Investigation of risk factors for tunneled hemodialysis catheters dysfunction: competing risk analysis of a tertiary center data.

BACKGROUND: Hemodialysis tunneled catheters are prone to failure due to infection or thrombosis. Prediction of catheter dysfunction chance and finding the predisposing risk factors might help clinicians to prolong proper catheter function. The multidimensional mechanism of failures following infection or thrombosis needs a multivariable and comprehensive analytic approach. METHODS: A longitudinal cross-sectional study was implemented on 1048 patients admitted for the first hemodialysis tunneled catheterization attempt between 2013 and 2019 in Shahid Hasheminejdad hospital, Tehran, Iran. Patients' information was extracted from digital and also paper records. Based on their criteria, single and multiple variable analyses were done separately in patients with catheter dysfunction due to thrombosis and infection. T-test and Chi-square test were performed in quantitative and categorical variables, respectively. Competing risk regression was performed under the assumption of proportionality for infection and thrombosis, and the sub-distributional hazard ratios (SHR) were calculated. All statistical inferences were made with a significance level of 0.05. RESULTS: Four hundred sixty-six patients were enrolled in the analysis based on study criteria. Samples' mean (SD) age was 54(15.54), and 322 (69.1%) patients were female. Three hundred sixty-five catheter dysfunction cases were observed due to thrombosis 123(26.4%) and infection 242(52%). The Median (range) time to catheter dysfunction event was 243(36-1131) days. Single variable analysis showed a statistically significant higher proportion of thrombosis in females (OR = 2.66, 95% CI: 1.77-4.00) and younger patients, respectively. Multivariate competing risk regression showed a statistically significant higher risk of thrombosis in females (Sub-distributional hazard (SHR) = 1.81), hypertensive (SHR = 1.82), and more obese patients (BMI SHR = 1.037). A higher risk of infection was calculated in younger (Age SHR = 0.98) and diabetic (SHR = 1.63) patients using the same method. CONCLUSION: Female and hypertensive patients are considerably at higher risk of catheter thrombosis, whereas diabetes is the most critical risk factor for infectious catheter dysfunction. Competing risk regression analysis showed a comprehensive result in the assessment of risk factors of catheter dysfunction.

Murine macrophages or their secretome delivered in alginate dressings enhance impaired wound healing in diabetic mice.

Diabetic foot ulceration is a devastating diabetic complication with unmet needs. We explored the efficacy of calcium-crosslinked alginate dressings in topically delivering primary macrophages and their secretome to diabetic wounds. The alginate bandages had a microporous structure that enabled even cell loading with prolonged cell survival and egress following wound placement. In vitro experiments showed that we could successfully differentiate and polarize primary murine bone marrow derived monocytes into M0, M1, M2a and M2c defined states with distinct gene expression, surface protein and secretome profiles. The primary macrophages were delivered in the bandages, migrated within the wounds and were still present for as long as 16 days post-injury. In wounds of db/db mice, treatment with all macrophage subtypes and their secretome, when compared to control, accelerated wound healing. Bulk RNA sequencing analysis and multiplex protein quantification of wound lysates revealed that M2c macrophages conditioned media had the most impact in wound healing affecting processes like neurogenesis, while M1 conditioned media promoted keratinization and epidermal differentiation. Collectively, our results indicate that alginate dressings can serve as a delivery platform for topical treatment of diabetic wounds and that conditioned media from distinctly polarized macrophages is equally or more effective than their parental cells in advancing wound healing and could therefore be a promising and technically advantageous alternative to cell therapy.

The effect of a planned lactation education program on the mother's breastfeeding practice and weight gain in low birth weight infants: a randomized clinical trial study.

BACKGROUND: Low birth weight (LBW) infants are more prone to possible growth disorders, and their mothers need more specific education sessions regarding breastfeeding practice. This study aimed to investigate the effect of a planned lactation education program on the mother's breastfeeding practice and weight gain in LBW infants. METHODS: A randomized clinical trial study was conducted on 80 mother-LBW infant dyads admitted to a gynecology and obstetrics hospital. The participants were selected randomly and divided into an experimental group and a control group, each with 40 mothers. Information on LBW infants' weight and the mothers' breastfeeding practice was collected using a questionnaire at birth. Then, a planned lactation education program was implemented in the experimental group in two sessions in the hospital and three 20-minute sessions in comprehensive health centers. Finally, the weight of 14-15 day-old and two-month-old LBW infants and the mothers' breastfeeding practice for 14-15 day-old LBW infants in the two groups were recollected and analyzed using SPSS software version 16. RESULTS: Comparing the LBW infants' weights and mothers' breastfeeding practice revealed no statistically significant difference between the two groups pre-intervention. However, significant differences were observed between the two groups post-intervention in terms of weight gain in the LBW infants over 14-15 days and two months of age (F = 4720.6, p < 0.001) and the mothers' breastfeeding practice for 14-15-day-old infants (p < 0.001). CONCLUSIONS: Given the positive impact of lactation education on the mother's breastfeeding practice and LBW infants' weight, planned lactation education courses should be applied for LBW infants' mothers. TRIAL REGISTRATION: This study was retrospectively registered in the Clinical Trial Registration Center of Iran, with the code: IRCT20120215009014N421 on 14/04/2022.

