focus on mucosal delivery with related opportunities, issues, and challenges

Efficient pharmacotherapy is mainly dependent on the effective localized delivery of therapeutic agents to the targeted biological site. Many potent therapeutics exhibit detrimental effects owing their systemic administration and off-target interactions. Hence, local drug formulations have become a necessity to optimize current treatments. Such formulations, however, must address, the unsuited physicochemical properties of drug molecules on one hand, and the obstructive nature of the targeted biological barrier on the other. In this context, nanosized drug delivery systems have literally taken modern medicine to a new dimension by providing adaptable vehicles able to transfer and stabilize therapeutics. Responsive nanogels, in particular, offer biocompatible and versatile tools that can be tuned to suit the targeted barrier requirements in order to facilitate smart delivery and controlled release of the payload. Aiming to overcome the highly challenging dermal and mucus barriers and provide respectively efficient non-invasive formulations of labile biomacromolecules, the goal of this project was the rational investigation of polyglycerol based nanogels exerting two different response mechanisms as promising vehicles for dermal and mucosal applications. In the dermal delivery approach, thermoresponsive dPG nanogels were modified to exhibit different volume phase transition temperatures (VPTTs) ranging between 33 – 47 °C using PNIPAM and PNIPMAM thermoresponsive polymers. All nanogels demonstrated high protein encapsulation efficiency (>80%), maintained integrity of protein cargo, and exhibited dermal penetration and subsequent VPTT-dependent protein release and delivery to the viable epidermis in excised human skin. Here, the equal co-polymerization of PNIPAM and PNIPMAM yielded nanogels with VPTT ~40 °C, which enabled to expand dermal applications to include using an external thermal trigger like NIR lamp resulting in pronounced protein delivery in a controlled local and temporal manner. As for the mucosal delivery approach, for the first time redox-responsive dPG nanogels based on PNIPMAM conjugated to a bifunctional disulfide linker were developed and comprehensively investigated for protein delivery across the mucus barrier. Addressing essential prerequisites for mucus permeation, the nanogels physicochemical properties were fine-tuned to yield hydrophilic nanogels with size range between 100 – 200 nm, inert surface, and intact disulfide linkages. Monitoring the interactions between the nanogels and native intestinal mucus, a gradual disulfides-dependent degradation of the nanogels in mucus was confirmed. Furthermore, rheological measurements indicated mucoadhesive interactions between the mucus gel and the disulfides-containing nanogels, meanwhile absorption studies in excised porcine jejunum revealed outstanding mucopenetration of the disulfides-containing nanogels and demonstrated the disulfides merit in facilitating efficient circumvention of the mucus filtering and clearance mechanisms. Similar findings were also confirmed in reconstructed human bronchial epithelial in vitro models following longer exposure period to the nanogels. In addition, the cytocompatibility of the nanogels was also demonstrated in various mucosal epithelial cell types and primary macrophages as well. Next, the therapeutic efficiency of the nanogels in delivering the biological protein-drug etanercept (ETN; 150 kDa) was examined. Here, high loading efficiency along with structural and functional stability of encapsulated ETN were observed. Moreover, in vitro release studies in mucus-relevant redox conditions confirmed