Asymmetric particles for pulmonary drug delivery

Targeted drug delivery and controlled release are current challenges in pulmonary drug delivery. The deposition pattern and clearance from deposition site are two key parameters for drug delivery carrier design. Asymmetric particles allow an increase in peripheral drug delivery compared to spherical particles and furthermore, affect particle clearance mechanisms from the lung. Therefore, the main aim of this thesis was to develop new synthesis strategies to produce well-dispersible, biocompatible, biodegradable microfibers with a variety of aspect ratios and porosities. The macrophage response to the resulting microfibers was investigated. The aerosolization properties of the resulting microfibers were examined. From the obtained results it can be concluded that: 1. A new template-assisted synthesis strategy to produce monodisperse microfibers with defined dimensions has been developed. 2. The technique has been extended to various materials and process parameters for cell testing, drug loading and aerosolization tests. 3. Microfibers were successfully taken up by macrophages, only when they were approached from the pointy end. 4. Aerosolization studies showed good dispersion properties of microfibers with relatively high fine particle fractions. In summary, this new technique may allow to produce microfibers for pulmonary drug delivery, which will lead to a better understanding of their in vivo behaviour such as mucoadhesion, macrophage interaction and deposition behaviour.Die aktuellen Herausforderungen der inhalativen Therapie sind die gezielte Wirkstoffdeposition und die kontrollierte Wirkstofffreisetzung in der Lunge. Asymmetrische Partikel haben dabei durch ihre erhöhte tiefe Lungendeposition und ihren Einfluss auf die Clearance-Mechanismen erhöhtes Interesse gefunden. Ziel dieser Arbeit war daher die Entwicklung einer neuen Herstellungsmethode, um gut vereinzelte, biokompatible, bioabbaubare Mikrofasern mit variablen Aspektverhältnissen und Porositäten zu generieren. Weiteres Ziel war die Testung der Makrophagen-Mikrofaser-Interaktion und des Aerosolisierungsverhaltens. Die gewonnenen Ergebnisse führen zu folgenden Aussagen: 1. Es wurde eine neue Methode zur Herstellung monodisperser Mikrofasern mit definierten Maßen entwickelt. 2. Mikrofasern aus diversen Materialien wurden in späteren Versuchen für Zelltests, Wirkstoffbeladung und Aerosolisierungsstudien verwendet. 3. Die Aufnahme von Mikrofasern durch Makrophagen zeigte eine Korrelation zum Faserdurchmesser, wobei diese nur vom spitzen Ende her aufgenommen wurden. 4. Aerosolisierungsstudien zeigten eine gute Dispergierung der Mikrofasern mit hohen Fine-Particle-Fractions. Die entwickelte Methode kann zu einer Optimierung der pulmonalen Wirkstoffapplikation und einem besseren Verständnis des Verhaltens asymmetrischer Partikel im Körper beitragen. Die Mukoadhesion, die Makrophagen-Interaktion und das Depositionsverhalten in der Lunge können mittels dieser Fasern weiter untersucht werden

Asymmetrische Partikel zur pulmonalen Wirkstoffapplikation

Targeted drug delivery and controlled release are current challenges in pulmonary drug delivery. The deposition pattern and clearance from deposition site are two key parameters for drug delivery carrier design. Asymmetric particles allow an increase in peripheral drug delivery compared to spherical particles and furthermore, affect particle clearance mechanisms from the lung. Therefore, the main aim of this thesis was to develop new synthesis strategies to produce well-dispersible, biocompatible, biodegradable microfibers with a variety of aspect ratios and porosities. The macrophage response to the resulting microfibers was investigated. The aerosolization properties of the resulting microfibers were examined. From the obtained results it can be concluded that: 1. A new template-assisted synthesis strategy to produce monodisperse microfibers with defined dimensions has been developed. 2. The technique has been extended to various materials and process parameters for cell testing, drug loading and aerosolization tests. 3. Microfibers were successfully taken up by macrophages, only when they were approached from the pointy end. 4. Aerosolization studies showed good dispersion properties of microfibers with relatively high fine particle fractions. In summary, this new technique may allow to produce microfibers for pulmonary drug delivery, which will lead to a better understanding of their in vivo behaviour such as mucoadhesion, macrophage interaction and deposition behaviour.Die aktuellen Herausforderungen der inhalativen Therapie sind die gezielte Wirkstoffdeposition und die kontrollierte Wirkstofffreisetzung in der Lunge. Asymmetrische Partikel haben dabei durch ihre erhöhte tiefe Lungendeposition und ihren Einfluss auf die Clearance-Mechanismen erhöhtes Interesse gefunden. Ziel dieser Arbeit war daher die Entwicklung einer neuen Herstellungsmethode, um gut vereinzelte, biokompatible, bioabbaubare Mikrofasern mit variablen Aspektverhältnissen und Porositäten zu generieren. Weiteres Ziel war die Testung der Makrophagen-Mikrofaser-Interaktion und des Aerosolisierungsverhaltens. Die gewonnenen Ergebnisse führen zu folgenden Aussagen: 1. Es wurde eine neue Methode zur Herstellung monodisperser Mikrofasern mit definierten Maßen entwickelt. 2. Mikrofasern aus diversen Materialien wurden in späteren Versuchen für Zelltests, Wirkstoffbeladung und Aerosolisierungsstudien verwendet. 3. Die Aufnahme von Mikrofasern durch Makrophagen zeigte eine Korrelation zum Faserdurchmesser, wobei diese nur vom spitzen Ende her aufgenommen wurden. 4. Aerosolisierungsstudien zeigten eine gute Dispergierung der Mikrofasern mit hohen Fine-Particle-Fractions. Die entwickelte Methode kann zu einer Optimierung der pulmonalen Wirkstoffapplikation und einem besseren Verständnis des Verhaltens asymmetrischer Partikel im Körper beitragen. Die Mukoadhesion, die Makrophagen-Interaktion und das Depositionsverhalten in der Lunge können mittels dieser Fasern weiter untersucht werden

