Nonlinear Control and Estimation of an Infammatory Immune Response

The immune response is a complex mechanism that can be triggered by biological or physical stresses on the organism. However an excessive and dys-regulated inflammatory response may lead to sepsis, a critical state, promoting tissue damage, organ dysfunction or even death.The main objective in this dissertation is to derive a strategy consisting of manipulating pro and anti-inflammatory mediators in order to direct the state of a virtual patient to a healthy equilibrium, after some disturbance from health due to infection. Two key challenges need to be addressed in solving such a problem: estimating the unmeasurable states of the inflammatory model as well as the model\u27s unknown rate parameters; and second, determining an appropriate strategy to effectively control the response.We initially study the nonlinear controllability, observability and identifiability of the inflammatory immune model. Then, we address the first challenge by comparing the performance of various nonlinear filters for state estimation in the presence of noise and incomplete information. For parameter estimation, a recently introduced approximate Markov chain Monte Carlo approach known as the Particle Metropolis- Hastings method is used. To control the highly nonlinear model, various model-based optimization approaches were investigated in which the control strategy is derived in terms of pro-inflammatory and anti-inflammatory response doses. Due to parameter variability and the difficult practical task of obtaining accurate state and parameter estimates in real time, a new model-free control methodology and its intelligent controllers is explored. The method does not rely on any precise modeling and the identification of each parameter of the inflammatory immune model is no longer needed for control design. The various methods are compared for performance to adequately control the responses in a diverse patient population as well as the clinical feasibility of the derived control protocol from the approach used

Applications of MATLAB in Science and Engineering

The book consists of 24 chapters illustrating a wide range of areas where MATLAB tools are applied. These areas include mathematics, physics, chemistry and chemical engineering, mechanical engineering, biological (molecular biology) and medical sciences, communication and control systems, digital signal, image and video processing, system modeling and simulation. Many interesting problems have been included throughout the book, and its contents will be beneficial for students and professionals in wide areas of interest

SUITE an Innovative Bioreactor Platform for in vitro Experiments

In-vitro cell cultures are a fundamental step in preclinical drug testing and are of great interest to the pharmaceutical industry. The most common method for culturing cells is in cell culture incubators. These are large and cumbersome and all mechanical stimuli are absent. They are nevertheless used ubiquitously and their results quoted as "standards" of in-vitro protocols. Several alternative culture methods have been proposed, and many systems are currently available commercially. Indeed, systems and devices for maintaining cells and tissues in controlled physical conditions, or bioreactors, have become an important tool in many areas of research. This is not only due to the growing interest in tissue engineering but also because it is now being increasingly recognised that cells respond not only to their biochemical, but also to their physical environment, and both cues are necessary to create a biomimetic habitat. However most bioreactors for cell culture and tissue engineering are cumbersome and only provide a few cues such as flow or strain, allowing limited control and flexibility. Since drug testing involves a large number of tests on identical cell cultures, a single well culture is inadequate and costly both in time and money. The High Throughput Screening (HTS), is a methodology for scientific experimentation widely used in drug discovery, based on a brute-force approach to collect a large amount of experimental data in less time and using less animals. The parallel nature of HTS makes it possible to collect a large amount of data from a small number of experiments and in a very short time. HTS, however, suffers from a significant problem that may affect the relevance of tests: the environment discrepancy problem. Another problem related with the actual drug testing and tissue engineering experiments is the enormous number of animals that have to be scarified every year. The aim of this study was to develop a generic platform or SUITE (Supervising Unit for In-vitro TEsting) for cell, tissue and organ culture composed of two main components: a universal control unit and an array of bioreactor chambers. The platform provides a biomimetic habitat to cells and tissues since the environment in the chambers is controlled and regulated to provide biomechanical and biophysical stimuli similar to those found in-vivo. In this work I describe how a new concept of cell culture bioreactor was developed by integrating different technologies and research fields. The data extracted using this new cell culture approach is more predictive of the in vivo response with respect to the multi-well approach, particularly for drug related studies. The starting point was a thorough analysis of currently used in-vitro methods; their pros and cons were assessed to exploit their advantages and overcome or circumvent their disadvantages. As far as the culture chamber is concerned, the approach was to use the methods and materials commonly employed in microfluidic fabrication, but at scales compatible with classical culture systems such as petri-dishes and multiwells. This renders the bioreactors more amenable to use by biologists and enables the use of cell densities comparable with classic systems as well as the use of conventional assaying techniques. In most cases, the cell culture chambers are thus made out of PDMS (Polydimethylsiloxane), using soft-moulding with micro- or mini-machined masters, or what we call Soft Milli-molding. A system on a plate Multi Compartmental Modular Bioreactor (MCmB) was developed using this technology. The MCmB is a modular chamber for high throughput multi compartmental bioreactor experiments. It is designed to be used in a wide range of applications and with various cell types. A precise stimulus application is also very important to better understand the correlation between physical variables and pathologies allowing a more accurate study of the tissue physiology and pathologies. For this reason in these thesis three additional stimulation chambers for vascular and articular cartilage stimulation respectively were also designed and tested. The control system was developed to be user-friendly, flexible and expandable to include new stimuli and was based on modular components, including motors and sensors. Importantly a single software interface was designed to allow data acquisition and monitoring of several chambers in series or in parallel. Using SUITE, high throughput experiments can be performed in an in vivo-like simulated environment for a long time to simulate different physiological or pathological scenarios or for toxicity testing of cells, tissues or in-vitro organ models