ETN retention in the nanogels for several hours and its sustained intact release upon nanogels degradation, which demonstrate the great potential of disulfides-containing nanogels for biomacromolecules delivery. Finally, topical application of ETN-loaded nanogels to human-based in vitro models of small intestinal tissue simulating IBD phenotype and bronchial epithelial tissue demonstrated efficient intraepithelial ETN delivery and subsequent anti-inflammatory effect. Throughout this investigation, serious issues pertaining to structural limitations in the available biological test systems for intestinal mucosa were revealed. Since these shortcomings significantly hamper drug absorption studies, multiple mucosal test systems were employed to validate the findings and allow a comprehensive and reliable assessment. Overall, this thesis introduces novel stimuli responsive nanogels as versatile and resilient tools for efficient local delivery of biomacromolecules to dermal and mucosal surfaces. It also demonstrates the role of the responsive modalities in facilitating the crossing of impervious biological barriers besides prompting a controlled release of the therapeutic payload. In addition, this work highlights critical problems in currently implemented test systems for predicting mucosal drug delivery and outlines present challenges in translating experimental approaches into tangible clinical success.Eine effiziente Pharmakotherapie hängt hauptsächlich davon ab, dass die therapeutischen Wirkstoffe effektiv an den biologischen Zielort gelangen. Viele potente Therapeutika weisen aufgrund ihrer systemischen Verabreichung und Off-Target Wechselwirkungen nachteilige und sogar schädliche Auswirkungen auf. Daher sind lokale Arzneimittelformulierungen zu einer Notwendigkeit geworden, um die derzeitigen Behandlungen zu optimieren. Solche Formulierungen müssen jedoch berücksichtigen die ungeeigneten physikochemischen Eigenschaften der Wirkstoffmoleküle einerseits, sowie die obstruktiven Eigenschaften der biologischen Zielbarriere andererseits. In diesem Zusammenhang haben Wirkstofftransportsysteme in Nanometer-Größe die moderne Medizin tatsächlich zu einer neuen Dimension gebracht, indem sie sich als flexible Vehikel, die die Therapeutika übertragen und stabilisieren herausgestellt haben. Vor allem responsive Nanogele bieten biokompatible und vielfältige Werkzeuge, die gemäß spezifischen Anforderungen der Zielbarriere angepasst werden können, um eine so genannte „smarte“ Verabreichung und kontrollierte Freisetzung des beladenen Mittels zu ermöglichen. Mit dem Ziel, die besonders anspruchsvollen Haut- und Schleimhautbarrieren zu überwinden und jeweils effiziente, nicht-invasive pharmazeutische Formulierungen für labilen Biomakromolekülen bereitzustellen, beruht sich der Schwerpunkt dieses Projekts auf die rationale Untersuchung von responsive Nanogele basierend auf Polyglycerin, die zwei unterschiedliche Response-Mechanismen aufweisen, als vielversprechende Transport-systeme für dermale und mukosale Anwendungen. Für den dermalen Ansatz wurden thermoresponsive Nanogele so modifiziert, dass sie unterschiedliche Volumenphasenübergangstemperaturen (VPTT) zwischen 33 und 47 °C aufweisen, wobei die thermoresponsiven Polymere PNIPAM und PNIPMAM verwendet wurden. Alle Nanogele zeigten eine hohe Protein-Verkapselungseffizienz (>80 %), bewahrten die Integrität des verkapselten Proteins, und konnten eine dermale Penetration mit VPTT-bedingter Freisetzung des Proteins und anschließender Abgabe in die lebensfähige Epidermis in exzidierter menschlicher Haut nachweisen. Durch die gleichmäßige Co-Polymerisation von Poly-N-Isopropylacrylamid (PNIPAM) und Poly-N-isopropylmethacrylamid (PNIPMAM) führte