Nanotechnology and microfluidics:formulation design and on-chip manufacture of nanoparticles

Nanoparticles offer an ideal platform for the delivery of small molecule drugs, subunit vaccines and genetic constructs. Besides the necessity of a homogenous size distribution, defined loading efficiencies and reasonable production and development costs, one of the major bottlenecks in translating nanoparticles into clinical application is the need for rapid, robust and reproducible development techniques. Within this thesis, microfluidic methods were investigated for the manufacturing, drug or protein loading and purification of pharmaceutically relevant nanoparticles. Initially, methods to prepare small liposomes were evaluated and compared to a microfluidics-directed nanoprecipitation method. To support the implementation of statistical process control, design of experiment models aided the process robustness and validation for the methods investigated and gave an initial overview of the size ranges obtainable in each method whilst evaluating advantages and disadvantages of each method. The lab-on-a-chip system resulted in a high-throughput vesicle manufacturing, enabling a rapid process and a high degree of process control. To further investigate this method, cationic low transition temperature lipids, cationic bola-amphiphiles with delocalized charge centers, neutral lipids and polymers were used in the microfluidics-directed nanoprecipitation method to formulate vesicles. Whereas the total flow rate (TFR) and the ratio of solvent to aqueous stream (flow rate ratio, FRR) was shown to be influential for controlling the vesicle size in high transition temperature lipids, the factor FRR was found the most influential factor controlling the size of vesicles consisting of low transition temperature lipids and polymer-based nanoparticles. The biological activity of the resulting constructs was confirmed by an invitro transfection of pDNA constructs using cationic nanoprecipitated vesicles. Design of experiments and multivariate data analysis revealed the mathematical relationship and significance of the factors TFR and FRR in the microfluidics process to the liposome size, polydispersity and transfection efficiency. Multivariate tools were used to cluster and predict specific in-vivo immune responses dependent on key liposome adjuvant characteristics upon delivery a tuberculosis antigen in a vaccine candidate. The addition of a low solubility model drug (propofol) in the nanoprecipitation method resulted in a significantly higher solubilisation of the drug within the liposomal bilayer, compared to the control method. The microfluidics method underwent scale-up work by increasing the channel diameter and parallelisation of the mixers in a planar way, resulting in an overall 40-fold increase in throughput. Furthermore, microfluidic tools were developed based on a microfluidics-directed tangential flow filtration, which allowed for a continuous manufacturing, purification and concentration of liposomal drug products

Eccentricity in Tubes - Experimental Development and Simulation-Based Analysis for an Automatically Adjustable Drawing Die

