Multilayer microcapsules for delivery, control and triggered release of bioactive compounds

PhDDeveloping of targeted drug delivery systems is currently a very important topic, which can be easily judged by a great number of papers published every year. Materials science proposes, among others, microcapsules as one of the possible solutions to the problem. Known for more than a decade by know, microcapsules, their properties, methods of encapsulation, release, control where under thorough investigation by several scientific groups in the world. Despite the fact that many factors were already studied, application of this system to drug delivery provides an enormous amount of work yet to be done, lying across several areas of science – biology, chemistry, physics, medicine. To be used as a technique of targeted delivery, not only the microcapsules should meet many constraints on their physical and chemical properties, but also the means of their control and release triggering irradiation should be applicable and harmless to living body. This means, that there's a lot more to do than to encapsulate the substances of interest and make sure they stay inside the capsules. This is why this research was devoted to investigation of stability of cargo encapsulated to layer-by-layer microcapsules constructed on silica and CaCO3 microparticles using various shell constructions with synthetic and biodegradable polyelectrolytes, nanoparticles, DNA, enzyme and other materials, methods of microcapsules control by magnetic field, which can be used for navigation of the carriers in-vivo to the place of interest and methods of release of encapsulated substances from the microcapsules, that are friendly to living body. The thesis starts with introduction and a literature review to help reader to get a better understanding on the structures discussed in this work and what have already been done in the area. These are followed by a short description of main materials and methods used to conduct this research. Three following chapters of experimental section describe the research itself. Chapter 4 shows feasibility of triggered IR-laser and high-frequency ultrasound release, including intracellular release. Reporting application of cargo using pH-sensitve dye is shown. Ultrasoundtriggered release at parameters, close to that currently used in medical applications, is shown to achieve up to 60% efficiency of previously reported highpower 20 kHz ultrasonic irradiation. Feasibility of laser-induced triggered release using microcapsules functionalized photo-sensitive dyes was also shown. In Chapter 5 retention of activity of DNA and enzyme molecules upon encapsulation was demonstrated. Activity of encapsulated substances was shown to be lower, than of free ones, but the accessibility and kinetics of reactions can be controlled by adjusting the construction of microcapsules. In Chapter 6 feasibility of control of cells impregnated with microcapsules functionalized with magnetite nanoparticles was shown at distances of up to 10 mm using usual constant magnets

Alpha-2-macroglobulin loaded microcapsules enhance human leukocyte functions and innate immune response

Synthetic microstructures can be engineered to deliver bioactive compounds impacting on their pharmacokinetics and pharmacodynamics. Herein, we applied dextran-based layer-by-layer (LbL) microcapsules to deliver alpha-2-macroglobulin (α2MG), a protein with modulatory properties in inflammation. Extending recent observations made with dextran-microcapsules loaded with α2MG in experimental sepsis, we focused on the physical and chemical characteristics of these microstructures and determined their biology on rodent and human cells. We report an efficient encapsulation of α2MG into microcapsules, which enhanced i) human leukocyte recruitment to inflamed endothelium and ii) human macrophage phagocytosis: in both settings microcapsules were more effective than soluble α2MG or empty microcapsules (devoid of active protein). Translation of these findings revealed that intravenous administration of α2MG-microcapsules (but not empty microcapsules) promoted neutrophil migration into peritoneal exudates and augmented macrophage phagocytic functions, the latter response being associated with alteration of bioactive lipid mediators as assessed by mass spectrometry. The present study indicates that microencapsulation can be an effective strategy to harness the complex biology of α2MG with enhancing outcomes on fundamental processes of the innate immune response paving the way to potential future development in the control of sepsis

Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis

Incorporation of locally produced signaling molecules into cell-derived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro, A2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil–endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis

Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis

These studies were supported by The Wellcome Trust (program 086867/Z/08) and the William Harvey Research Foundation to MP, the United Kingdom Intensive Care Society to CJH and the National Institutes of Health GM Grant P01GM095967 (awarded to Charles N. Serhan). LVN is supported by an Arthritis Research UK Career Development Fellowship (19909). EPSRC Seed Funding Cross disciplinary Grant (QMUL) awarded to GBS and MP. This work forms part of the research themes contributing to the translational research portfolio of Barts and The London NIHR Cardiovascular BRU

Prevalence of Risk Factors of Thromboembolic Complications in Women after Major Joint Arthroplasty in the Republic of Sakha (Yakutia)

The aim of this study was to assess the risk factors for thromboembolic complications after total arthroplasty of large joints in women in Yakutia conditions to optimize the management tactics of this category of patients. The average age of women was 59.98±11.56 years in the age range from 50 to 70 years. In order to validate the study, women were divided into 2 groups. The main group consisted of 284 women undergoing total knee arthroplasty (Group 1). The comparison group included 147 women undergoing total hip arthoplasty (Group 2). The study demonstrated that hypertension was more common in patients of Group 1 than in patients of Group 2. However, the incidence of coronary heart disease and heart rhythm disorder was detected most frequently in patients with total hip arthroplasty. Obesity, thrombosis of the veins of the lower extremities, and liver disease were detected with almost the same frequency in women with total knee arthroplasty and those with total hip arthroplasty. The frequency of occurrence of complications depending on the risk factors for thromboembolic complications and the type of surgical treatment of the joint was equal in the two groups of studied patients

Contralateral delay activity as a marker of visual working memory capacity: a multi-site registered replication

Visual working memory (VWM) is a temporary storage system capable of retaining information that can be accessed and manipulated by higher cognitive processes, thereby facilitating a wide range of cognitive functions. Electroencephalography (EEG) is used to understand the neural correlates of VWM with high temporal precision, and one commonly used EEG measure is an event-related potential called the contralateral delay activity (CDA). In a landmark study by Vogel and Machizawa (2004), the authors found that the CDA amplitude increases with the number of items stored in VWM and plateaus around three to four items, which is thought to represent the typical adult working memory capacity. Critically, this study also showed that the increase in CDA amplitude between two-item and four-item arrays correlated with individual subjects’ VWM performance. Although these results have been supported by subsequent studies, a recent study suggested that the number of subjects used in experiments investigating the CDA may not be sufficient to detect differences in set size and to provide a reliable account of the relationship between behaviorally measured VWM capacity and the CDA amplitude. To address this, the current study, as part of the #EEGManyLabs project, aims to conduct a multi-site replication of Vogel and Machizawa's (2004) seminal study on a large sample of participants, with a pre-registered analysis plan. Through this, our goal is to contribute to deepening our understanding of the neural correlates of visual working memory

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

Measurement of differential cross sections for top quark pair production using the lepton plus jets final state in proton-proton collisions at 13 TeV

National Science Foundation (U.S.