zu Nanogelen mit einer VPTT von ca. ~40 °C, was eine Erweiterung der dermalen Anwendungen ermöglichte, indem eine Verwendung externer Wärmequellen, wie einer Nahinfrarot-Lampe löst eine ausgeprägte Abgabe von Proteinen in die Haut auf kontrollierte lokale und zeitliche Weise aus. Was den Schleimhaut Ansatz betrifft, wurden zum ersten Mal Redox-responsive Nanogele aus PNIPMAM Polymer mit bifunktionellen Disulfid-Vernetzer entwickelt und für die Verabreichung von Proteinen über die Schleimbarriere umfassend untersucht. Mit Blick auf die wesentlichen Voraussetzungen für effiziente Mukus-Permeation, wurden die physikochemischen Eigenschaften der Nanogelen feinjustiert, um hydrophile Nanogelen mit einer Größe zwischen 100 und 200 nm, einer inerten Oberfläche, sowie intakten Disulfid-Bindungen zu erhalten. Die Überwachung von Wechselwirkungen zwischen den Nanogelen und nativem Darmschleim bestätigte einen allmählichen Disulfid-abhängigen Abbau der Nanogele in Mukus. Außerdem deuteten rheologische Messungen auf mucoadhäsive Wechselwirkung zwischen Mukus und Disulfid-haltigen Nanogelen hin. Zugleich zeigten Absorptionsstudien in frisch exzidiertem Schweine-Jejunum eine hervorragende Mukopenetration der Disulfid-haltigen Nanogelen und belegten die Vorzüge von Disulfiden in Bezug auf eine effiziente Überwindung der Mukus-korrelierten Filter- und Clearance-Mechanismen. Ähnliche Ergebnisse wurden auch in rekonstruierten menschlichen bronchialen Epithelmodellen in vitro nach längerer Expositionsdauer zu den Nanogelen bestätigt. Zudem wurde die Zytokompatibilität der Nanogelen auch in verschiedenen Schleimhautepithelzelltypen sowie primären Makrophagen nachgewiesen. Als Nächstes wurde die therapeutische Effizienz der Nanogelen bei der Verabreichung vom Biologikum-Protein Etanercept (ETN; 150 kDa) untersucht. Dabei wurden eine hohe Verkapslungs-effizienz sowie eine strukturelle und funktionelle Stabilität des verkapselten ETN festgestellt. Zudem ergaben in vitro Freisetzungsstudien unter Mukus-relevanten Redox-Bedingungen, dass ETN mehrere Stunden lang in den Nanogelen aufbewahrt geblieben ist und weiterhin schrittweise unversehrt freigesetzt wurde beim Abbau der Nanogelen, was das große Potenzial von Disulfid-haltigen Nanogelen für die Verabreichung von Biomakromolekülen belegte. Die topische Anwendung von ETN-beladenen Nanogelen auf humane in vitro Modelle des Dünndarmgewebes, die das Krankheitsbild der chronisch-entzündlichen Darmerkrankung (IBD) simulieren, und auf bronchiales Epithelgewebe zeigten schließlich eine effiziente intraepitheliale ETN Verabreichung und entsprechende entzündungshemmende Wirkung. Im Laufe dieser Untersuchung wurden ernste Probleme in Bezug auf strukturelle Einschränkungen in den verfügbaren biologischen Testsystemen für die Darmschleimhaut festgestellt. Da solche Mängel die Studien zur Arzneimittelabsorption erheblich beeinträchtigen, wurden mehrere Schleimhaut-Testsysteme hierzu eingesetzt, um die Ergebnisse zu validieren und eine umfassende und zuverlässige Bewertung zu ermöglichen. Insgesamt sind in dieser Arbeit neue responsive Nanogele als vielseitige und flexible Werkzeuge für die effiziente lokale Abgabe von Biomakromolekülen an die Haut- und Schleimhautoberflächen dargestellt. Weiterhin wird die Rolle der responsiven Modalitäten bei der Durchquerung von den robusten biologischen Barrieren neben der kontrollierten Freisetzung der therapeutischen Fracht demonstriert. Außerdem wurden kritische Probleme bei den bestehenden Testsystemen zur Voraussage von Medikamenten-Verabreichung über die Schleimhäute hervorgehoben und die aktuellen Herausforderungen erläutert, um den entsprechenden experimentellen Verfahren in greifbaren klinischen Erfolg umzusetzen