Ein permanentes Ziel der Fertigung ist die Erhöhung der Produktionseffizienz durch Reduzierung der Durchlaufzeiten bei gleichzeitiger Kostenreduktion und Verbesserung der Produktqualität. Auch die Rohrherstellung - eines der ältesten bekannten Fertigungsverfahren - ist diesem permanenten Druck ausgesetzt. Rohre finden ihren weitgestreuten Einsatz mit unterschiedlichsten Anforderungen zum Transport von Feststoffen, Flüssigkeiten und Gasen in den verschiedensten Bereichen wie der Energiewirtschaft, der Automobil-, Luft- und Raumfahrt oder auch der Medizinindustrie. Da in all diesen Bereichen die Rohrqualität eine entscheidende Rolle spielt, ist die Herstellung von qualitativ hochwertigen und teilweise hochpräzisen Rohren in der Rohrfertigung eine Herausforderung. Dies ist die Motivation dieser Arbeit zur Entwicklung einer neuen Vorrichtung zur Herstellung von Hochpräzisionsrohren. Die Entwicklung einer neuen Methode zur gezielten lokalen Veränderung der Wandstärke des Rohres wurde bereits im Vorfeld mit verschiedenen Ansätzen untersucht. Die Modifizierung und Kontrolle der Rohrexzentrizität sind wesentlich für Anwendungen mit engen Toleranzanforderungen. Eine der kürzlich entwickelten Methoden zur Änderung der Exzentrizität von Rohren ist das Kippen der Ziehmatrize. In dieser Arbeit wird diese Entwicklung fortgeführt und zu einer dynamisch in-line verstellbaren Matrize, zur kontrollierten Beeinflussung der Exzentrizität eines Rohres für den industriellen Einsatz, erweitert. Dazu wird in Abhängigkeit von der einlaufenden Exzentrizität des Rohres die Ziehmatrize in die geeignete Position gekippt. Das entsprechende Aggregat wurde im Rahmen eines AiF-Projekts in Zusammenarbeit mit den Firmen Bültmann GmbH (Entwicklung und Bau der Anlage), Fest AG (Steuerung), GE AG (US-Messtechnik) zusammen mit dem Institut für Metallurgie der TU Clausthal entwickelt und getestet. Die drei wesentlichen Schritte zur Entwicklung der dynamisch verstellbaren Matrize sind: • Entwicklung einer dynamisch verstellbaren Matrize, die den Matrizenhalter um 360 °- bis zu 4° transversal zur Ziehrichtung neigen kann. • Untersuchung der effektiven Parameter der Exzentrizität von gezogenen Rohren durch Kippen der Matrize und Entwicklung eines Regressionsmodells zur Vorhersage der Exzentrizität der Rohre nach dem Ziehen. Das Modell wird für die Ermittlung der optimalen Kippwinkel der Matrize verwendet. • Entwicklung eines Steuer- und Regelsystems zur Korrelation der Messdaten des US-In-Line-Messsystems zur Ermittlung der Exzentrizität des Rohres vor dem Ziehen mit der Kippung der Ziehmatrize. In diesem Konzept wird der Ist-Zustand (Wanddicke) des einlaufenden Rohres über sechs US-Sensoren ermittelt und daraus die Exzentrizität berechnet. Mit den entwickelten Algorithmen wird die Kippung der Ziehmatrize, die für diese Exzentrizitätslage zu einer definierten Exzentrizität am auslaufenden Rohr führt, vorgegeben und dynamisch eingestellt. Sowohl das Ziehen mit festem wie auch mit fliegendem Dorn wurde mit dem Kippen kombiniert. Darüber hinaus werden in dieser Arbeit auch der Kippeffekt und das entsprechende Ziehverfahren auf die Eigenspannungsausbildung in den gezogenen Rohren betrachtet.A goal of the manufacturing industry is to increase the efficiency of the production reducing through-put time as well as cost of the production and increasing the product quality. Tube manufacturing, as one of the oldest known manufacturing processes, is also still moving towards this goal. Since tubes are known as products to transport fluids and gases, they find their applications in areas such as energy, automobile, aerospace and medical industries. Due to the fact that the tube quality plays a crucial role in all these areas, producing high quality and high precise tubes still is challenging in tube manufacturing. This challenge is the motivation for the development of a new device to produce high precision tubes, which is the main aim of this study. To change the wall thickness of the tube aiming to modify its eccentricity was studied using different approaches. Modifying and controlling the eccentricity of tubes is important for reaching tight tolerance requirements. One of the recently developed method for changing the eccentricity of tube is tilting the drawing die. Developing a dynamic, in-line adjustable die for controlled influencing the eccentricity of a tube for industrial use is studied in this thesis, aiming on changing the drawing conditions by tilting the die with defined tilting angles and positions using fixed and floating plugs. This device was designed and developed in the framework of an AiF project with cooperation of Bültmann GmbH, Fest AG and GE AG, for developing the mechanical, control and measuring system of the device, respectively. It was tested at the Institute of Metallurgy at Clausthal University of Technology. The three major steps for developing the dynamic adjustable die are summarized in the following: • Developing a dynamic adjustable die, which can tilt the die holder in 360 ° position up to 4 ° transversal to the drawing direction. • Studying the involved effective parameters on the final eccentricity of drawn tubes by tilting the die and developing a regression model for predicting the eccentricity of the tubes after drawing, which is used to find the proper tilting angle of the die during drawing. • Developing a control and regulation system to correlate the movement of the die and the in-line US measuring system, which is integrated for measuring the initial eccentricity of the tube and with these data targeting the tilting position. The incoming wall thickness condition is measured by the US-device and used to control the (exit) eccentricity of the tube by dynamically adjusting the die. Two tube drawing methods - drawing with fixed plug and floating plug - are combined with die tilting. Moreover, the tilting effect and drawing method on the residual stresses of the drawn tubes are investigated in this study