Polyelectrolyte multilayer microcapsules templated on spherical, elliptical and square calcium carbonate particles

Recent studies have revealed that a variety of shaped particles can interact with cells in a different way. Elongated particles can be effectively and quickly internalized intercellularly compared with other configurations. Herein we present the potential of fabrication of anisotropic polyelectrolyte multilayer capsules formed by coating spherical, ellipsoid-like and square calcium carbonate (CaCO3) particles. By varying the intermixing speed, time, pH value and ratio of initial ingredients during precipitation such CaCO3 templates are produced. Particles loaded with FITC-dextran and coated with polyelectrolytes could maintain the templated shape after core removal. Quantitative data are derived from analysis of confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) measurements

Laser-Induced Cell Detachment, Patterning, and Regrowth on Gold Nanoparticle Functionalized Surfaces

We report on the selective cell detachment from nanoengineered gold nanoparticle (AuNP) surfaces triggered by laser irradiation, which occurs in a nonthermal manner. The gold nanoparticle-based surfaces reveal good adhesion of NIH3T3 fibroblast cells. Patterning is achieved by lithographic microcontact printing, selective gold nanoparticle deposition, and by laser beam profiling. It is shown that the effectiveness of fibroblast cell detachment depends on the cell age, laser power, and AuNP patterning profile. Heat distribution and temperature rise around gold nanoparticle functionalized surfaces is modeled, revealing low heating of nanoparticles by laser illumination. The nonthermal photochemical mechanism of cell detachment due to production of reactive oxygen species under illumination of gold nanoparticles by green laser light is studied. We also demonstrate that cells migrate from unirradiated areas leading to their reattachment and surface recovery which is important for controlled spatial organization of cells in wound healing and tissue engineering. Research presented in this work is targeted at designing biointerfaces for cell cultures

Patchiness of embedded particles and film stiffness control through concentration of gold nanoparticles

Patchy particles are fabricated using a method of embedding-into and extracting-from thick, biocompatible, gel-like HA/PLL films. Control over the patchiness is achieved by adjusting the stiffness of films, which affects embedding and masking of particles. The stiffness is adjusted by the concentration of gold nanoparticles adsorbed onto the surface of the films

Immune cell activation by enterotoxin gene cluster (egc)-encoded and non-egc superantigens from Staphylococcus aureus

The species Staphylococcus aureus harbors 19 superantigen gene loci, six of which are located in the enterotoxin gene cluster (egc). Although these egc superantigens are far more prevalent in clinical S. aureus isolates than non-egc superantigens, they are not a prominent cause of toxic shock. Moreover, neutralizing Abs against egc superantigens are very rare, even among carriers of egc-positive S. aureus strains. In search of an explanation, we have tested two non-exclusive hypotheses: 1) egc and non-egc superantigens have unique intrinsic properties and drive the immune system into different directions and 2) egc and non-egc superantigens are released by S. aureus under different conditions, which shape the immune response. A comparison of three egc (SEI, SElM, and SElO) and three non-egc superantigens (SEB, SElQ, and toxic shock syndrome toxin-1) revealed that both induced proliferation of human PBMC with comparable potency and elicited similar Th1/Th2-cytokine signatures. This was supported by gene expression analysis of PBMC stimulated with one representative superantigen from each group (SEI and SEB). They induced very similar transcriptional changes, especially of inflammation-associated gene networks, corresponding to a very strong Th1- and Th17-dominated immune response. In contrast, the regulation of superantigen release differed markedly between both superantigen groups. Egc-encoded proteins were secreted by S. aureus during exponential growth, while non-egc superantigens were released in the stationary phase. We conclude that the distinct biological behavior of egc and non-egc superantigens is not due to their intrinsic properties, which are very similar, but caused by their differential release by S. aureus

Yearbook of Private International Law.

Private International Law on the Move In line with ist predecessors, Volume XV (2013/2014) of the Yearbook of Private International Law offers a comprehensive insight into the contemporary trends of private international law in terms of both theoretical thinking and practical achievements. The volume includes two contributions from prominent scholars on freedom of movement of public documents and records within the EU, a whole section on Brussels Ibis Regulation, a dozen national reports on recognition and enforcement of foreign judgments*outside the EU from Turkey to Australia, from Russian Federation to Egypt, from South Korea to Commonwealth Africa as well as an overview of the new codification in Albania. Two essays on internal conflict of laws and on the challenges posed by cross-border coordination in insolvency matters complete this valuable collection