Antecedents and Consequences of Work-Family Conflict in Qatar

Purpose This paper examines the effect of causal factors, such as work-life harmony, work- family conflict, co-worker and supervisor support, as well as spouse support, on workload and job stress and employee psychological ill-being (depression/anxiety). Design/methodology/approach A large convenience sample of 807 families from Qatar was surveyed. Using SPSS, the researchers used factor analysis to establish construct validity, based on two suitability tests: the Kaisers-Meyer-Olkin (KMO) measure of sampling adequacy and the Bartless test of sphericity. The dimensions were found to be reliable and valid. Findings Findings from regression analysis show that five independent variables, as well as gender, are significant in predicting staff members’ perceived employee psychological ill-being in Qatar. In addition, results of the recursive model reveal that work-life harmony, supervisor’s and spouse’s support lead to less perceived employee psychological ill-being. However, workload, job stress and work-family conflict lead to more perceived employee psychological ill-being in Qatar. Practical implications Findings of this investigation provide strategic insights and practical thinking that have important implications for understanding and overcoming employee psychological ill-being. What’s more, this paper contributes to the limited knowledge about the effects of stressful working conditions in combination with low levels of spouse support and co-worker and supervisor support on work-life conflict and higher levels of depression and anxiety. Originality This article empirically correlates three fields of management research: Managerial Psychology, Employee Well-Being and Work-Life Balance

Work-Life -Balance in Qatar: Implementing Tows Analysis as a Variant of the Classic Strategic Tool, SWOT

Purpose The overall goal of this paper is to explore via Gap and TOWS analysis if organizations are offering innovative benefits from the perspective of married employees that make being a working dad or mom easier in Qatar. Design/methodology/approach A large convenient sample of 824 working Qataris were surveyed, using a 15-item instrument based on previous research. The researchers used factor analysis to ascertain construct validity, based on two suitability tests: First, the Kaisers-Meyer-Olkin (KMO) measure of sampling adequacy generated a score of 0.807, well above the recommended level of 0.50. Second, the Bartless test of sphericity result was significant (Chi Square = 2079.671, P= 0.00), indicating that there are adequate inter-correlations between the items which allow the use of factor analysis. Findings Findings of the gap analysis validate the trust – building model between leaders and followers from the employee’s perspective. The responses identified in this study enhance the trust in leaders who behave ethically, treat employees fairly, and promote work-life balance. This is an indication that Qatar’s National Vision 2030 introduced by Qatar government is transforming organizations’ values and attitudes in Qatar so that they perform beyond expectations. Additionally, findings of TWOS analysis identified four employer benefits items that are considered opportunities and eight employer benefits items that are identified as threats for the organizations in Qatar as a whole. Also, findings of path analysis confirm that the impact of “gap in perceived supervisor support” on “gap in perceived development of a caring organization” is strengthened via the intervening of “gap in perceived child-friendly working hours” and “gap in perceived parental leave”. Originality Qatar’s National Vision 2030 has set new future trends that demand changes in organizational culture and the empirical findings of this article should help decision and policy makers in Qatar to determine where change is possible and to focus on priorities as well as possibilities

Determinants of Banks’ Profitability: Panel Data from Qatar

Purpose : The aim of this paper is to investigate the main determinants of banks’ profitability and answer the question “what is the effect of liquidity and risk variables on the explained variation of banks’ performance in Qatar?” Design/ methodology /approach : A sample of six major lender banks for the period 2008-2015 is retrieved from the worldwide bankscope database. The dependent variable “Return on Average Assets (ROAA)” is taken as a function of independent variables that are basically liquidity and risk variables. Findings : Findings of this study show that variation in the independent variable “Total Capital Ratio %” positively and significantly affects the explained variation in performance of banks in Qatar measured by “ROAA”, while variation in “Cost to Income Ratio”, negatively and significantly impacts the variation in performance of banks in Qatar. At the same time, variation in “Reserves for impaired Loans/A nonperforming loan (NPL)” and variation in “Loan to Assets Ratio” significantly and negatively affect ROAA of banks in Qatar. Practical implications : It is recommended to replicate the findings of this study in each of the other GCC country before building an econometric model to cluster the GCC banks into homogeneous segments. Originality : The research problem is based on review of literature and investigation in a novel way using EViews 9 and Panel Data

