Novel formulations for antigen delivery using biodegradable polymers: new approaches for the use of new and established adjuvants

The use of immunological adjuvants has been established since 1924 and ever since many candidates have been extensively researched in vaccine development. The controlled release of vaccine is another area of biotechnology research, which is advancing rapidly with great potential and success. Encapsulation of peptide and protein drugs within biodegradable microspheres has been amongst the most successful of approaches within the past decade. The present studies have focused on combining the advantages of microsphere delivery systems composed of biodegradable polylactide (PLLA) and polylactide-co-glycolide (PLGA) polymers with that of safe and effective adjuvants. The research efforts were directed to the development of single-dose delivery vehicles which, can be manufactured easily, safely, under mild and favourable conditions to the encapsulated antigens. In pursuing this objective non ionic block copolymers (NIBCs) (Pluronics@ LI01 and L121) were incorporated within poly-dl-lactide (PDLA) micorospheres prepared with emulsification-diffusion method. LI0I and L121 served both as adjuvants and stabilising agents within these vaccine delivery vehicles. These formulations encapsulating the model antigens lysozyme, ovalbumin (OVA) and diphtheria toxoid (DT) resulted in high entrapment efficiency (99%), yield (96.7%) and elicited high and sustained immune response (IgG titres up to 9427) after one single administration over nine months. The structural integrity of the antigens was preserved within these formulations. In evaluating new approaches for the use of well-established adjuvants such as alum, these particles were incorporated within PLLA and PLGA microspheres at much lesser quantities (5-10 times lower) than those contained within conventional alum-adsorbed vaccines. These studies focused on the incorporation of the clinically relevant tetanus toxoid (TT) antigen within biodegradable microspheres. The encapsulation of both alum particles and TT antigen within these micropheres resulted in preparations with high encapsulation efficiency (95%) and yield (91.2%). The immune response to these particles was also investigated to evaluate the secretion of serum IgG, IgG1, IgG2a and IgG2b after a single administration of these vaccines. The Splenic cells proliferation was also investigated as an indication for the induction of cell mediated immunity. These particles resulted in high and sustained immune response over a period of 14 months. The stability of TT within particles was also investigated under dry storage over a period of several months. NIBC microspheres were also investigated as potential DNA vaccine delivery systems using hepatitis B plasmid. These particles resulted in micro spheres of 3-5 μm diameter and were shown to preserve the integrity of the encapsulated (27.7% entrapment efficiency) hepatitis B plasmid.

Sustained delivery of salbutamol and beclometasone from spray-dried double emulsions

The sustained delivery of multiple agents to the lung offers potential benefits to patients. This study explores the preparation of highly respirable dual-loaded spray-dried double emulsions. Spray-dried powders were produced from water-in-oil-in-water (w/o/w) double emulsions, containing salbutamol sulphate and/or beclometasone dipropionate in varying phases. The double emulsions contained the drug release modifier polylactide co-glycolide (PLGA 50 : 50) in the intermediate organic phase of the original micro-emulsion and low molecular weight chitosan (Mw<190 kDa: emulsion stabilizer) and leucine (aerosolization enhancer) in the tertiary aqueous phase. Following spray-drying resultant powders were physically characterized: with in vitro aerosolization performance and drug release investigated using a Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. Powders generated were of a respirable size exhibiting emitted doses of over 95% and fine particle fractions of up to 60% of the total loaded dose. Sustained drug release profiles were observed during dissolution for powders containing agents in the primary aqueous and secondary organic phases of the original micro-emulsion; the burst release of agents was witnessed from the tertiary aqueous phase. The novel spray-dried emulsions from this study would be expected to deposit and display sustained release character in the lung.

Capillary siphons and their application in the fuel delivery system of direct methanol fuel cells

The objective of the work is to develop a fuel delivery system for potable direct methanol fuel cell. Currently, one of the most fundamental limitations of direct methanol fuel cells is that the fuel supplied to the anode of the DMFC must be a very dilute aqueous methanol solution (usually 0.5∼1.5 M). If a DMFC is filled with a dilute aqueous methanol solution, the fuel cell operation time per refuel would be very short, which would considerably diminish the advantage of a DMFC over a conventional battery. To overcome this difficulty, a complex fuel delivery system based on the modern micro system technology was proposed by the author. The proposed fuel delivery system would include micro-pumps, a methanol sensor, and a control unit. The fuel delivery system adds considerable costs to the fuel cell system and consume considerable amount of electricity from the fuel cell, which in turn significantly reduces the net power output of the fuel cell. As a result, the DMFC would have tremendous difficulty to compete with the conventional battery technology in terms of costs and power output. ^ This work presents a novel passive fuel delivery system for direct methanol fuel cells. In this particular system, a methanol fuel and an aqueous methanol solution are stored separately in two containers and a wick is disposed between the two containers in a siphon fashion, with the container of the aqueous methanol solution communicating with the anode of the DMFC. Methanol is siphoned from the methanol container to the aqueous solution container in-situ when the methanol in the aqueous methanol solution is consumed during the operation of the fuel cell. Through a proper selection of the wick and the containers, the methanol concentration near the anode of the DMFC could be maintained within a preferable range. ^

Managing chronic widespread pain in primary care : a qualitative study of patient perspectives and implications for treatment delivery

Funding The MUSICIAN trial was supported by an award from Arthritis Research UK, Chesterfield, UK. Grant number: 17292. The funding body approved the design of the study. They played no role in the collection, analysis, and interpretation of data or the writing of the manuscript.