Contact Mechanics and Adhesion of Polymeric Soft Matter Particles in Aqueous Environment

In the framework of this thesis, a study was conducted dealing with a strategy to change the mechanical properties of microgel particles using inwards-interweaving self-assembly post-synthesis. This technique was invented by my cooperation partners of the Trau group, and they prepared all particles studied. Exemplarily, agarose microparticles were used to interweave a defined shell of complexed poly(allylamine) (PA) and poly(styrenesulfonic acid) (PSS) into such particles. Thereby, the shell thickness can be well-defined. Adjusting the concentration of PA and the incubation time, the filling of the particles can be readily controlled up to complete filling. By adding excessive PSS, the diffusion-controlled shell formation stops by complexation. The shell thickness of individual particles was determined through fluorescence-labeled PA and confocal laser scanning microscopy. The mechanical properties of single particles were inferred by AFM with an attached colloidal probe (CP). Here, a non-linear increase of the elastic modulus (E-modulus) from 10 to 190 kPa was determined while the shell thickness increased from 10 to 24 µm. After adding a second shell, a further gain to 520 kPa on average can be realized. Furthermore, a new concept was developed by Mr. Fery and me to change the surface mechanical properties of mircogel particles by applying a thermal trigger. Meanwhile, a particular focus was laid to maintain constant adhesive properties at every temperature. First, crosslinked poly(N-isopropyl acrylamide) (PNIPAM) particles are prepared by droplet microfluidics. These gelled particles are injected into a second microfluidic device and surrounded by an aqueous solution of uncrosslinked poly(acrylamide) (PAAM). At a second junction, droplets are formed via the cut-off effect of the continuous organic solvent. The droplets now contain the crosslinked PNIPAM core and a thin uncrosslinked PAAM liquid shell. After a short diffusion of PAAM polymers into the core they are crosslinked by UV-light. These experiments were performed by our cooperation partners of the Seiffert group. I applied temperature-controlled CP-AFM to obtain the resulting adhesive and mechanical properties of individual particles. Here, the core-shell particles behaved similarly to plain PNIPAM particles displaying the typical increase in E-modulus at temperatures above 34°C, however lower in magnitude. Further, no temperature effect on the interfacial interaction for these core-shell particles was detected. While one focus of the study above was on constant adhesion, in the following section, a new synthetic approach for mussel inspired underwater adhesives, and their characterization is presented. Based on a peptide sequence of ten amino acids, which is found frequently in natural mussel foot proteins, a new polymerization route was developed by my cooperation partners of the Börner group. Possible reaction pathways were investigated with specifically designed model reaction and analyzed using mass spectroscopy and gel permeation chromatography. The resulting polymers were further characterized using high-performance liquid chromatography and SDS-page. Nanometer thick coatings of these synthetic polymers revealed an excellent persistence even against highly concentrated salt solutions measured by quartz crystal microbalance with dissipation experiments. My contribution was the investigation of the work of adhesion necessary to detach a microparticle from such a coating by CP-AFM in an aqueous environment. Here, the newly developed synthetic polymer provided higher adhesive strength, up to 10.9 mJ m- 2, compared to comparable natural mussel foot proteins.Im Rahmen dieser Arbeit, wurde eine Studie durchgeführt, welche die Möglichkei¬ten der nachträglichen Elastizitätsveränderung von Mikrogelpartikeln mittels „nach Innen gerichteter, verwebender Selbstassemblierung“ (engl. inwards-interweaving self-as¬sembly) beleuchtet. Diese Technik wurde von meinen Kooperationspartnern aus der Gruppe von Herrn Trau entwickelt. Am Bespiel von Agarose Mikropartikeln, kann mittels dieser Technik eine definierte Schale aus Polyallylamin (PA) und Polystyrolsulfonsäure (PSS) in das Partikel verwoben werden. Die Schalendicke kann dabei kontrolliert variiert werden, bis hin zur vollständigen Ausfüllung des Partikels, in dem