A Structural Equation Modeling Approach to Understanding the Causes of Psychological Distress during the Covid-19 Pandemic in Qatar

Purpose - The purpose of this study is to determine how blended learning, teleworking challenges, knowledge, strategic responses in crisis situations, perceived seriousness, peoples' adherence to Covid-19 preventative measures, social stigma, age and gender relate to the outcome variable “Psychological Distress during the Covid-19 pandemic” in Qatar. Design/methodology/approach - The data analyzed in this study was originated from a nationally online (web) survey of residents in Qatar during the Corona crisis in 2020. The number of questionnaires with complete data on valid items for multivariate analysis is 1683. By using factor analysis as a data reduction technique and to establish the construct validity of the questionnaire, Kaisers-Meyer-Olkin (KMO) and the Bartless test of sphericity showed that eight extracted dimensions are valid and can be used in the structural equation model (path analysis). Findings - In regressing the outcome variable “Psychological distress due to Covid-19 "on the seven extracted dimensions as well as on “Age” and “Gender”, it is found that  the multiple coefficient of determination is highly significant. “Psychological distress due to Covid-19” is determined by all explanatory significant variables.  Moreover, the study findings suggest that the explanatory variables indentified in the causal model generate both positive and negative direct effects. What’s more, the outcome variable “Psychological Distress due to Covid-19” is a complex observable phenomenon calling for multiple interventions. Apart from individual significant direct positive or negative effects, all indirect effects with the exception of knowledge increase the total (as the sum of direct and indirect) effects. Findings of this study provide strategic insights and useful thinking that have significant implications for understanding “Psychological distress due to Covid-19.” Original value - To the best of the researchers’ knowledge, this is the first path analytical investigation of “Psychological distress due to Covid-19” in Qatar. This novel context should provide a useful base for further studies as well as for policy making

Morphine Stimulates Cell Migration of Oral Epithelial Cells by Delta-Opioid Receptor Activation

Oral mucositis is one of the most common side effects of chemoradiation regimens and manifestation can be dose-limiting for the therapy, can impair the patient's nutritional condition and quality of life due to severe pain. The therapeutic options are limited; often only an alleviation of the symptoms such as pain reduction by using systemic opioids is possible. Stimulating opioid receptors on peripheral neurons and dermal tissue, potent analgesic effects are induced e.g. in skin grafted patients. Advantageous effects on the cell migration and, thus, on the wound healing process are described, too. In this study, we investigated whether opioid receptors are also expressed on oral epithelial cells and if morphine can modulate their cell migration behavior. The expression of the opioid receptors MOR, DOR and KOR on primary human oral epithelial cells was verified. Furthermore, a significantly accelerated cell migration was observed following incubation with morphine. The effect even slightly exceeded the cell migration stimulating effect of TGF-ß: After 14 h of morphine treatment about 86% of the wound area was closed, whereas TGF-ß application resulted in a closed wound area of 80%. With respect to morphine stimulated cell migration we demonstrate that DOR plays a key role and we show the involvement of the MAPK members Erk 1/2 and p38 using Western blot analysis

Zinculose: A New Fibrous Material with Embedded Zinc Particles

In this paper, we report a simple and inexpensive procedure to make a composite material of cellulose fibers with embedded zinc micoparticles. This fibrous material is produced by sedimentation and is referred to as “Zinculose”. Zinculose increases the surface contact area between a sample fluid and zinc microparticles. The effect of different parameters including fiber content, zinc content, water volume, applied weight and its duration on the thickness of produced Zinculose were investigated. Results show that thickness depends on the amount of initial fiber and zinc while other parameters investigated had little to no effect. Measured porosity values for Zinculose ranged between 0.699 and 0.843. Characterization of flow in Zinculose exhibits a linear relationship between distance and the square root of time which is a distinctive feature of capillary driven flow in porous media. This is an important quality that allows Zinculose to be easily incorporated into any paper-based microfluidic device that requires a sample to flow and interact with zinc microparticles without disrupting the flow path between different sections of the device. An application is presented in which a strip of Zinculose is used to convert nitrate to nitrite. With the use of Zinculose in a paper-based microfluidic device, a conversion efficiency of 27% nitrate to nitrite was achieved. This represents a 36% enhancement over what has been previously published when zinc microparticles were not embedded within the fibers of the paper channel