Revisiting the Dissimilarity Representation in the Context of Regression

In machine learning, a natural way to represent an instance is by using a feature vector. However, several studies have shown that this representation may not accurately characterize an object. For classification problems, the dissimilarity paradigm has been proposed as an alternative to the standard feature-based approach. Encoding each object by pairwise dissimilarities has been demonstrated to improve the data quality because it mitigates some complexities such as class overlap, small disjuncts, and low-sample size. However, its suitability and performance when applied to regression problems have not been fully explored. This study redefines the dissimilarity representation for regression. To this end, we have carried out an extensive experimental evaluation on 34 datasets using two linear regression models. The results show that the dissimilarity approach decreases the error rates of both the traditional linear regression and the linear model with elastic net regularization, and it also reduces the complexity of most regression datasets

Silikonielastomeerin koostumuksen optimointi kahdessa kontrolloidun lääkeannostelun sovelluksessa

The goal of controlled release (CR) is to improve the spatial and temporal presentation of an active pharmaceutical ingredient (API) in the body. It can, for example, reduce the systemic side effects of a drug, facilitate its absorption to the body and improve patient compliance and convenience. Polymers play an essential role in CR technology. Silicone polymers have been used as biomaterials for decades thanks to their biocompatibility and biostability and they have also found their place in controlled release applications. Elastomer materials are usually compounded with large amounts of fillers to improve their properties. The most common filler for silicone elastomers is amorphous silica (silicon dioxide), which is mainly used to improve the mechanical properties of the material. In this work, the effect of silica concentration of a silicone elastomer on the drug release rate from two diffusion-controlled drug delivery devices is studied. The elastomer material acts as a diffusion-controlling membrane in these two products. The goals of this thesis work were, firstly, to find a material composition that could be used for the two products and, secondly, to create a simple empirical model that could be used to predict drug release rates from the products. The performance of this material was also compared with materials that were currently in use. The specimen manufacturing process consisted of typical elastomer processing, such as mixing, extrusion and heat vulcanization as well as product-specific assembly methods. Through material and specimen characterization and in vitro release rate analysis, suitable material compositions were found and successful statistical models created, explaining up to 97% of variance in drug release rate, depending on the studied time point and API. For one of the two active ingredients studied, it was found that the storage time between manufacturing and use must be controlled due to different diffusional properties of the API. This thesis acted as a step towards the introduction of these materials into product manufacturing.Kontrolloidulla lääkeannostelulla (Controlled Release Drug Delivery) pyritään lääkeaineen annostelupaikan, -ajan ja -nopeuden optimointiin. Sen avulla voidaan muun muassa vähentää lääkkeen systeemisiä sivuvaikutuksia, parantaa lääkkeen imeytymistä elimistöön ja edistää potilaiden hoitomyöntyvyyttä. Polymeerit ovat hyvin keskeisessä osassa kontrolloidun lääkeannostelun tekniikassa. Silikonipolymeerejä on käytetty laajalti biomateriaaleina jo kymmeniä vuosia niiden biokompatibiliteetin ja biostabiilisuuden ansiosta ja niitä on hyödynnetty myös kontrolloidun lääkeannostelun sovelluksissa. Kuten elastomeerimateriaaleihin yleisesti, myös silikonielastomeereihin sekoitetaan merkittäviä määriä täyteaineita materiaalin ominaisuuksien parantamiseksi. Silikonielastomeereilla yleisin käytetty täyteaine on amorfinen silika (piidioksidi), jota käytetään pääasiassa materiaalin mekaanisten ominaisuuksien parantamiseksi. Tässä työssä tutkittiin silikonielastomeerin silikapitoisuuden vaikutusta lääkeaineen vapautumisnopeuteen kahdesta eri tuotteesta, joissa materiaali toimii diffuusiota kontrolloivana membraanina. Lisäksi materiaalia verrattiin jo käytössä oleviin silikonielastomeereihin. Työn tavoitteena oli yhtäältä löytää materiaalikoostumus, joka mahdollistaisi materiaalin käyttämisen molemmissa valmisteissa ja toisaalta luoda yksinkertainen empiirinen malli, joka kuvaisi materiaalin täyteainepitoisuuden vaikutusta tuotespesifiseen lääkeaineen vapautumisnopeuteen. Näytteenvalmistuksessa käytettiin tyypillisiä elastomeerien prosessointimenetelmiä, kuten sekoitusta, ekstruusiota ja lämpövulkanointia sekä tuotteille ominaisia kokoonpanomenetelmiä. Materiaalien karakterisoinnin ja tuotenäytteiden in vitro vapautumisnopeusanalyysien avulla löydettiin käyttökelpoinen materiaalikoostumus molemmille tuotteille. Lisäksi toisella tuotteista havaittiin, että tuotteiden varastointiaikaa ennen käyttöä on kontrolloitava kyseisen lääkeaineen diffuusio-ominaisuuksien vuoksi. Vapautumisnopeutta mallinnettiin onnistuneesti lineaarisella regressiolla täyteainepitoisuuden sekä tuotteen dimensioita kuvaavan tekijän funktiona. Mallit pystyivät käytetystä lääkeaineesta ja aikapisteestä riippuen selittämään jopa 97 % vapautumisnopeuden varianssista. Työ toimi askeleena kohti materiaalien käyttöönottoa