die Konzentration von PA und die Inkubationszeit angepasst werden. Durch Zugabe eines Überschusses an PSS wird der diffusionsgesteuerte Schalenaufbau durch Komplexierung beendet. Die Schalendicke der individuellen Partikel wurde mittels Fluoreszenzmarkierung und konfokaler Laser Raster¬mikroskopie (engl. confocal laser scanning microscopy) ermittelt. Die mechanische Cha¬rakterisierung einzelner Partikel durch AFM und kolloidaler Sonde (engl. colloidal probe, CP) ergab eine nicht lineare Erhöhung des Elastizitätsmoduls (E-Modul) von 10 auf 190 kPa bei einem Schalendicken Zuwachs von 10 auf 24 µm. Durch eine zweite Schale, in der Ersten, konnte der E-Modul auf im Mittel 520 kPa gesteigert werden. Weiterführend, wurde von mir und Herrn Fery ein neues Konzept entwickelt, um eine mechanische, oberflächliche Verhärtung von Mikrogelpartikel durch Temperaturver¬änderung zu induzieren mit einem Augenmerk, dass sich die Adhäsionseigenschaften nicht verändern. Zunächst wurden von meinen Kooperationspartnern aus der Gruppe von Herrn Seiffert vernetzte Poly-N-isopropylacrylamid (PNIPAM) Partikel mittels Tropfenmikroflu¬idik hergestellt. In einem zweiten Mikrofluidik Experiment wurde diese Partikel mit einer wässrigen Lösung von Polyacrylamid (PAAM, unvernetzt) umgeben bevor es zu einer Tropfenbildung in der organischen Phase kommt. Nach kurzer Diffusionszeit der PAAM Polymerketten in die Kernpartikel, wurde die PAAM Schale mittels UV-Licht querver-netzt. In temperaturkontrollierten CP-AFM Untersuchungen habe ich die resultierenden Adhäsions- und mechanischen Eigenschaften auf der Einzelpartikel Ebene bestimmt. Hier¬bei konnte bei den Kern-Schale Partikeln der für bloße PNIPAM Partikel typische E-Modul anstieg oberhalb von 34°C nachgewiesen werden, jedoch mit verminderten Absolutwerten. Eine begleitende Veränderung der adhäsiven Eigenschaften der Kern-Schale Partikel konnte dabei nicht beobachtet werden. Lag ein Fokus der vorherigen Arbeit auf konstanten Wechselwirkungen, behandelt der dritte Teil der Ergebnisse, einen neuen Synthese Ansatz zur Herstellung Muschel in¬spirierter Unterwasser Adhäsiva und deren Charakterisierung. Basierend auf einer natürli¬chen Peptidsequenz, wurde eine enzymatische Polymerisationsroute von meinen Koopera¬tionspartner aus der Börner Gruppe entwickelt. Der Reaktionsverlauf wurde durch neu de¬signte Modelreaktion untersucht und mittels Massenspektroskopie und GPC analysiert, das resultierende Polymer zusätzlich mit HPLC und SDS-page. Nanometer dicke Beschichtun¬gen dieser Muschel inspirierten Polymer wiesen eine sehr gute Beständigkeit gegen hoch konzentrierten Salzlösung in QCM-D Experimenten auf. Die Adhäsionsarbeit, welche nö¬tig ist um eine Mikropartikel von diesen in wässeriger Lösung zu entfernen, wurde von mir mittels CP-AFM bestimmt. Nach meiner Erweiterung einer bekannten Adhäsionstheorie, konnten für das synthetische Polymer höhere Werte als für vergleichbare Natürliche von bis zu 10.9 mJ m-2 bestimmt werden

Spacelab Science Results Study

Beginning with OSTA-1 in November 1981 and ending with Neurolab in March 1998, a total of 36 Shuttle missions carried various Spacelab components such as the Spacelab module, pallet, instrument pointing system, or mission peculiar experiment support structure. The experiments carried out during these flights included astrophysics, solar physics, plasma physics, atmospheric science, Earth observations, and a wide range of microgravity experiments in life sciences, biotechnology, materials science, and fluid physics which includes combustion and critical point phenomena. In all, some 764 experiments were conducted by investigators from the U.S., Europe, and Japan. The purpose of this Spacelab Science Results Study is to document the contributions made in each of the major research areas by giving a brief synopsis of the more significant experiments and an extensive list of the publications that were produced. We have also endeavored to show how these results impacted the existing body of knowledge, where they have spawned new fields, and if appropriate, where the knowledge they produced has been applied

Proceedings of the 10th International Chemical and Biological Engineering Conference - CHEMPOR 2008

This volume contains full papers presented at the 10th International Chemical and Biological Engineering Conference - CHEMPOR 2008, held in Braga, Portugal, between September 4th and 6th, 2008.FC