Factors influencing reading news on the mobile devices in Qatar in light of augmented reality (AR) & Virtual reality (VR)

Purpose: The purpose of this study is to examine and better understand the factors influencing reading news on the mobile devices in Qatar from the viewpoint of intention to adopt augmented reality (AR) and virtual reality (VR). Design/Methodology/Approach: A large convenience sample of 699 respondents from Qatar was surveyed. The researcher employed KMO measure of sampling adequacy and the Bartless test of sphericity to establish the construct validity of the instrument using advanced SPSS. The four extracted and rotated dimensions were found to be reliable and valid. Main Findings: Findings from Multiple Regression Analysis have confirmed two out of six hypotheses. Two independent variables (1) nationality and (2) interest in using AR & VR out of six explanatory variables are significant in predicting the use of mobile devices to follow regional and international news in Qatar from the viewpoint of intention to adopt augmented reality (AR) and virtual reality (VR). Implications: Gone are the days when Qataris have to wait to get the traditional printed newspapers. A more proactive approach from decision makers in Qatar’s newspaper printing industry is needed to benefit from the findings of this research and the digitalization of international news. Novelty: This article empirically correlates two fields of research: the digital copy of the real world and reading international news.This work was supported by the Social and Economic Survey Research Institute, Qatar University and is sponsored by the Qatar National Research Fund. The researcher would like to acknowledge Dr. Justin Gengler for making the data available. The author would also like to thank Mr. John Lee Holmes, Mr. Abdulrahman Rahmany, Mr. Anis Miladi and Mr. Isam Mohamed Abdel Hameed in giving so generously of their time at various stages of the data collection and entry

A Structural Equation Model of Perceived University Image In Qatar: Student Perspective

The aim of this research is to examine the factors that influence student perceptions of the image of Qatar’s national university, Qatar University. The study is constructed on related research on perceptions of organizational image and explores institutional image perceptions in the state of Qatar. Based on data collected from a sample of 1427 students in Qatar, this study uses factor analysis in order to identify the variables that influence students’ perceptions of Qatar University. The findings of this study indicate that the way students perceive Qatar University is determined by four main factors: Quality of education, comparability of educational standards, the facilities and extracurricular activities provided, and graduates’ employability. The paper concludes with recommendations for institutional policy and future research

A New Paper-Based Microfluidic Device for Improved Detection of Nitrate in Water

In this paper, we report a simple and inexpensive paper-based microfluidic device for detecting nitrate in water. This device incorporates two recent developments in paper-based technology suitable for nitrate detection and has an optimized microfluidic design. The first technical advancement employed is an innovative fibrous composite material made up of cotton fibers and zinc microparticles that can be incorporated in paper-based devices and results in better nitrate reduction. The second is a detection zone with an immobilized reagent that allows the passage of a larger sample volume. Different acids were tested—citric and phosphoric acids gave better results than hydrochloric acid since this acid evaporates completely without leaving any residue behind on paper. Different microfluidic designs that utilize various fluid control technologies were investigated and a design with a folding detection zone was chosen and optimized to improve the uniformity of the signal produced. The optimized design allowed the device to achieve a limit of detection and quantification of 0.53 ppm and 1.18 ppm, respectively, for nitrate in water. This accounted for more than a 40% improvement on what has been previously realized for the detection of nitrate in water using paper-based technology