Silikonielastomeerin koostumuksen optimointi kahdessa kontrolloidun lääkeannostelun sovelluksessa

The goal of controlled release (CR) is to improve the spatial and temporal presentation of an active pharmaceutical ingredient (API) in the body. It can, for example, reduce the systemic side effects of a drug, facilitate its absorption to the body and improve patient compliance and convenience. Polymers play an essential role in CR technology. Silicone polymers have been used as biomaterials for decades thanks to their biocompatibility and biostability and they have also found their place in controlled release applications. Elastomer materials are usually compounded with large amounts of fillers to improve their properties. The most common filler for silicone elastomers is amorphous silica (silicon dioxide), which is mainly used to improve the mechanical properties of the material. In this work, the effect of silica concentration of a silicone elastomer on the drug release rate from two diffusion-controlled drug delivery devices is studied. The elastomer material acts as a diffusion-controlling membrane in these two products. The goals of this thesis work were, firstly, to find a material composition that could be used for the two products and, secondly, to create a simple empirical model that could be used to predict drug release rates from the products. The performance of this material was also compared with materials that were currently in use. The specimen manufacturing process consisted of typical elastomer processing, such as mixing, extrusion and heat vulcanization as well as product-specific assembly methods. Through material and specimen characterization and in vitro release rate analysis, suitable material compositions were found and successful statistical models created, explaining up to 97% of variance in drug release rate, depending on the studied time point and API. For one of the two active ingredients studied, it was found that the storage time between manufacturing and use must be controlled due to different diffusional properties of the API. This thesis acted as a step towards the introduction of these materials into product manufacturing.Kontrolloidulla lääkeannostelulla (Controlled Release Drug Delivery) pyritään lääkeaineen annostelupaikan, -ajan ja -nopeuden optimointiin. Sen avulla voidaan muun muassa vähentää lääkkeen systeemisiä sivuvaikutuksia, parantaa lääkkeen imeytymistä elimistöön ja edistää potilaiden hoitomyöntyvyyttä. Polymeerit ovat hyvin keskeisessä osassa kontrolloidun lääkeannostelun tekniikassa. Silikonipolymeerejä on käytetty laajalti biomateriaaleina jo kymmeniä vuosia niiden biokompatibiliteetin ja biostabiilisuuden ansiosta ja niitä on hyödynnetty myös kontrolloidun lääkeannostelun sovelluksissa. Kuten elastomeerimateriaaleihin yleisesti, myös silikonielastomeereihin sekoitetaan merkittäviä määriä täyteaineita materiaalin ominaisuuksien parantamiseksi. Silikonielastomeereilla yleisin käytetty täyteaine on amorfinen silika (piidioksidi), jota käytetään pääasiassa materiaalin mekaanisten ominaisuuksien parantamiseksi. Tässä työssä tutkittiin silikonielastomeerin silikapitoisuuden vaikutusta lääkeaineen vapautumisnopeuteen kahdesta eri tuotteesta, joissa materiaali toimii diffuusiota kontrolloivana membraanina. Lisäksi materiaalia verrattiin jo käytössä oleviin silikonielastomeereihin. Työn tavoitteena oli yhtäältä löytää materiaalikoostumus, joka mahdollistaisi materiaalin käyttämisen molemmissa valmisteissa ja toisaalta luoda yksinkertainen empiirinen malli, joka kuvaisi materiaalin täyteainepitoisuuden vaikutusta tuotespesifiseen lääkeaineen vapautumisnopeuteen. Näytteenvalmistuksessa käytettiin tyypillisiä elastomeerien prosessointimenetelmiä, kuten sekoitusta, ekstruusiota ja lämpövulkanointia sekä tuotteille ominaisia kokoonpanomenetelmiä. Materiaalien karakterisoinnin ja tuotenäytteiden in vitro vapautumisnopeusanalyysien avulla löydettiin käyttökelpoinen materiaalikoostumus molemmille tuotteille. Lisäksi toisella tuotteista havaittiin, että tuotteiden varastointiaikaa ennen käyttöä on kontrolloitava kyseisen lääkeaineen diffuusio-ominaisuuksien vuoksi. Vapautumisnopeutta mallinnettiin onnistuneesti lineaarisella regressiolla täyteainepitoisuuden sekä tuotteen dimensioita kuvaavan tekijän funktiona. Mallit pystyivät käytetystä lääkeaineesta ja aikapisteestä riippuen selittämään jopa 97 % vapautumisnopeuden varianssista. Työ toimi askeleena kohti materiaalien käyttöönottoa