A Novel Three-Dimensional Skin Disease Model to Assess Macrophage Function in Diabetes.

A major challenge in the management of patients suffering from diabetes is the risk of developing nonhealing foot ulcers. Most in vitro methods to screen drugs for wound healing therapies rely on conventional 2D cell cultures that do not closely mimic the complexity of the diabetic wound environment. In addition, while three-dimensional (3D) skin tissue models of human skin exist, they have not previously been adapted to incorporate patient-derived macrophages to model inflammation from these wounds. In this study, we present a 3D human skin equivalent (HSE) model incorporating blood-derived monocytes and primary fibroblasts isolated from patients with diabetic foot ulcers (DFUs). We demonstrate that the monocytes differentiate into macrophages when incorporated into HSEs and secrete a cytokine profile indicative of the proinflammatory M1 phenotype seen in DFUs. We also show how the interaction between fibroblasts and macrophages in the HSE can guide macrophage polarization. Our findings take us a step closer to creating a human, 3D skin-like tissue model that can be applied to evaluate the response of candidate compounds needed for potential new foot ulcer therapies in a more complex tissue environment that contributes to diabetic wounds. Impact statement This study is the first to incorporate disease-specific, diabetic macrophages into a three-dimensional (3D) model of human skin. We show how to fabricate skin that incorporates macrophages with disease-specific fibroblasts to guide macrophage polarization. We also show that monocytes from diabetic patients can differentiate into macrophages directly in this skin disease model, and that they secrete a cytokine profile mimicking the proinflammatory M1 phenotype seen in diabetic foot ulcers. The data presented here indicate that this 3D skin disease model can be used to study macrophage-related inflammation in diabetes and as a drug testing tool to evaluate new treatments for the disease.

Multifunctional Synthetic Protein Nanoparticles via Reactive Electrojetting.

Protein nanoparticles are a promising approach for nanotherapeutics, as proteins combine versatile chemical and biological function with controlled biodegradability. In this work, the development of an adaptable synthesis method is presented for synthetic protein nanoparticles (SPNPs) based on reactive electrojetting. In contrast to past work with electrohydrodynamic cojetting using inert polymers, the jetting solutions are comprised of proteins and chemically activated macromers, designed to react with each other during the processing step, to form insoluble nanogel particles. SPNPs made from a variety of different proteins, such as transferrin, insulin, or hemoglobin, are stable and uniform under physiological conditions and maintain monodisperse sizes of around 200 nm. SPNPs comprised of transferrin and a disulfide containing macromer are stimuli-responsive, and serve as markers of oxidative stress within HeLa cells. Beyond isotropic SPNPs, bicompartmental nanoparticles containing human serum albumin and transferrin in two distinct hemispheres are prepared via reactive electrojetting. This novel platform provides access to a novel class of versatile protein particles with nanoscale architectures that i) can be made from a variety of proteins and macromers, ii) have tunable biological responses, and iii) can be multicompartmental, a prerequisite for controlled release of multiple drugs.

Microencapsulation of Live Cells in Synthetic Polymer Capsules.

In cell therapies, it is advantageous to encapsulate live cells in protective, semipermeable microparticles for controlled release of cytokines, growth factors, monoclonal antibodies, or insulin. Here, a modified electrospraying approach with an organic solution of poly(lactide-co-glycolide) (PLGA) polymer is used to create synthetic PLGA capsules that effectively protect live cells. Using a design of experiment (DOE) methodology, the effect of governing jetting parameters on encapsulation efficiency, yield, and size is systematically evaluated. On the basis of this analysis, the interaction between bovine serum albumin concentration and core flow rate is the most dominant factor determining core encapsulation efficiency as well as the microcapsule size. However, the interaction between shell solvent ratio and shell flow rate predominantly defines the particle yield. To validate these findings, live cells have been successfully encapsulated in microcapsules using optimized parameters from the DOE analysis and have survived the electrohydrodynamic jetting process. Extending the currently available toolkit for cell microencapsulation, these biodegradable, semi-impermeable cell-laden microcapsules may find a range of applications in areas such as tissue engineering, regenerative medicine, and drug delivery.

