) of the drug was achieved. NPs were produced with either a core-shell (CS) or a matrix (uniform) structure. It was shown that CS NPs had the most sustained release of the 2 formulations, demonstrating a slower linear release post initial "burst" and longer duration. The role of particle architecture on the rate of drug release in vitro was confirmed by fitting the experimental data with various kinetic models. This indicated that the release process was a simple diffusion mechanism. The CS NPs were effectively internalized into the endolysosomal compartments of cancer cells and demonstrated an increased cytotoxic efficacy (concentration of a drug that gives half maximal response [EC50] reaching 6.2 µM) compared to free drug (EC50 =9 µM) and uniform CDDP-distributed NPs (EC50 =7.6 µM) in vitro. Thus, these experiments indicate that engineering the structure of PLGA NPs can be exploited to control both the dosage and the release characteristics for improved clinical chemotherapy treatment.

Electrosprayed nanoparticle delivery system for controlled release.

This study utilises an electrohydrodynamic technique to prepare core-shell lipid nanoparticles with a tunable size and high active ingredient loading capacity, encapsulation efficiency and controlled release. Using stearic acid and ethylvanillin as model shell and active ingredients respectively, we identify the processing conditions and ratios of lipid:ethylvanillin required to form nanoparticles. Nanoparticles with a mean size ranging from 60 to 70nm at the rate of 1.37×10(9) nanoparticles per minute were prepared with different lipid:ethylvanillin ratios. The polydispersity index was ≈21% and the encapsulation efficiency ≈70%. It was found that the rate of ethylvanillin release was a function of the nanoparticle size, and lipid:ethylvanillin ratio. The internal structure of the lipid nanoparticles was studied by transmission electron microscopy which confirmed that the ethylvanillin was encapsulated within a stearic acid shell. Fourier transform infrared spectroscopy analysis indicated that the ethylvanillin had not been affected. Extensive analysis of the release of ethylvanillin was performed using several existing models and a new diffusive release model incorporating a tanh function. The results were consistent with a core-shell structure.

Electrohydrodynamic encapsulation of cisplatin in poly (lactic-co-glycolic acid) nanoparticles for controlled drug delivery.

Targeted delivery of potent, toxic chemotherapy drugs, such as cisplatin, is a significant area of research in cancer treatment. In this study, cisplatin was successfully encapsulated with high efficiency (>70%) in poly (lactic-co-glycolic acid) polymeric nanoparticles by using electrohydrodynamic atomization (EHDA) where applied voltage and solution flow rate as well as the concentration of cisplatin and polymer were varied to control the size of the particles. Thus, nanoparticles were produced with three different drug:polymer ratios (2.5, 5 and 10wt% cisplatin). It was shown that smaller nanoparticles were produced with 10wt% cisplatin. Furthermore, these demonstrated the best sustained release (smallest burst release). By fitting the experimental data with various kinetic models it was concluded that the release is dependent upon the particle morphology and the drug concentration. Thus, these particles have significant potential for cisplatin delivery with controlled dosage and release period that are crucial chemotherapy parameters.

Analysis of blink dynamics in patients with blepharoptosis.

Owing to the rapid movements of the human upper eyelid, a high-speed camera was used to record and characterize voluntary blinking and the blink dynamics of blepharoptosis patients were compared to a control group. Twenty-six blepharoptosis patients prior to surgery and 45 control subjects were studied and the vertical height of the palpebral aperture (PA) was measured manually at 2 ms intervals during each blink cycle. The PA and blinking speed were plotted with respect to time and a predictive model was generated. The blink dynamic was analysed in closing and opening phases, and revealed a reduced speed of the initial opening phase in ptotic patients, suggesting intrinsic muscle function change in ptosis pathogenesis. The PA versus time curve for each subject was reconstructed using custom-built parameters; however, there were significant differences between the two groups. Those parameters used included the rate of closure, the delay between opening and closing, rate of initial opening, rate of slow opening (nonlinear function) and the 'switch point' between those two rates of opening. The model was tested against a new group of subjects and was able to discriminate ptosis patients from controls with 80% accuracy.

Bistable collective behavior of polymers tethered in a nanopore.

Polymer-coated pores play a crucial role in nucleo-cytoplasmic transport and in a number of biomimetic and nanotechnological applications. Here we present Monte Carlo and Density Functional Theory approaches to identify different collective phases of end-grafted polymers in a nanopore and to study their relative stability as a function of intermolecular interactions. Over a range of system parameters that is relevant for nuclear pore complexes, we observe two distinct phases: one with the bulk of the polymers condensed at the wall of the pore, and the other with the polymers condensed along its central axis. The relative stability of these two phases depends on the interpolymer interactions. The existence the two phases suggests a mechanism in which marginal changes in these interactions, possibly induced by nuclear transport receptors, cause the pore to transform between open and closed configurations, which will influence transport through the pore.

System among the corticosteroids: specificity and molecular dynamics.

Understanding how structural features determine specific biological activities has often proved elusive. With over 161,000 steroid structures described, an algorithm able to predict activity from structural attributes would provide manifest benefits. Molecular simulations of a range of 35 corticosteroids show striking correlations between conformational mobility and biological specificity. Thus steroid ring A is important for glucocorticoid action, and is rigid in the most specific (and potent) examples, such as dexamethasone. By contrast, ring C conformation is important for the mineralocorticoids, and is rigid in aldosterone. Other steroids that are less specific, or have mixed functions, or none at all, are more flexible. One unexpected example is 11-deoxycorticosterone, which the methods predict (and our activity studies confirm) is not only a specific mineralocorticoid, but also has significant glucocorticoid activity. These methods may guide the design of new corticosteroid agonists and antagonists. They will also have application in other examples of ligand-receptor interactions.