Occlusion of the left atrial appendage using catheter-delivered hydrogels for prevention of thromboembolic phenomena

textThe Left Atrial Appendage, once thought to be "a relatively insignificant portion of cardiac anatomy," has currently been realized to possess "important pathological associations [1a]" particularly in its role in promoting serious, frequent thromboembolic events common in individuals suffering from Atrial Fibrillation. Prior approaches to mitigating these events have either required invasive procedures, proved less than fully effective, or presented with problematic sequelae of their own. This work will present a new procedure that addresses both the prevention of the thromboembolic events and the correction of the shortcomings of the major prior methods utilized. A compliant hydrogel that can conform to the geometry of the appendage is proposed as a more effective method of occluding the chamber. This material would be transported to the LAA in liquid form via a multi-lumen catheter, and then solidify within the chamber to form a solid plug. Previous research has identified a candidate hydrogel, comprised of PEG-tetra-thiol and Dextran vinyl sulfone as a candidate hydrogel for this application. Experimental work has investigated fluid properties of the material, as well as degradation and swelling properties of the material. Results from this experimentation were used for fluid transport analysis, and for evaluation of anchoring force of the hydrogel within the chamber. Finally, subfunctions of the occlusion procedure were modeled and tested. During the actual procedure, a catheter balloon will isolate the appendage from the rest of the heart. A model was developed to study interactions between the appendage and this balloon. Additionally, due to fast solidification time, hydrogel components in the surgical procedure will be mixed in a mixing chamber at the tip of the catheter. Potential mixing chamber designs were modeled, and a ternary diffusion model was developed to better understand hydrogel mixing. Prototypes for both these subfunctions were built and tested as well. Additional analysis looked at the overall occlusion procedure, and how various subfunctions interacted with each other.Mechanical Engineerin

Tube and Sheet Metal Forming Processes and Applications

At present, the manufacturing industry is focused on the production of lighter weight components with better mechanical properties and always fulfilling all the environmental requirements. These challenges have caused a need for developing manufacturing processes in general, including obviously those devoted in particular to the development of thin-walled metallic shapes, as is the case with tubular and sheet metal parts and devices.This Special Issue is thus devoted to research in the fields of sheet metal forming and tube forming, and their applications, including both experimental and numerical approaches and using a variety of scientific and technological tools, such as forming limit diagrams (FLDs), analysis on formability and failure, strain analysis based on circle grids or digital image correlation (DIC), and finite element analysis (FEA), among others.In this context, we are pleased to present this Special Issue dealing with recent studies in the field of tube and sheet metal forming processes and their main applications within different high-tech industries, such as the aerospace, automotive, or medical sectors, among others