Persistence, distribution, and impact of distinctly segmented microparticles on cochlear health following in vivo infusion.

Delivery of pharmaceuticals to the cochleae of patients with auditory dysfunction could potentially have many benefits from enhancing auditory nerve survival to protecting remaining sensory cells and their neuronal connections. Treatment would require platforms to enable drug delivery directly to the cochlea and increase the potential efficacy of intervention. Cochlear implant recipients are a specific patient subset that could benefit from local drug delivery as more candidates have residual hearing; and since residual hearing directly contributes to post-implantation hearing outcomes, it requires protection from implant insertion-induced trauma. This study assessed the feasibility of utilizing microparticles for drug delivery into cochlear fluids, testing persistence, distribution, biocompatibility, and drug release characteristics. To allow for delivery of multiple therapeutics, particles were composed of two distinct compartments; one containing polylactide-co-glycolide (PLGA), and one composed of acetal-modified dextran and PLGA. Following in vivo infusion, image analysis revealed microparticle persistence in the cochlea for at least 7 days post-infusion, primarily in the first and second turns. The majority of subjects maintained or had only slight elevation in auditory brainstem response thresholds at 7 days post-infusion compared to pre-infusion baselines. There was only minor to limited loss of cochlear hair cells and negligible immune response based on CD45+ immunolabling. When Piribedil-loaded microparticles were infused, Piribedil was detectable within the cochlear fluids at 7 days post-infusion. These results indicate that segmented microparticles are relatively inert, can persist, release their contents, and be functionally and biologically compatible with cochlear function and therefore are promising vehicles for cochlear drug delivery. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1510-1522, 2016.

Engineering of nanoparticle size via electrohydrodynamic jetting.

Engineering the physical properties of particles, especially their size, is an important parameter in the fabrication of successful carrier systems for the delivery of therapeutics. Here, various routes were explored for the fabrication of particles in the nanosize regime. It was demonstrated that the use of a charged species and/or solvent with high dielectric constant can influence the size and distribution of particles, with the charged species having a greater effect on the size of the particles and the solvent a greater effect on the distribution of the particles. In addition to the fabrication of nanoparticles, their fractionation into specific size ranges using centrifugation was also investigated. The in vitro particle uptake and intracellular transport of these nanoparticles was studied as a function of size and incubation period. The highest level of intralysosomal localization was observed for the smallest nanoparticle group (average of 174 nm), followed by the groups with increasing sizes (averages of 378 and 575 nm), most likely due to the faster endosomal uptake of smaller particles. In addition, the internalization of nanoparticle clusters and number of nanoparticles per cell increased with longer incubation periods. This work establishes a technological approach to compartmentalized nanoparticles with defined sizes. This is especially important as relatively subtle differences in size can modulate cell uptake and determine intercellular fate. Future work will need to address the role of specific targeting ligands on cellular uptake and intracellular transport of compartmentalized nanoparticles.

Long-circulating Janus nanoparticles made by electrohydrodynamic co-jetting for systemic drug delivery applications.

BACKGROUND: Nanoparticles with controlled physical properties have been widely used for controlled release applications. In addition to shape, the anisotropic nature of the particles can be an important design criterion to ensure selective surface modification or independent release of combinations of drugs. PURPOSE: Electrohydrodynamic (EHD) co-jetting is used for the fabrication of uniform anisotropic nanoparticles with individual compartments and initial physicochemical and biological characterization is reported. METHODS: EHD co-jetting is used to create nanoparticles, which are characterized at each stage with scanning electron microscopy (SEM), structured illumination microscopy (SIM), dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). Surface immobilization techniques are used to incorporate polyethylene glycol (PEG) and I(125) radiolabels into the nanoparticles. Particles are injected in mice and the particle distribution after 1, 4 and 24 hours is assessed. RESULTS AND DISCUSSION: Nanoparticles with an average diameter of 105.7 nm are prepared by EHD co-jetting. The particles contain functional chemical groups for further surface modification and radiolabeling. The density of PEG molecules attached to the surface of nanoparticles is determined to range between 0.02 and 6.04 ligands per square nanometer. A significant fraction of the nanoparticles (1.2% injected dose per mass of organ) circulates in the blood after 24 h. CONCLUSION: EHD co-jetting is a versatile method for the fabrication of nanoparticles for drug delivery. Circulation of the nanoparticles for 24 h is a pre-requisite for subsequent studies to explore defined targeting of the nanoparticles to a specific anatomic site.

Dual-stimuli-responsive microparticles.