European student mobility and intercultural learning at a portuguese university

The purpose of this study is to understand, impact and evaluate the development of intercultural communicative competencies among European credit-seeking exchange students and other sojourners through purposeful intercultural pedagogy. This pedagogy encompasses intentional intercultural- educational approaches which aim to support and enhance sojourners’ intercultural learning throughout the study abroad cycle (pre-departure, in-country and reentry phases). To test and validate these pedagogies a 20-hour intervention was designed and implemented among two cohorts of 31 sojourners during the in-country phase of their sojourn in Portugal. The process to develop and validate the intercultural intervention was driven by a mixed-methods methodology which combined quantitative and qualitative data to triangulate, complement and expand research results from a pragmatic stance. The mixed methods research design adopted is multi-phased and encompasses a multi-case study and an evaluative component. The multi-case component is embodied by sojourner cohorts: (1) the primary case study involves 19 incoming students at the University of Aveiro (Portugal) as participants in the European exchange program Campus Europae; (2) the second case study comprises three incoming Erasmus students and nine highly skilled immigrants at the same university. All 31 sojourners attended two intermediate Portuguese as Foreign Language classrooms where the intervention was employed. Data collection was extensive and involved collecting, analyzing and mixing quantitative and qualitative strands across four research phases. These phases refer to the: (1) development, (2) implementation and (3) evaluation of the intervention, as well as to (4) a stakeholder analysis of the external value of the intervention and of the Campus Europae program. Data collection instruments included pre and posttest questionnaires and semi-structured interviews. Results confirm the intercultural effectiveness of the intervention and the positive impact upon research participants’ intercultural gains. This impact was, however, greater in case study 2. Among explanatory variables, three stand out: (1) participant meaning-making abilities, (2) host language proficiency and related variables, and (3) type of sojourn or exchange programs. Implications for further research highlight the need to systematize purposeful intercultural pedagogy in sojourner populations in general, and in European credit student mobility in particular. In the latter case, these pedagogies should be part of the design and delivery of credit-bearing exchange programs in pre- departure, in-country and re-entry phases. Implications for practice point to the urge to improve intercultural practices in: macro (higher education institutions), mezzo (exchange programs) and micro (sojourner language classrooms) contexts where this research took place, and wider social scenarios they represent.

Computer-based tools for assessing micro-longitudinal patterns of cognitive function in older adults

Patterns of cognitive change over micro-longitudinal timescales (i.e., ranging from hours to days) are associated with a wide range of age-related health and functional outcomes. However, practical issues with conducting high-frequency assessments make investigations of micro-longitudinal cognition costly and burdensome to run. One way of addressing this is to develop cognitive assessments that can be performed by older adults, in their own homes, without a researcher being present. Here, we address the question of whether reliable and valid cognitive data can be collected over micro-longitudinal timescales using unsupervised cognitive tests.In study 1, 48 older adults completed two touchscreen cognitive tests, on three occasions, in controlled conditions, alongside a battery of standard tests of cognitive functions. In study 2, 40 older adults completed the same two computerized tasks on multiple occasions, over three separate week-long periods, in their own homes, without a researcher present. Here, the tasks were incorporated into a wider touchscreen system (Novel Assessment of Nutrition and Ageing (NANA)) developed to assess multiple domains of health and behavior. Standard tests of cognitive function were also administered prior to participants using the NANA system.Performance on the two “NANA” cognitive tasks showed convergent validity with, and similar levels of reliability to, the standard cognitive battery in both studies. Completion and accuracy rates were also very high. These results show that reliable and valid cognitive data can be collected from older adults using unsupervised computerized tests, thus affording new opportunities for the investigation of cognitive function.

Integrated micro fuel cells with on-board hydride reactors and autonomous control schemes