The need for smart materials in the area of biotechnology has fueled the development of numerous stimuli-responsive polymers. Many of these polymers are responsive to pH, light, temperature, or oxidative stress, and yet very few are responsive toward multiple stimuli. Here we report on the synthesis of a novel dual-stimuli-responsive poly(ethylene glycol)-based polymer capable of changing its hydrophilic properties upon treatment with UV light (exogenous stimulus) and markers of oxidative stress (endogenous stimulus). From this polymer, smart microparticles and fibers were fabricated and their responses to either stimulus separately and in conjunction were examined. Comparison of the degradation kinetics demonstrated that the polymer became water-soluble only after both oxidation and irradiation with UV light, which resulted in selective degradation of the corresponding particles. Furthermore, in vitro experiments demonstrated successful uptake of these particles by Raw 264.7 cells. Such dual-stimuli-responsive particles could have potential applications in drug delivery, imaging, and tissue engineering.

Chemically orthogonal three-patch microparticles.

Compared to two-dimensional substrates, only a few methodologies exist for the spatially controlled decoration of three-dimensional objects, such as microparticles. Combining electrohydrodynamic co-jetting with synthetic polymer chemistry, we were able to create two- and three-patch microparticles displaying chemically orthogonal anchor groups on three distinct surface patches of the same particle. This approach takes advantage of a combination of novel chemically orthogonal polylactide-based polymers and their processing by electrohydrodynamic co-jetting to yield unprecedented multifunctional microparticles. Several micropatterned particles were fabricated displaying orthogonal click functionalities. Specifically, we demonstrate novel two- and three-patch particles. Multi-patch particles are highly sought after for their potential to present multiple distinct ligands in a directional manner. This work clearly establishes a viable route towards orthogonal reaction strategies on multivalent micropatterned particles.

Multimodal delivery of irinotecan from microparticles with two distinct compartments.

In the last several decades, research in the field of drug delivery has been challenged with the fabrication of carrier systems engineered to deliver therapeutics to the target site with sustained and controlled release kinetics. Herein, we report the fabrication of microparticles composed of two distinct compartments: i) one compartment containing a pH responsive polymer, acetal-modified dextran, and PLGA (polylactide-co-glycolide), and ii) one compartment composed entirely of PLGA. We demonstrate the complete release of dextran from the microparticles during a 10-hour period in an acidic pH environment and the complete degradation of one compartment in less than 24h. This is in congruence with the stability of the same microparticles in neutral pH over the 24-hour period. Such microparticles can be used as pH responsive carrier systems for drug delivery applications where their cargo will only be released when the optimum pH window is reached. The feasibility of the microparticle system for such an application was confirmed by encapsulating a cancer therapeutic, irinotecan, in the compartment containing the acetal-modified dextran polymer and the pH dependent release over a 5-day period was studied. It was found that upon pH change to an acidic environment, over 50% of the drug was first released at a rapid rate for 10h, similar to that observed for the dextran release, before continuing at a more controlled rate for 4 days. As such, these microparticles can play an important role in the fabrication of novel drug delivery systems due to the selective, controlled, and pH responsive release of their encapsulated therapeutics.

Photoswitchable particles for on-demand degradation and triggered release.

On-demand degradable polymer particles are fabricated via electrospraying of a solution of acetal-protected dextran that further includes 2-(4-methoxystyryl)-4,6-bis(trichloromethyl)-1,3,5-triazine as a photoacid generator. The illumination of UV light gives rise to photoacid and activates the catalytic deprotection of hydroxyl groups of dextran, leading to controlled dissolution of the microparticles in water.

Spontaneous shape reconfigurations in multicompartmental microcylinders.

Nature's particles, such as spores, viruses or cells, are adaptive--i.e., they can rapidly alter major phenomenological attributes such as shape, size, or curvature in response to environmental changes. Prominent examples include the hydration-mediated opening of ice plant seeds, actuation of pine cones, or the ingenious snapping mechanism of predatory Venus flytraps that rely on concave-to-convex reconfigurations. In contrast, experimental realization of reconfigurable synthetic microparticles has been extremely challenging and only very few examples have been reported so far. Here, we demonstrate a generic approach towards dynamically reconfigurable microparticles that explores unique anisotropic particle architectures, rather than direct synthesis of sophisticated materials such as shape-memory polymers. Solely enabled by their architecture, multicompartmental microcylinders made of conventional polymers underwent active reconfiguration including shape-shifting, reversible switching, or three-way toggling. Once microcylinders with appropriate multicompartmental architectures were prepared by electrohydrodynamic cojetting, simple exposure to an external stimulus, such as ultrasound or an appropriate solvent, gives rise to interfacial stresses that ultimately cause reversible topographical reconfiguration. The broad versatility of the electrohydrodynamic cojetting process with respect to materials selection and processing suggests strategies for a wide range of dynamically reconfigurable adaptive materials including those with prospective applications for sensors, reprogrammable microactuators, or targeted drug delivery.