Miniaturization of power generators to the MEMS scale, based on the hydrogen-air fuel cell, is the object of this research. The micro fuel cell approach has been adopted for advantages of both high power and energy densities. On-board hydrogen production/storage and an efficient control scheme that facilitates integration with a fuel cell membrane electrode assembly (MEA) are key elements for micro energy conversion. Millimeter-scale reactors (ca. 10 µL) have been developed, for hydrogen production through hydrolysis of CaH2 and LiAlH4, to yield volumetric energy densities of the order of 200 Whr/L. Passive microfluidic control schemes have been implemented in order to facilitate delivery, self-regulation, and at the same time eliminate bulky auxiliaries that run on parasitic power. One technique uses surface tension to pump water in a microchannel for hydrolysis and is self-regulated, based on load, by back pressure from accumulated hydrogen acting on a gas-liquid microvalve. This control scheme improves uniformity of power delivery during long periods of lower power demand, with fast switching to mass transport regime on the order of seconds, thus providing peak power density of up to 391.85 W/L. Another method takes advantage of water recovery by backward transport through the MEA, of water vapor that is generated at the cathode half-cell reaction. This regulation-free scheme increases available reactor volume to yield energy density of 313 Whr/L, and provides peak power density of 104 W/L. Prototype devices have been tested for a range of duty periods from 2-24 hours, with multiple switching of power demand in order to establish operation across multiple regimes. Issues identified as critical to the realization of the integrated power MEMS include effects of water transport and byproduct hydrate swelling on hydrogen production in the micro reactor, and ambient relative humidity on fuel cell performance.

Design of Polyamine-Grafted Starches for Nucleotide Analogue Delivery: In Vitro Evaluation of the Anticancer Activity

International audience

Nucleic-Acid Delivery Using Lipid Nanocapsules

International audience

Lipid-based nanoformulations for peptide delivery

International audience

Development of multifunctional lipid nanocapsules for the co-delivery of paclitaxel and CpG-ODN in the treatment of glioblastoma

International audience

Micro and nanosystems for delivering local anesthetics

Introduction: One of the most common strategies for pain control during and after surgical procedures is the use of local anesthetics. Prolonged analgesia can be safely achieved with drug delivery systems suitably chosen for each local anesthetic agent.Areas covered: This review considers drug delivery formulations of local anesthetics designed to prolong the anesthetic effect and decrease toxicity. The topics comprise the main drug delivery carrier systems (liposomes, biopolymers, and cyclodextrins) for infiltrative administration of local anesthetics. A chronological review of the literature is presented, including details of formulations as well as the advantages and pitfalls of each carrier system. The review also highlights pharmacokinetic data on such formulations, and gives an overview of the clinical studies published so far concerning pain control in medicine and dentistry.Expert opinion: The design of novel drug delivery systems for local anesthetics must focus on how to achieve higher uploads of the anesthetic into the carrier, and how to sustain its release. This comprehensive review should be useful to provide the reader with the current state-of-art regarding drug delivery formulations for local anesthetics and their possible clinical applications.

Household portfolio allocation, risk attitudes and credit constraints : evidence from the eurozone

Mestrado em Economia Monetária e Financeira

Ihwg-μnir: A Miniaturised Near-infrared Gas Sensor Based On Substrate-integrated Hollow Waveguides Coupled To A Micro-nir-spectrophotometer.

A miniaturised gas analyser is described and evaluated based on the use of a substrate-integrated hollow waveguide (iHWG) coupled to a microsized near-infrared spectrophotometer comprising a linear variable filter and an array of InGaAs detectors. This gas sensing system was applied to analyse surrogate samples of natural fuel gas containing methane, ethane, propane and butane, quantified by using multivariate regression models based on partial least square (PLS) algorithms and Savitzky-Golay 1(st) derivative data preprocessing. The external validation of the obtained models reveals root mean square errors of prediction of 0.37, 0.36, 0.67 and 0.37% (v/v), for methane, ethane, propane and butane, respectively. The developed sensing system provides particularly rapid response times upon composition changes of the gaseous sample (approximately 2 s) due the minute volume of the iHWG-based measurement cell. The sensing system developed in this study is fully portable with a hand-held sized analyser footprint, and thus ideally suited for field analysis. Last but not least, the obtained results corroborate the potential of NIR-iHWG analysers for monitoring the quality of natural gas and petrochemical gaseous products.

Influence Of Delivery Method On Neuroprotection By Bone Marrow Mononuclear Cell Therapy Following Ventral Root Reimplantation With Fibrin Sealant.

The present work compared the local injection of mononuclear cells to the spinal cord lateral funiculus with the alternative approach of local delivery with fibrin sealant after ventral root avulsion (VRA) and reimplantation. For that, female adult Lewis rats were divided into the following groups: avulsion only, reimplantation with fibrin sealant; root repair with fibrin sealant associated with mononuclear cells; and repair with fibrin sealant and injected mononuclear cells. Cell therapy resulted in greater survival of spinal motoneurons up to four weeks post-surgery, especially when mononuclear cells were added to the fibrin glue. Injection of mononuclear cells to the lateral funiculus yield similar results to the reimplantation alone. Additionally, mononuclear cells added to the fibrin glue increased neurotrophic factor gene transcript levels in the spinal cord ventral horn. Regarding the motor recovery, evaluated by the functional peroneal index, as well as the paw print pressure, cell treated rats performed equally well as compared to reimplanted only animals, and significantly better than the avulsion only subjects. The results herein demonstrate that mononuclear cells therapy is neuroprotective by increasing levels of brain derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF). Moreover, the use of fibrin sealant mononuclear cells delivery approach gave the best and more long lasting results.